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Breast Cancer Guidelines

EVIDENCE-BASED MANAGEMENT FOR BREAST CANCER

Patients are clinically grouped into one of the following categories:

  • Operable Breast Cancer
  • Large Operable Breast Cancer
  • Locally Advanced Breast Cancer
  • Metastatic Breast Cancer

Criteria

Operable Breast Cancer:
T< 5cm, N0 or N1 mobile, M0

Large Operable Breast Cancer:
T> 5cm with no skin involvement, N0 or N1, M0

Locally Advanced Breast Cancer
I. Skin involvement in the form of oedema, ulceration, infiltration, satellite nodules
II. Matted or fixed axillary lymph nodes
III. Ipsilateral supraclavicular/internal mammary lymph node(s)
IV. Fixity to chest wall
V. Arm oedema
No evidence of distant metastasis.

OPERABLE BREAST CANCER

Clinical Examination & Investigations:
I. Documentation of exact extent of primary tumour and axillary node(s)
II. Pathological confirmation of diagnosis by FNAC/ Incision biopsy
III. Bilateral film mammogram (mandatory if BCT is contemplated)
IV. Routine pre-anaesthetic tests including chest X-ray & LFT
V. ER / PgR if neoadjuvant chemotherapy is planned
Note: A strong clinical suspicion for malignancy over-rules both negative FNAC or mammography for excision biopsy.

Metastatic work up: Is not recommended routinely in operable breast cancer, as the incidence of metastasis is <2%. These tests have a low sensitivity and are not cost-effective.

Surgical Options:
I. Breast Conservative Therapy (BCT)[1-4] Wide excision with complete axillary clearance up to apex.
II. Modified Radical Mastectomy (MRM)
NB: Sentinel node biopsy is presently an investigational procedure

Contraindications to BCT:
1. Multicentric disease (> 1 quadrant)
2. Extensive microcalcification on mammogram
3. Doubtful compliance with adjuvant radiotherapy
4. Pregnancy (1[st] / 2[nd] trimesters & precious child)
5. Satisfactory cosmesis unlikely (relative contraindication)

Options for BCT for relatively large tumours:

  • Down-staging with neo-adjuvant Chemotherapy.
  • BCT with latissimus dorsi reconstruction

Model Histopathology Report

  • Tumour size (all 3 dimensions)
  • Tumour type
  • Tumour grade (Modified Richardson Bloom Score)
  • Presence of extensive intraductal carcinoma (EIC)*
  • Lymphovascular embolisation
  • Cut Margin status[5] (gross positive/ focal positive/ negative) in case of lumpectomy or wide excision**
  • No. of positive/total axillary lymph node dissected
  • Receptor status: ER and PgR (by IHC or EIA)

    Note:
    * EIC is defined as presence of DCIS in more than 25% of any low power field within or outside the tumour and is a strong predictor of local recurrence after BCT.
    ** Gross +ve cut margin is extensive involvement of a cut margin or more than 3 foci of invasive or in-situ carcinoma in any inked margin (Requires revision excision or mastectomy).
    ** Focal positive cut margin is 3 or less foci of invasive or in-situ carcinoma in any inked margin (Revision surgery only if EIC positive).

    ADJUVANT THERAPY
    Modalities
    Systemic: Hormone-therapy [6-8] and or Polychemotherapy [9-12]
    Loco-regional: Radiotherapy [2-4,12-15]

Candidates for Adjuvant Systemic Therapy: All women with node-positive breast cancer and / or >1 cm tumor [11,12.]

  ER or PgR +ve ER & PgR -ve
Premenopausal Chemotherapy + Hormonal therapy Chemotherapy only
Postmenopausal Hormonal therapy +/- Chemotherapy Hormonal therapy + Chemotherapy

Ovarian ablation considered in pre-menopausal women > 40 years with ER positive tumour. [7]
In postmenopausal women with ER positive tumor, Tamoxifen or Anastrozole can be used. [8]

Doses and schedules of adjuvant systemic therapy

I. Adjuvant Hormone therapy
Tamoxifen: 20 mg/day for a period of 5 years
Anastrazole: 2.5 mg / day for a period of 5 years

II. Adjuvant Polychemotherapy (iv bolus or infusion) [9-12]
CAF: D1 only at 3 weekly intervals X 6 cycles
Cyclophosphamide 600 mg/m2
Adriamycin 60 mg/m2
5-fluorouracil 600 mg/m2

CEF: D1 only at 3 weekly intervals X 6 cycles
Cyclophosphamide 500 mg/m2
Epirubicin 90 mg/m2
5-fluorouracil 500 mg/m2

AC: D1 only at 3 weekly intervals X 4 cycles
Cyclophosphamide 600 mg/m2
Adriamycin 60 mg/m2

CMF: D1 and D8 at monthly intervals X 6 cycles
Cyclophosphamide 600 mg/m2
Methotrexate 40 mg/m2
5-fluorouracil 600 mg/m2

Candidates for Adjuvant Loco-regional Radiotherapy
I. Breast conservation surgery: All patients should receive radiotherapy [1-3].

II. Post MRM: T >5cm, skin/chest wall involvement or axillary node metastases.[13-14] In the absence of other risk factors, locoregional RT may be avoided for <4 metastatic axillary nodes if the axillary surgery was adequate[12]

III. For women who receive post op RT, the radiation target volume includes Breast / chest wall in all cases and SCF nodes when >3 axillary nodes are +ve12. Dose recommended: equivalent to 45 to 50Gy / 25# / 5 wks. Tumour bed boost with electrons or 192Iridium implant (LDR or HDR), equivalent to 10-15Gy is recommended for all BCTs. [4]

Routine postop irradiation of axilla is not recommended unless there is known or suspected residual axillary disease. Similarly, routine irradiation of internal mammary nodes is not recommended pending the results of the large EORTC trial examining the survival benefit of internal mammary RT possible cardiac morbidity / mortality with IMC irradiation [2,15]

LOCALLY ADVANCED BREAST CANCER

Investigations
I. Incision Biopsy for tissue diagnosis and receptor study.
II. Mammography or breast sonography for baseline documentation of tumour size.
III. Following Metastatic work-up is recommended

  • Chest radiography
  • Ultrasound abdomen
  • Liver Function Test
  • Radionuclide Bone Scan
  • Relevant skeletal X-Rays

Treatment Plan Multi-modal therapy [16-18]

Sequence Neo-adjuvant chemotherapy followed by surgery followed by completion chemotherapy and then locoregional RT (plus tamoxifen if ER +ve).

Neo-adjuvant Chemotherapy with CAF / CEF

  • Dose schedules are same as for adjuvant chemotherapy
  • Clinical documentation of response at each cycle (primary tumour & nodal size) till maximum tumour shrinkage is achieved (i.e. measurements at two consecutive CT cycles is constant) or there is clinical progression (usually 2 - 6 cycles).

    Surgical Treatment Options
    I. If clinical and radiological (mammography) complete response, index quadrantectomy with axillary clearance (BCT).
    II. If partial response with radiological evidence of residual disease, (a) BCT where feasible or (b) SMAC
    III. If static disease or progressive disease, SMAC with or without reconstruction for skin cover so that post-operative radiation can be instituted early.
    IV. In case of disease progression locally with inoperability of disease, may consider for preoperative radiotherapy followed by reassessment for surgical excision later.

    Completion of remaining cycles of Chemotherapy: (Total 6 cycles) However, if there was no response or disease progression during pre-operative chemotherapy, post operative RT is given first followed by consideration of 2[nd] line chemotherapy.

Tamoxifen (if ER / PR +ve) for a period of 5 years.

Postoperative Radiotherapy: All patients with LABC should receive RT to the breast or chest wall to a dose equivalent of 50Gy / 25# / 5 wks (or 45Gy / 20# / 4 wks).If BCT has been performed a tumor bed boost of 15 Gy in 6 fractions with appropriate electrons is recommended. Routine postoperative irradiation of axilla is not recommended unless there is known or suspected residual axillary disease. Similarly, routine irradiation of internal mammary nodes is not recommended pending the results of the large EORTC trial examining the survival benefit of internal mammary RT possible cardiac morbidity / mortality with IMC irradiation[2,15] is awaited.

FOLLOW-UP AFTER PRIMARY TREATMENT OF BREAST CANCER

I. Bi-annual Physical Examination (PE) for 5 years followed
by yearly checkup.
II. Mammography once in 18 months.
III. No other investigations in asymptomatic patients for early detection of metastasis, since it is -

  • Not cost-effective
  • Does not prolong survival 19,20
  • Detection and disclosure of spread of disease may be psychologically harmful to an asymptomatic patient with an incurable metastatic disease.

If recurrence or symptoms suggestive of metastasis, relevant investigations to be done

  • Chest radiography
  • Ultrasound abdomen
  • Liver Function Test
  • Radionuclide Bone Scan
  • Skeletal survey of suspicious or weight bearing areas
  • CT / MRI, where indicated

    Treatment of Isolated loco-regional recurrence21,22
  • Resectable: Surgery + radiotherapy
    On completion of loco-regional treatment if there is no evaluable disease then,
    tamoxifen (for ER or PgR +ve tumour) till progression.21 There is no evidence
    that early institution of chemotherapy (in ER -ve tumours) prolongs survival,
    hence it is not recommended.
  • Unresectable or within the field of previous radiotherapy:
    Chemotherapy followed by assessment for surgery.

 

 

METASTATIC BREAST CANCER

Goal of management is palliation.
Options & Principles of Management
  • Hormone therapy
  • Chemotherapy
  • Radiotherapy
  • Surgery : Pleurodesis, Palliative mastectomy
    Spinal decompression
  • Analgesics, Anti-emetics, Sedatives
  • Others : Bisphosphonates
    Nerve blocks

Decision to use chemotherapy or hormone therapy is based on receptor status, disease-free interval (DFI), tempo of recurrent disease and the site of metastasis (whether life-threatening).

Hormone therapy: For ER or PgR +ve ; exclusive bone & soft tissue metastasis, Slow tempo of disease or DFI>1 year.
1st line: Tamoxifen (20 mg) / Letrozole (2.5mg)22
2nd/3rdline: Letrozole (2.5mg) / Exemestane (25mg)
Medroxy-progesterone acetate: 100 mg tid
Megesterol acetate: 40 mg qid
Oophorectomy - in premenopausal ER & or PgR positive women as second line treatment.

Chemotherapy: For ER & PR -ve disease, Visceral metastasis, Fast tempo of disease or DFI<1 year.

1st line CAF / CEF
2nd line Paclitaxel (3 wkly 135mg infusion over 3hrs) Docetaxel (3 wkly 100mg infusion over 3hrs)
(Taxanes + carboplatin or adriamycin)
Mitomycin + Mitoxantrone + Methotrexate
(Doses: Mitomycin & Mitoxantrone 10mg/m2 Methotrexate 40 mg/m2 )
3rd line CMF

Radiotherapy:

Bone metastases23: For pain relief, preventing or treating neurological and skeletal complications of bone metastases.

  • For isolated or few bone metastases: Localized RT to a dose of 8Gy single fraction or 20Gy/5#/1wk if there is a risk of pathological fracture or impending / established cord compression.
  • For widespread bone metastases: Hemi Body Irradiation (HBI); Upper HBI 6Gy / 1#; Lower HBI 8Gy/1#. When both halves of the body have to be treated there should be a interval of 6 weeks.

Brain metastasis: For relieving / preventing neurological manifestation of brain metastases.

  • For solitary brain metastases (extracranial disease controlled) AND good
    performance status: Whole brain RT (30Gy/10#/2wks). Whenever feasible, consider surgical excision prior to whole brain RT or Radiosurgery boost after whole brain RT
  • For multiple brain mets OR uncontrolled extracranial disease OR poor performance status: Whole brain RT (20Gy/5#/1wk or 12Gy/2#/3 days).

Choroidal Metastases: Palliative RT (20Gy/5# or 30Gy/10#)

Bisphosphonates24
For lytic bone metastasis in weight bearing areas: Pamidronate I.V 90mg, 4 weekly (or other bisphosphonates) as an adjuvant to RT for prevention of fractures & pain relief.

BREAST CANCER SCREENING

  • Periodic screening by mammography results in reduction of mortality from breast
    cancer of about 30%, in women above the age of 50.26
  • No convincing evidence of benefit in women <50 years.25
  • Mammography breast screening programme is however not sustainable in developing countries.
  • Physical Examination (PE) of breast by trained personnel has a sensitivity of 75% and specificity of over 90% 27 in detection of breast cancers and may prove to be an alternative to mammography.
  • Periodic PE of breast by trained health workers along with health education is being compared with only health education in an ongoing NIH sponsored randomized trial.
  • Breast Self Examination (BSE) by patient may help in identifying interval cancers early but there is no evidence that BSE improves survival. 27

FAMILY HISTORY OF BREAST CANCER

Family history of breast cancer confers a 2-3 fold increased risk of breast cancer. 5-10% of women have hereditary breast cancer where the risk is over 50 fold. Hereditary breast cancers are related to mutations in BRCA1 and BRCA2 genes.28,29 Genetic testing provides information in a research setting but its use in routine practice needs much evaluation, social debate & counseling. First-degree blood relatives can be tested after confirming mutation in these genes in the index cases. A negative genetic testing does not entirely eliminate the risk of breast cancer, and a positive test cannot be remedied easily or prevented from being transmitted vertically. Such patients should be referred to the cancer genetics clinic for genetic counseling and testing as appropriate.


BREAST CANCER
Breast Conserative Therapy
1
EBM

1. Breast conserving therapy versus mastectomy in early stage breast cancer: a meta-analysis of 10-year survival.
Morris AD, Morris RD, et al; Cancer J Sci Am 1997; 3: 6-12.
BACKGROUND: The randomized trials comparing breast-conserving therapy (BCT), i.e., surgery and radiation to the breast, with mastectomy in early-stage breast cancer use a variety of protocols. Meta-analysis may assist in understanding the impact of these differences on survival. PURPOSE: To evaluate the possible variations of the relative efficacy of BCT and mastectomy in terms of overall survival according to tumor size, nodal status, and use of adjuvant radiation therapy. METHODS: The most recent published results and, where available, updated patient-level data from randomized controlled trials of BCT and mastectomy for early-stage breast cancer were combined in a meta-analysis using a random effects model. Pooled survival rates and odds ratios were generated according to subgroups of nodal status and tumor size. Five- and 10-year odds ratios were also determined according to adjuvant radiation protocol. RESULTS: The pooled odds ratio comparing 10-year survival for BCT and mastectomy was 0.91. The odds ratios comparing the two treatment regimens were not significant after grouping according to tumor size and nodal status. When more than 50% of node-positive patients in both the mastectomy and BCT arms received adjuvant radiation, both arms had similar survival rates. When less than 50% of node-positive patients in both arms received adjuvant nodal radiation, the odds ratio was 0.69, and patients receiving BCT had a survival advantage. CONCLUSIONS: Patients allocated to BCT have survival rates at least as high as patients allocated to mastectomy. When all protocols were combined, nodal status and tumor size did not significantly alter the relative survival rates. However, under some conditions, particularly for node-positive patients, BCT may confer a relative survival advantage over mastectomy. In particular, mastectomy without adjuvant radiation appears to be inferior to BCT for node-positive patients.

2. Effects of radiotherapy and surgery in early breast cancer: An overview of randomized trials. EBCTCG, N Eng J Med 1995, 333: 1444-1455.
BACKGROUND. Randomized trials of radiotherapy and surgery for early breast cancer may have been too small to detect differences in long-term survival and recurrence reliably. We therefore performed a systematic overview (meta-analysis) of the results of such trials. METHODS. Information was sought on each subject from investigators who conducted trials that began before 1985 and that compared local therapies for early breast cancer. Data on mortality were available from 36 trials comparing radiotherapy plus surgery with the same type of surgery alone, 10 comparing more extensive surgery with less extensive surgery, and 18 comparing more extensive surgery with less extensive surgery plus radiotherapy. Information on mortality was available for 28,405 women (97.4 percent of the 29,175 women in the trials). RESULTS. The addition of radiotherapy to surgery resulted in a rate of local recurrence that was three times lower than the rate with surgery alone, but there was no significant difference in 10-year survival; among a total of 17,273 women enrolled in such trials, mortality was 40.3 percent with radiotherapy and 41.4 percent without radiotherapy (P = 0.3). Radiotherapy was associated with a reduced risk of death due to breast cancer (odds ratio, 0.94; 95 percent confidence interval, 0.88 to 1.00; P = 0.03), which indicates that, after 10 years, there would be about 0 to 5 fewer deaths due to breast cancer per 100 women. However, there was an increased risk of death from other causes (odds ratio, 1.24; 95 percent confidence interval, 1.09 to 1.42; P = 0.002). This, together with the age-specific death rates, implies, after 10 years, a few extra deaths not due to breast cancer per 100 older women or per 1000 younger women. During the first decade or two after diagnosis, the excess in the rate of such deaths that was associated with radiotherapy was much greater women who were over 60 years of age at randomization (15.3 percent vs. 11.1 percent [339 vs. 249 deaths]) than among those under 50 (2.5 percent vs. 2.0 percent [62 vs. 49 deaths]). Breast-conserving surgery involved some risk of recurrence in the remaining tissue, but no significant differences in overall survival at 10 years were found in the studies of mastectomy versus breast-conserving surgery plus radiotherapy (4891 women), more extensive surgery versus less extensive surgery (4818 women), or axillary clearance versus radiotherapy as adjuncts to mastectomy (4370 women). CONCLUSIONS. Some of the local therapies for breast cancer had substantially different effects on the rates of local recurrence--such as the reduced recurrence with the addition of radiotherapy to surgery--but there were no definite differences in overall survival at 10 years.

3. Twenty-year follow-up of a randomized trial comparing total mastectomy, lumpectomy, and lumpectomy plus irradiation for the treatment of invasive breast cancer. Fisher B, et al. NSABP; N Engl J Med. 2002;347:1233-41

BACKGROUND: In 1976, we initiated a randomized trial to determine whether lumpectomy with or without radiation therapy was as effective as total mastectomy for the treatment of invasive breast cancer. METHODS: A total of 1851 women for whom follow-up data were available and nodal status was known underwent randomly assigned treatment consisting of total mastectomy, lumpectomy alone, or lumpectomy and breast irradiation. Kaplan-Meier and cumulative-incidence estimates of the outcome were obtained. RESULTS: The cumulative incidence of recurrent tumor in the ipsilateral breast was 14.3 percent in the women who underwent lumpectomy and breast irradiation, as compared with 39.2 percent in the women who underwent lumpectomy without irradiation (P<0.001). No significant differences were observed among the three groups of women with respect to disease-free survival, distant-disease-free survival, or overall survival. The hazard ratio for death among the women, who underwent lumpectomy alone, as compared with those who underwent total mastectomy, was 1.05 (95 percent confidence interval, 0.90 to 1.23; P=0.51). The hazard ratio for death among the women who underwent lumpectomy followed by breast irradiation, as compared with those who underwent total mastectomy, was 0.97 (95 percent confidence interval, 0.83 to 1.14; P=0.74). Among the lumpectomy-treated women whose surgical specimens had tumor-free margins, the hazard ratio for death among the women who underwent postoperative breast irradiation, as compared with those who did not, was 0.91 (95 percent confidence interval, 0.77 to 1.06; P=0.23). Radiation therapy was associated with a marginally significant decrease in deaths due to breast cancer. This decrease was partially offset by an increase in deaths from other causes. CONCLUSIONS: Lumpectomy followed by breast irradiation continues to be appropriate therapy for women with breast cancer, provided that the margins of resected specimens are free of tumor and an acceptable cosmetic result can be obtained.

4. Recurrence rates after treatment of breast cancer with standard radiotherapy with or without additional radiation. Bartelink H, et al. NEJM 2001; 345:1378-87.

BACKGROUND: Radiotherapy prevents local recurrence of breast cancer after breast-conserving surgery. We evaluated the effect of a supplementary dose of radiation to the tumor bed on the rates of local recurrence among patients who received radiotherapy after breast-conserving surgery for early breast cancer. METHODS: After lumpectomy and axillary dissection, patients with stage I or II breast cancer received 50 Gy of radiation to the whole breast in 2-Gy fractions over a five-week period. Patients with a microscopically complete excision were randomly assigned to receive either no further local treatment (2657 patients) or an additional localized dose of 16 Gy, usually given in eight fractions by means of an external electron beam (2661 patients). RESULTS: During a median follow-up period of 5.1 years, local recurrences were observed in 182 of the 2657 patients in the standard-treatment group and 109 of the 2661 patients in the additional-radiation group. The five-year actuarial rates of local recurrence were 7.3 percent (95 percent confidence interval, 6.8 to 7.6 percent) and 4.3 percent (95 percent confidence interval, 3.8 to 4.7 percent), respectively (P<0.001), yielding a hazard ratio for local recurrence of 0.59 (99 percent confidence interval, 0.43 to 0.81) associated with an additional dose. Patients 40 years old or younger benefited most; at five years, their rate of local recurrence was 19.5 percent with standard treatment and 10.2 percent with additional radiation (hazard ratio, 0.46 [99 percent confidence interval, 0.23 to 0.89]; P=0.002). At five years in the age group 41 to 50 years old, no differences were found in rates of metastasis or overall survival (which were 87 and 91 percent, respectively). CONCLUSIONS: In patients with early breast cancer who undergo breast-conserving surgery and receive 50 Gy of radiation to the whole breast, an additional dose of 16 Gy of radiation to the tumor bed reduces the risk of local recurrence, especially in patients younger than 50 years of age.

5. Pathologic margin involvement and the risk of recurrence in patients treated with breast-conserving therapy. Gage I, Schnitt SJ, et al. Cancer 1996;78:1921-8
BACKGROUND: The relationship between the microscopic margins of resection and ipsilateral breast recurrence (IBR) after breast-conserving therapy for carcinomas with or without an extensive intraductal component (EIC) has not been adequately defined. METHODS: Of 1,790 women with unilateral clinical Stage I or II breast carcinoma treated with radiation therapy as part of breast-conserving therapy, 343 had invasive ductal histology evaluable for an extensive intraductal component (EIC), had inked margins that were evaluable for an review of their pathology slides, and received > or = 60 Gray to the tumor bed; these 343 women constitute the study population. The median follow-up was 109 months. All available slides were reviewed by one of the study pathologists. Final inked margins of excision were classified as negative > 1 mm (no invasive or in situ ductal carcinoma within 1 mm of the inked margin); negative-1 mm, or close carcinoma < or = 1 mm from the inked margin but not at the margin); or positive (carcinoma at the inked margin). A focally positive margin was defined as invasive or in situ ductal carcinoma at the margin in three or fewer low-power fields. The first site of recurrent disease was classified as either ipsilateral breast recurrence (IBR) or distant metastasis/regional lymph node failure. RESULTS: Crude rates for the first site of recurrence were calculated first for all 340 patients evaluable at 5 years, then separately for the 272 patients with EIC-negative cancers and the 68 patients with EIC-positive cancers. The 5-year rate of IBR for all patients with negative margins was 2%; and for all patients with positive margins, the rate was 16%. Among patients with negative margins, the 5-year rate of IBR was 2% for all patients with close margins (negative < or = 1 mm) and 3% for those with negative > 1 mm margins. For patients with close margins, the rates were 2% and 0% for EIC-negative and EIC-positive tumors, respectively; the corresponding rates for patients with negative margins > 1 mm were 1% and 14%. The 5-year rate of IBR for patients with focally positive margins was 9% (9% for EIC-negative and 7% for EIC-positive patients). The 5-year crude rate of IBR for patients with greater than focally positive margins was 28% (19% for EIC-negative and 42% for EIC-positive patients). CONCLUSIONS: Patients with negative margins of excision have a low rate of recurrence in the treated breast, whether the margin is > 1 mm or < or = 1 mm and whether the carcinoma is EIC-negative or EIC-positive. Among patients with positive margins, those with focally positive margins have a considerably lower risk of local recurrence than those with more than focally positive margins, and could be considered for breast-conserving therapy.

Breast Conservation Surgery is the gold standard for early breast cancer. Modified radical mastectomy remains the standard of treatment when disease is multi-centric or compliance to postoperative radiotherapy is doubtful.


BREAST CANCER
Adjuvant Systemic Therapy
2
EBM

6. Tamoxifen for early breast cancer.
Cochrane Database Syst Rev 2001;(1):CD000486
Early Breast Cancer Trialists' Collaborative Group.
In this report, the Early Breast Cancer Trialists' Collaborative Group present their third 5-yearly systematic overview (meta-analysis) of treatment with tamoxifen. SELECTION CRITERIA: All randomised trials that began before 1990 and compared adjuvant tamoxifen for any duration versus no such treatment for women with early breast cancer. Information was obtained and analysed centrally on each of 37,000 women in 55 such trials, comprising about 87% of the worldwide evidence. RESULTS: Nearly 8000 of the women had a low, or zero, level of the oestrogen-receptor protein (ER) measured in their primary tumour. Among them, the overall effects of tamoxifen appeared to be small, and subsequent analyses of recurrence and total mortality are restricted to the remaining women (18,000 with ER-positive tumours, plus nearly 12,000 more with untested tumours, of which an estimated 8000 would have been ER-positive). For trials of 1 year, 2 years, and about 5 years of adjuvant tamoxifen, the proportional recurrence reductions produced among these 30,000 women during about 10 years of follow-up were 21% (SD 3), 29% (SD 2), and 47% (SD 3), respectively, with a highly significant trend towards greater effect with longer treatment (2p<0.00001). The corresponding proportional mortality reductions were 12% (SD 3), 17% (SD 3), and 26% (SD 4), respectively, and again the test for trend was significant (2p=0.003). The absolute improvement in recurrence was greater during the first 5 years, whereas the improvement in survival grew steadily larger throughout the first 10 years. The proportional mortality reductions were similar for women with node-positive and node-negative disease, but the absolute mortality reductions were greater in node-positive women. In the trials of about 5 years of adjuvant tamoxifen the absolute improvements in 10-year survival were 10.9% (SD 2.5) for node-positive (61.4% vs 50.5% survival, 2p<0.00001) and 5.6% (SD 1.3) for node-negative (78.9% vs 73.3% survival, 2p<0.00001). These benefits appeared to be largely irrespective of age, menopausal status, daily tamoxifen dose (which was generally 20 mg), and of whether chemotherapy had been given to both groups. In terms of other outcomes among all women studied (ie, including those with "ER-poor" tumours), the proportional reductions in contralateral breast cancer were 13% (SD 13), 26% (SD 9), and 47% (SD 9) in the trials of 1, 2, or about 5 years of adjuvant tamoxifen. The incidence of endometrial cancer was approximately doubled in trials of 1 or 2 years of tamoxifen and approximately quadrupled in trials of 5 years of tamoxifen (although the number of cases was small and these ratios were not significantly different from each other). The absolute decrease in contralateral breast cancer was about twice as large as the absolute increase in the incidence of endometrial cancer. Tamoxifen had no apparent effect on the incidence of colorectal cancer or, after exclusion of deaths from breast or endometrial cancer, on any of the other main categories of cause of death (total nearly 2000 such deaths; overall relative risk 0.99 [SD 0.05]). CONCLUSIONS: For women with tumours that have been reliably shown to be ER-negative, adjuvant tamoxifen remains a matter for research. However, some years of adjuvant tamoxifen treatment substantially improves the 10-year survival of women with ER-positive tumours and of women whose tumours are of unknown ER status, with the proportional reductions in breast cancer recurrence and in mortality appearing to be largely unaffected by other patient characteristics or treatments.

7. Ovarian ablation for early breast cancer
Cochrane Database Syst Rev 2000;(3):CD000485
Early Breast Cancer Trialists' Collaborative Group.
In this report, the Early Breast Cancer Trialists' Collaborative Group present their third 5-yearly systematic overview (meta-analysis), now with 15 years' follow-up. SELECTION CRITERIA: All properly randomised trials that began recruiting before 1990 which compared the ablation or suppression of ovarian function, sometimes with the addition of prednisone, versus no such adjuvant treatment for women with operable breast cancer. In practice, all the trials that can be reviewed here began before 1980, and all involved surgical or therapeutic ablation. Data were obtained for 12 of the 13 studies that assessed ovarian ablation by irradiation or surgery, all of which began before 1980, but not for the four studies that assessed ovarian suppression by drugs, all of which began after 1985. Menopausal status was not consistently defined across trials; therefore, the main analyses are limited to women aged under 50 (rather than "premenopausal") when randomised. Oestrogen receptors were measured only in the trials of ablation plus cytotoxic chemotherapy versus the same chemotherapy alone. MAIN RESULTS: Among 2102 women aged under 50 when randomised, most of whom would have been premenopausal at diagnosis, 1130 deaths and an additional 153 recurrences were reported. 15-year survival was highly significantly improved among those allocated ovarian ablation (52.4 vs 46.1%, 6.3 [SD 2.3] fewer deaths per 100 women, logrank 2p=0.001), as was recurrence-free survival (45.0 vs 39.0%, 2p=0.0007). The numbers of events were too small for any subgroup analyses to be reliable. The benefit was, however, significant both for those with ("node positive") and for those without ("node negative") axillary spread when diagnosed. In the trials of ablation plus cytotoxic chemotherapy versus the same chemotherapy alone, the benefit appeared smaller (even for women with oestrogen receptors detected on the primary tumour) than in the trials in the absence of chemotherapy (where the observed survival improvements were about six per 100 node-negative women and 12 per 100 node-positive women). Among 1354 women aged 50 or over when randomised, most of whom would have been perimenopausal or postmenopausal, there was only a non-significant improvement in survival and recurrence-free survival. CONCLUSIONS: In women aged under 50 with early breast cancer, ablation of functioning ovaries significantly improves long-term survival, at least in the absence of chemotherapy. Further randomised evidence is needed on the additional effects of ovarian ablation in the presence of other adjuvant treatments, and to assess the relevance of hormone-receptor measurements.

8. Anastrozole alone or in combination with tamoxifen versus tamoxifen alone for adjuvant treatment of postmenopausal women with early breast cancer: first results of the ATAC randomised trial. The ATAC Trialists' Group. Lancet; 2002 22;2131-9

BACKGROUND: In the adjuvant setting, tamoxifen is the established treatment for postmenopausal women with hormone-sensitive breast cancer. However, it is associated with several side effects including endometrial cancer and thromboembolic disorders. We aimed to compare the safety and efficacy outcomes of tamoxifen with those of anastrozole alone and the combination of anastrozole plus tamoxifen for 5 years. METHODS: Participants were postmenopausal patients with invasive operable breast cancer who had completed primary therapy and were eligible to receive adjuvant hormonal therapy. The primary endpoints were disease-free survival and occurrence of adverse events. Analysis for efficacy
was by intention to treat. FINDINGS: 9366 patients were recruited, of whom 3125 were randomly assigned anastrozole, 3116 tamoxifen, and 3125 combination. Median follow-up was 33.3 months. 7839 (84%) patients were known to be hormone-receptor-positive. Disease-free survival at 3 years was 89.4% on anastrozole and 87.4% on tamoxifen (hazard ratio 0.83 [95% CI 0.71-0.96], p=0.013). Results with the combination were not significantly different from those with tamoxifen alone (87.2%, 1.02 [0.89-1.18], p=0.8). The improvement in disease-free survival with anastrozole was seen in the subgroup of hormone-receptor-positive patients, but not the receptor-negative patients. Incidence of contralateral breast cancer was significantly lower with anastrozole than with tamoxifen (odds ratio 0.42 [0.22-0.79], p=0.007). Anastrozole was significantly better tolerated than tamoxifen with respect to endometrial cancer (p=0.02), vaginal bleeding and discharge (p<0.0001 for both), cerebrovascular events (p=0.0006), venous thromboembolic events (p=0.0006), and hot flushes (p<0.0001). Tamoxifen was significantly better tolerated than anastrozole with respect to musculoskeletal disorders and fractures (p<0.0001 for both). INTERPRETATION: Anastrozole is an effective and well-tolerated endocrine option for the treatment of postmenopausal patients with hormone-sensitive early breast cancer. Longer follow-up is required before a final benefit:risk assessment can be made.

9. Multi-agent chemotherapy for early breast cancer.
Cochrane Database Syst Rev 2002;(1):CD000487
Early Breast Cancer Trialists' Collaborative Group.

In this report, the Early Breast Cancer Trialists' Collaborative Group present their updated systematic overview (meta-analysis) of treatment with polychemotherapy. All randomised trials that began before 1990 and involved treatment groups that differed only with respect to the chemotherapy regimens were compared. Analyses involved about 18,000 women in 47 trials of prolonged polychemotherapy versus no chemotherapy, about 6000 in 11 trials of longer versus shorter polychemotherapy, and about 6000 in 11 trials of anthracycline-containing regimens versus CMF (cyclophosphamide, methotrexate, and fluorouracil). RESULTS: For recurrence, polychemotherapy produced substantial and highly significant proportional reductions both among women aged under 50 at randomisation (35% [SD 4] reduction; 2p <0.00001) and among those aged 50-69 (20% [SD 3] reduction; 2p <0.00001); few women aged 70 or over had been studied. For mortality, the reductions were also significant both among women aged under 50 (27% [SD 5] reduction; 2p <0.00001) and among those aged 50-69 (11% [SD 3] reduction; 2p=0.0001). The recurrence reductions emerged chiefly during the first 5 years of follow-up, whereas the difference in survival grew throughout the first 10 years. After standardisation for age and time since randomisation, the proportional reductions in risk were similar for women with node-negative and node-positive disease. Applying the proportional mortality reduction observed in all women aged under 50 at randomisation would typically change a 10-year survival of 71% for those with node-negative disease to 78% (an absolute benefit of 7%), and of 42% for those with node-positive disease to 53% (an absolute benefit of 11%). The smaller proportional mortality reduction observed in all women aged 50-69 at randomisation would translate into smaller absolute benefits, changing a 10-year survival of 67% for those with node-negative disease to 69% (an absolute gain of 2%) and of 46% for those with node-positive disease to 49% (an absolute gain of 3%). The age-specific benefits of polychemotherapy appeared to be largely irrespective of menopausal status at presentation, oestrogen receptor status of the primary tumour, and of whether adjuvant tamoxifen had been given. In terms of other outcomes, there was a reduction of about one-fifth (2p=0.05) in contralateral breast cancer, which has already been included in the analyses of recurrence, and no apparent adverse effect on deaths from causes other than breast cancer (death rate ratio 0.89 [SD 0.09]). The directly randomised comparisons of longer versus shorter durations of polychemotherapy did not indicate any survival advantage with the use of more than about 3-6 months of polychemotherapy. By contrast, directly randomised comparisons did suggest that, compared with CMF alone, the anthracycline-containing regimens studied produced somewhat greater effects on recurrence (2p=0.006) and mortality (69% vs 72% 5-year survival; log-rank 2p=0.02). But this comparison is one of many that could have been selected for emphasis, the 99% CI reaches zero, and the results of several of the relevant trials are not yet available. CONCLUSIONS: Some months of adjuvant polychemotherapy (eg, with CMF or an anthracycline-containing regimen) typically produces an absolute improvement of about 7-11% in 10-year survival for women aged under 50 at presentation with early breast cancer, and of about 2-3% for those aged 50-69 (unless their prognosis is likely to be extremely good even without such treatment). Treatment decisions involve consideration not only of improvements in cancer recurrence and survival but also of adverse side-effects of treatment, and this report makes no recommendations as to who should or should not be treated.

10. Phase III Trial comparing two doses of Epirubicin combined with cyclophosphamide with Cyclophosphamide, Methotrexate, and Fluorouracil in node-positive breast cancer.
Piccart MJ, et el: J Clin Oncol, 19(12), 2001: 3103-3110.
PURPOSE: To compare a full-dose epirubicin-cyclophosphamide (HEC) regimen with classical cyclophosphamide, methotrexate, and fluorouracil (CMF) therapy and with a moderate-dose epirubicin-cyclophosphamide regimen (EC) in the adjuvant therapy of node-positive breast cancer. PATIENTS AND METHODS: Node-positive breast cancer patients who were aged 70 years or younger were randomly allocated to one of the following treatments: CMF for six cycles (oral cyclophosphamide); EC for eight cycles (epirubicin 60 mg/m(2), cyclophosphamide 500 mg/m(2); day 1 every 3 weeks); and HEC for eight cycles (epirubicin 100 mg/m(2), cyclophosphamide 830 mg/m(2); day 1 every 3 weeks). RESULTS: Two hundred fifty-five, 267, and 255 eligible patients were treated with CMF, EC, and HEC, respectively. Patient characteristics were well balanced among the three arms. One and three cases of congestive heart failure were reported in the EC and HEC arms, respectively. Three cases of acute myeloid leukemia were reported in the HEC arm. After 4 years of median follow-up, no statistically significant differences were observed between HEC and CMF (event-free survival [EFS]: hazards ratio [HR] = 0.96, 95% confidence interval [CI], 0.70 to 1.31, P =.80; distant-EFS: HR = 0.97, 95% CI, 0.70 to 1.34, P =.87; overall survival [OS]: HR = 0.97, 95% CI, 0.65 to 1.44, P =.87). HEC is more effective than EC (EFS: HR = 0.73, 95% CI, 0.54 to 0.99, P =.04; distant-EFS: HR = 0.75, 95% CI, 0.55 to 1.02, P =.06; OS HR = 0.69, 95% CI, 0.47 to 1.00, P =.05). CONCLUSION: This three-arm study does not show an advantage in favor of an adequately dosed epirubicin-based regimen over classical CMF in the adjuvant therapy of node-positive pre- and postmenopausal women with breast cancer. Moreover, this study confirms that there is a dose-response curve for epirubicin in breast cancer adjuvant therapy.

11. ESMO Minimum Clinical Recommendations for diagnosis, adjuvant treatment and follow-up of primary breast cancer. Annals of Oncology 12: 1047-48, 2001. (No abstract available)

12. National Institute of Health. Consensus Development Conference Statement: Adjuvant Therapy for Breast Cancer. Nov 1-3 2000, J Natl Cancer Inst Monogr 2001: 30: 5-15.
OBJECTIVE: Our goal was to provide health-care providers, patients, and the general public with an assessment of currently available data regarding the use of adjuvant therapy for breast cancer. PARTICIPANTS: The participants included a non-Federal, non-advocate, 14-member panel representing the fields of oncology, radiology, surgery, pathology, statistics, public health, and health policy as well as patient representatives. In addition, 30 experts in medical oncology, radiation oncology, biostatistics, epidemiology, surgical oncology, and clinical trials presented data to the panel and to a conference audience of 1000. EVIDENCE: The literature was searched with the use of MEDLINE for January 1995 through July 2000, and an extensive bibliography of 2230 references was provided to the panel. Experts prepared abstracts for their conference presentations with relevant citations from the literature. Evidence from randomized clinical trials and evidence from prospective studies were given precedence over clinical anecdotal experience. CONSENSUS PROCESS: The panel, answering predefined questions, developed its conclusions based on the evidence presented in open forum and the scientific literature. The panel composed a draft statement, which was read in its entirety and circulated to the experts and the audience for comment. Thereafter, the panel resolved conflicting recommendations and released a revised statement at the end of the conference. The panel finalized the revisions within a few weeks after the conference. The draft statement was made available on the World Wide Web immediately after its release at the conference and was updated with the panel's final revisions. The statement is available at http://consensus.nih.gov. CONCLUSIONS: The panel concludes that decisions regarding adjuvant hormonal therapy should be based on the presence of hormone receptor protein in tumor tissues. Adjuvant hormonal therapy should be offered only to women whose tumors express hormone receptor protein. Because adjuvant polychemotherapy improves survival, it should be recommended to the majority of women with localized breast cancer regardless of lymph node, menopausal, or hormone receptor status. The inclusion of anthracyclines in adjuvant chemotherapy regimens produces a small but statistically significant improvement in survival over non-anthracycline-containing regimens. Available data are currently inconclusive regarding the use of taxanes in adjuvant treatment of lymph node-positive breast cancer. The use of adjuvant dose-intensive chemotherapy regimens in high-risk breast cancer and of taxanes in lymph node-negative breast cancer should be restricted to randomized trials. Ongoing studies evaluating these treatment strategies should be supported to determine if such strategies have a role in adjuvant treatment. Studies to date have included few patients older than 70 years. There is a critical need for trials to evaluate the role of adjuvant chemotherapy in these women. There is evidence that women with a high risk of locoregional tumor recurrence after mastectomy benefit from postoperative radiotherapy. This high-risk group includes women with four or more positive lymph nodes or an advanced primary cancer. Currently, the role of postmastectomy radiotherapy for patients with one to three positive lymph nodes remains uncertain and should be tested in a randomized controlled trial. Individual patients differ in the importance they place on the risks and benefits of adjuvant treatments. Quality of life needs to be evaluated in selected randomized clinical trials to examine the impact of the major acute and long-term side effects of adjuvant treatments, particularly premature menopause, weight gain, mild memory loss, and fatigue. Methods to support shared decision-making between patients and their physicians have been successful in trials; they need to be tailored for diverse populations and should be tested for broader dissemination.

Adjuvant chemotherapy reduces death due to breast cancer by 25% (RR) in premenopausal women. Effect is halved in postmenopausal women. Adjuvant tamoxifen reduces death in hormone sensitive breast cancer by 26% (RR) irrespective of menopausal status.


BREAST CANCER -
Adjuvant loco-regional radiotherapy
3
EBM

13. DBCG 82B Danish Breast Cancer Cooperative Group randomized trial: Postmastectomy radiotherapy in high-risk premenopausal breast cancer patients given adjuvant chemotherapy. Overgaard M et al. N Engl J Med 1997; 337:949-55
Irradiation after mastectomy can reduce locoregional recurrences in women with breast cancer, but whether it prolongs survival remains controversial. We conducted a randomized trial of radiotherapy after mastectomy in high-risk premenopausal women, all of whom also received adjuvant systemic chemotherapy with cyclophosphamide, methotrexate, and fluorouracil (CMF). METHODS: A total of 1708 women who had undergone mastectomy for pathological stage II or III breast cancer were randomly assigned to receive eight cycles of CMF plus irradiation of the chest wall and regional lymph nodes (852 women) or nine cycles of CMF alone (856 women). The median length of follow-up was 114 months. The end points were locoregional recurrence, distant metastases, disease-free survival, and overall survival. RESULTS: The frequency of locoregional recurrence alone or with distant metastases was 9 percent among the women who received radiotherapy plus CMF and 32 percent among those who received CMF alone (P<0.001). The probability of survival free of disease after 10 years was 48 percent among the women assigned to radiotherapy plus CMF and 34 percent among those treated only with CMF (P<0.001). Overall survival at 10 years was 54 percent among those given radiotherapy and CMF and 45 percent among those who received CMF alone (P<0.001). Multivariate analysis demonstrated that irradiation after mastectomy significantly improved disease-free survival and overall survival, irrespective of tumor size, the number of positive nodes, or the histopathological grade. CONCLUSIONS: The addition of postoperative irradiation to mastectomy and adjuvant chemotherapy reduces locoregional recurrences and prolongs survival in high-risk premenopausal women with breast cancer.

14. DBCG 82C Danish Breast Cancer Cooperative Group randomized trial: Postmastectomy radiotherapy in high-risk postmenopausal breast cancer patients given adjuvant tamoxifen. Overgaard M, et al. Lancet 1999;353:1641-8
Postmastectomy radiotherapy is associated with a lower locoregional recurrence rate and improved disease-free and overall survival when combined with chemotherapy in premenopausal high-risk breast-cancer patients. However, whether the same benefits apply also in postmenopausal women treated with adjuvant tamoxifen for similar high-risk cancer is unclear. In a randomised trial among postmenopausal women who had undergone mastectomy, we compared adjuvant tamoxifen alone with tamoxifen plus postoperative radiotherapy. METHODS: Between 1982 and 1990, postmenopausal women with high-risk breast cancer (stage II or III) were randomly assigned adjuvant tamoxifen (30 mg daily for 1 year) alone (689) or with postoperative radiotherapy to the chest wall and regional lymph nodes (686). Median follow-up was 123 months. The endpoints were first site of recurrence (locoregional recurrence, distant metastases, or both), and disease-free and overall survival. FINDINGS: Locoregional recurrence occurred in 52 (8%) of the radiotherapy plus tamoxifen group and 242 (35%) of the tamoxifen only group (p<0.001). In total there were 321 (47%) and 411 (60%) recurrences, respectively. Disease-free survival was 36% in the radiotherapy plus tamoxifen group and 24% in the tamoxifen alone group (p<0.001). Overall survival was also higher in the radiotherapy group (385 vs 434 deaths; survival 45 vs 36% at 10 years, p=0.03). INTERPRETATION: Postoperative radiotherapy decreased the risk of locoregional recurrence and was associated with improved survival in high-risk postmenopausal breast-cancer patients after mastectomy and limited axillary dissection, with 1 year of adjuvant tamoxifen treatment. Improved survival in high-risk breast cancer can best be achieved by a strategy of both locoregional and systemic tumour control.

15. Radiotherapy for early breast cancer
Cochrane Database Syst Rev 2002;(2):CD003647
Early Breast Cancer Trialists' Collaborative Group.

OBJECTIVES: In this report the Early Breast Cancer Trialists' Collaborative Group present their systematic overview of treatment with radiotherapy. SELECTION CRITERIA: A meta-analysis was done of 10-year and 20-year results from 40 unconfounded randomised trials of radiotherapy for early breast cancer. Radiotherapy fields generally included not only chest wall (or breast) but also axillary, supraclavicular, and internal mammary nodes. DATA COLLECTION AND ANALYSIS: Data collection involved central review of individual patient data on recurrence and cause-specific mortality from 20,000 women. MAIN RESULTS: A reduction of approximately two-thirds in local recurrence was seen in all trials, largely independent of the type of patient or type of radiotherapy (8.8% vs 27.2% local recurrence by year 10). Hence, to assess effects on breast cancer mortality of substantially better local control, results from all trials were combined. Breast cancer mortality was reduced (2p=0.0001) but other, particularly vascular, mortality was increased (2p=0.0003), and overall 20-year survival was 37.1% with radiotherapy versus 35.9% control (2p=0.06). There was little effect on early deaths, but log rank analyses of later deaths indicate that, on average after year 2, radiotherapy reduced annual mortality rates from breast cancer by 13.2% (SE 2.5) but increased those from other causes by 21.2% (SE 5.4). Nodal status, age, and decade of follow-up strongly affected the ratio of breast cancer mortality to other mortality, and hence affected the ratio of absolute benefit to absolute hazard from these proportional changes in mortality. REVIEWER'S CONCLUSIONS: Radiotherapy regimens able to produce the two-thirds reduction in local recurrence seen in these trials, but without long-term hazard, would be expected to produce an absolute increase in 20-year survival of about 2-4% (except for women at particularly low risk of local recurrence). The average hazard seen in these trials would, however, reduce this 20-year survival benefit in young women and reverse it in older women.

 

 

 

 

 

Post-operative RT is mandatory following breast conservation surgery and saves lives when administered post-mastectomy in women with T > 5cm and / or N > 3

BREAST CANCER - LABC
Multimodal therapy / Neoadjuvant CT
4
EBM

Evidence from the NSABP B-18 randomized trial and other retrospective studies have shown that neoadjuvant chemotherapy effectively reduces the primary tumor size in nearly 80% cases. Tumour regression increases the feasibility of BCT in large operable and locally advanced cancers. However, anterior chemotherapy has not resulted in any improvement in disease-free or overall survival. A good response to chemotherapy does indicate a better prognosis. No large randomised evidence is available to assess effect of neoadjuvant chemotherapy in locally advanced breast cancer.

16. Effect of preoperative chemotherapy on the outcome of women with operable breast cancer.
Fisher B, et al. NSABP J Clin Oncol, 16:1998:2672-85

PURPOSE: To determine, in women with primary operable breast cancer, if preoperative doxorubicin (Adriamycin) and cyclophosphamide (Cytoxan; AC) therapy yields a better outcome than postoperative AC therapy, if a relationship exists between outcome and tumor response to preoperative chemotherapy, and if such therapy results in the performance of more lumpectomies. PATIENTS AND METHODS: Women (1,523) enrolled onto National Surgical Adjuvant Breast and Bowel Project (NSABP) B-18 were randomly assigned to preoperative or postoperative AC therapy. Clinical tumor response to preoperative therapy was graded as complete (cCR), partial (cPR), or no response (cNR). Tumors with a cCR were further categorized as either pathologic complete response (pCR) or invasive cells (pINV). Disease-free survival (DFS), distant disease-free survival (DDFS), and survival were estimated through 5 years and compared between treatment groups. In the preoperative arm, proportional-hazards models were used to investigate the relationship between outcome and tumor response. RESULTS: There was no significant difference in DFS, DDFS, or survival (P = .99, .70, and .83, respectively) among patients in either group. More patients treated preoperatively than postoperatively underwent lumpectomy and radiation therapy (67.8% v 59.8%, respectively). Rates of ipsilateral breast tumor recurrence (IBTR) after lumpectomy were similar in both groups (7.9% and 5.8%, respectively; P = .23). Outcome was better in women whose tumors showed a pCR than in those with a pINV, cPR, or cNR (relapse-free survival [RFS] rates, 85.7%, 76.9%, 68.1%, and 63.9%, respectively; P < .0001), even when baseline prognostic variables were controlled. CONCLUSION: Preoperative chemotherapy is as effective as postoperative chemotherapy, permits more lumpectomies, is appropriate for the treatment of certain patients with stages I and II disease, and can be used to study breast cancer biology. Tumor response to preoperative chemotherapy correlates with outcome and could be a surrogate for evaluating the effect of chemotherapy on micrometastases; however, knowledge of such a response provided little prognostic information beyond that which resulted from postoperative therapy.

17. The efficacy of neoadjuvant chemotherapy compared to postoperative therapy in the treatment of locally advanced breast cancer. Cunningham JD et al. Cancer Invest 1998;16:80-6.

The current approach to the treatment of locally advanced breast cancer is sequential chemotherapy, surgery and/or radiation, and consolidation chemotherapy. Although significant tumor response is seen with this regimen, there are few studies that compare this approach to postoperative chemotherapy. The purpose of this study was to compare the disease-free and overall survival of patients with locally advanced breast cancer treated with neoadjuvant chemotherapy and surgery to patients treated with surgery followed by adjuvant chemotherapy. Ninety-four patients with stage IIB, IIIA, and IIIB breast cancer were treated with a standardized chemotherapy regimen. The first group, 60 patients who were followed prospectively, was treated with neoadjuvant chemotherapy (NCT) consisting of vincristine, prednisone, cytoxan, methotrexate, and 5-FU (CVFMP) followed by surgery and consolidation chemotherapy with adriamycin. The second group, 34 patients evaluated retrospectively, had surgery followed by postoperative chemotherapy (PCT) with CVFMP followed by adriamycin. Overall median follow-up was 38 months. In the NCT group, 45/60 (75%) patients had a clinical response to induction therapy and the median reduction in tumor size was 50%. The rates of local recurrence, distant recurrence, and death from disease were similar in the two groups. The time to local recurrence was similar for the two groups. However, the median time to distant recurrence was shorter in the NCT group (19 month vs. 31 months, p = NS). Overall median survival among the NCT patients was shorter than for the PCT group (30 vs. 47 months, p = NS). The current study suggests that postoperative therapy is comparable to a neoadjuvant regimen in patients with locally advanced breast cancer with regard to local recurrence, distant recurrence, and overall survival.

18. Relationship of clinical and pathologic response to neoadjuvant chemotherapy and outcome of locally advanced breast cancer.
Gajdos C, Tartter PI, et al. J Surg Oncol 2002; 80: 4-11.

BACKGROUND AND OBJECTIVES: Neoadjuvant chemotherapy in locally advanced breast cancers produces histologically evaluable changes and frequently reduces the size of the primary tumor. Local clinical response to neoadjuvant chemotherapy may correlate with response of distant metastases. Therefore, clinical or pathological factors, which predict or assess response to treatment, may predict outcome after consideration for initial extent of disease. METHODS: To identify pretreatment characteristics of locally advanced breast cancers which predict clinical and pathologic response to neoadjuvant chemotherapy as well as survival and to assess the utility of postoperative histologic changes, we retrospectively studied one hundred forty-four patients with locally advanced breast cancer treated with neoadjuvant chemotherapy between January 1975 and July 1996. Patients were identified through pathology records of the Mount Sinai Medical Center and via one of the author's clinical databases. Pathologic and clinical responses to neoadjuvant chemotherapy were correlated with survival. Stepwise logistic regression was used to identify variables most significantly related to clinical response and pathologic axillary lymph node involvement. RESULTS: Complete clinical response with no palpable tumor was noted in 7/86 patients (8%) and complete pathologic response was achieved in 18/138 patients (13%). Both clinical (P = 0.038) and pathologic response (P = 0.011) were related to tumor size at the time of diagnosis: smaller tumors were more likely to respond to chemotherapy than larger tumors. Histologic evidence of chemotherapeutic effect, i.e., cytoplasmic vacuolization, change in the number of mitoses and localized fibrosis in lymph nodes did not correlate with clinical or pathologically measured response. Clinical and pathologic response was not associated with age, histology, differentiation, or type of chemotherapy. No residual tumor was found in the axillary nodes of 27% (37) of the patients. Age and complete pathologic response were the only variables significantly related to pathologic nodal status. Eighty-four percent of the 61 patients under 50 years of age had nodal involvement compared to 65% of older patients (P = 0.014). Fifty percent of complete pathologic responders had positive axillary lymph nodes compared to 76% of patients who did not have a complete pathologic response (P = 0.020). Distant disease-free (P = 0.039) and overall survival (P = 0.035) were related to the number of involved axillary lymph nodes. After consideration for pathologic lymph node status, no other variable was significantly related to distant disease-free or overall survival in multivariate analysis. No variable was significantly related to local disease-free survival. Age, clinical tumor size, clinical lymph node status, clinical response, type of chemotherapy, histology, differentiation, chemotherapy effects on primary tumor and lymph nodes, decline in the number of mitoses, and degree of fibrosis in nodes were not predictive of distant recurrence or overall survival. CONCLUSIONS: This study of patients treated with neoadjuvant chemotherapy for locally advanced breast cancers found little evidence that measurable clinical or pathologic changes attributable to chemotherapy predicted survival. Axillary lymph node status, associated with young age, was the most important prognostic indicator in these patients.

Neoadjuvant chemotherapy does not improve survival in breast cancer but it facilitates breast conservation


 

 


BREAST CANCER -
Follow-up after primary treatment
5
EBM

19. Intensive diagnostic follow-up after treatment of primary breast cancer: a randomised trial.
Rosselli Del Turco M, Palli D, Cariddi A: . JAMA. 1994; 271: 1593-97.National Research Council Project on Breast Cancer follow-up.
OBJECTIVE. To evaluate the effectiveness of early detection of intrathoracic and bone metastases in reducing mortality in breast cancer patients. DESIGN. Randomized clinical trial allocating breast cancer patients to two alternative follow-up protocols (intensive vs clinical) for at least 5 years. SETTING. Twelve breast clinics (referral centers) in different areas in Italy. PATIENTS. A total of 1243 consecutive patients (either premenopausal or postmenopausal) surgically treated for unilateral invasive breast carcinoma with no evidence of metastases. The two study groups were well balanced in terms of clinical and prognostic characteristics. INTERVENTION. Patients in both treatment groups had physical examination and mammography, while patients of the intensive follow-up group had, in addition, chest roentgenography and bone scan every 6 months. MAIN OUTCOME MEASURES. Vital status at 5 years was the main outcome; information was available for all except five patients (0.4%). Relapse-free survival was also analyzed. RESULTS. Overall, 393 recurrences (104 local and 289 distant) were observed during the study. Increased detection of isolated intrathoracic and bone metastases was evident in the intensive follow-up group compared with the clinical follow-up group (112 vs 71 cases), while no difference was observed for other sites and for local and/or regional recurrences. The 5-year relapse-free survival rate was significantly higher for the clinical follow-up group, with patients in the intensive follow-up group showing earlier detection of recurrences. No difference in 5-year overall mortality (18.6% vs 19.5%) was observed between the two follow-up groups. CONCLUSIONS. Periodic chest roentgenography and bone scan allow earlier detection of distant metastases, but anticipated diagnosis appears to be the only effect of intensive follow-up, and no impact on prognosis is evident after 5 years. Periodic intensive follow-up with chest roentgenography and bone scan should not be recommended as a routine policy.

20. Impact of follow-up testing on survival & health-related quality of life in breast cancer patients. A multi-center randomised controlled trial. The GIVIO Investigators:
JAMA 1994; 271: 1587-92

OBJECTIVE. To assess prospectively the impact on survival and health-related quality of life of two follow-up protocols in patients with early breast cancer. DESIGN. Randomized controlled clinical trial. SETTING. Multicenter study involving 26 general hospitals in Italy. PATIENTS: A consecutive sample of 1320 women younger than 70 years with stage I, II, and III unilateral primary breast cancer. INTERVENTION: Patients were randomly assigned to an intensive surveillance, which included physician visits and performance of bone scan, liver echography, chest roentgenography, and laboratory tests at predefined intervals (n = 655), or to a control regimen (n = 665), in which patients were seen by their physicians at the same frequency but only clinically indicated tests were performed. Both groups received a yearly mammogram aimed at detecting contralateral breast cancer. MAIN OUTCOME MEASURES. Primary end points were overall survival and health-related quality of life. RESULTS. Compliance to the two follow-up protocols was more than 80%. At a median follow-up of 71 months, no difference was apparent in overall survival with 132 deaths (20%) in the intensive group and 122 deaths (18%) in the control group. No significant differences were apparent in time to detection of recurrence between the two groups. Measurements of health-related quality of life (ie, overall health and quality-of-life perception, emotional well-being, body image, social functioning, symptoms, and satisfaction with care) at 6, 12, 24, and 60 months of follow-up did not show differences by type of care received. CONCLUSIONS. Results of this trial support the view that a protocol of frequent laboratory tests and roentgenography after primary treatment for breast cancer does not improve survival or influence health-related quality of life. Routine use of these tests should be discouraged.

No intensive investigations to be done to detect metastasis during routine follow-up of women after completion of primary treatment. Investigate only when symptomatic.


BREAST CANCER -
Recurrent breast cancer
6
EBM

21. First isolated loco-regional recurrence following mastectomy for breast cancer: Results of a Phase III multi-center study comparing systemic treatment with observation after excision and radiation.
M. Borner, M. Bacchi, Goldirsh et al. J Clin Oncol 1994;12: 2071-77.
PURPOSE: We performed a randomized phase III multicenter study to compare systemic treatment versus no treatment after complete excision and radiotherapy for isolated first locoregional recurrence in patients with breast cancer. PATIENTS AND METHODS: One hundred sixty-seven good-risk patients with an estrogen receptor (ER+) positive recurrence or, in case of unknown receptor status, a disease-free interval (DFI) of greater than 12 months and < or = three recurrent tumor nodules each < or = 3 cm in diameter were entered onto the study. They were randomized to observation subsequent to local treatment or to receive tamoxifen (TAM) until disease progression. Seventy-nine percent of the patients were postmenopausal. RESULTS: The median observation period for the entire study population was 6.3 years. The median disease-free survival (DFS) duration was 26 months for observation and 82 months for TAM patients (P = .007). This was mainly due to the reduction of further local recurrences, whereas the occurrence of early distant metastases was delayed. A multivariate analysis identified DFI and treatment with TAM as significant prognostic factors for DFS. The 5-year overall survival (OS) rates were 76% and 74%, respectively (P = .77). DFI was also a prognostic factor for OS. CONCLUSION: Systemic therapy with TAM after isolated locoregional recurrence of breast cancer significantly increased 5-year DFS rates from 36% to 59% compared with observation alone and prolonged median DFS by more than 4.5 years in patients with ER+ tumors or in the case of unknown ER status with a DFI of greater than 12 months and minimal tumor burden. Treatment with TAM currently has no significant impact on OS, but the median survival duration of the study population has not yet been reached.

22. Superior efficacy of letrozole versus tamoxifen as first-line therapy for postmenopausal women with advanced breast cancer: results of a phase III study of the International Letrozole Breast Cancer Group.
Mouridsen H, et al, J Clin Oncol: 2001;19:2596-606
PURPOSE: To compare the efficacy and tolerability of tamoxifen with that of letrozole, an oral aromatase inhibitor, with tamoxifen as first-line therapy in postmenopausal women with advanced breast cancer. PATIENTS AND METHODS: Nine hundred seven patients were randomly assigned letrozole 2.5 mg once daily (453 patients) or tamoxifen 20 mg once daily (454 patients). Patients had estrogen receptor- and/or progesterone receptor-positive tumors, or both receptors were unknown. Recurrence during adjuvant antiestrogen therapy or within the following 12 months or prior endocrine therapy for advanced disease precluded enrollment. One prior chemotherapy regimen for metastatic disease was allowed. The primary end point was time to progression (TTP). Secondary end points included overall objective response rate (ORR), its duration, rate and duration of clinical benefit, time to treatment failure (TTF), overall survival, and tolerability. RESULTS: TTP was significantly longer for letrozole than for tamoxifen (median, 41 v 26 weeks). Treatment with letrozole reduced the risk of progression by 30% (hazards ratio, 0.70; 95% confidence interval, 0.60 to 0.82, P =.0001). TTP was significantly longer for letrozole irrespective of dominant site of disease, receptor status, or prior adjuvant antiestrogen therapy. Similarly, TTF was significantly longer for letrozole (median, 40 v 25 weeks). ORR was higher for letrozole (30% v 20%; P =.0006), as was the rate of clinical benefit (49% v 38%; P =.001). Survival data are currently immature and not reported here. Both treatments were well tolerated. CONCLUSION: Letrozole was significantly superior to tamoxifen in TTP, TTF, ORR, and clinical benefit rate. Our results support its use as first-line endocrine therapy in postmenopausal women with advanced breast cancer.

23. Radiotherapy for the palliation of painful bone metastasis.
McQuay HJ, Collins SL, Carroll D et al.
Cochrane Database Syst Rev 2000;(2):CD001793
BACKGROUND: Radiotherapy is used commonly to provide pain relief for painful bone metastases, and there is a perception that of the three-quarters of patients who achieve pain relief, half of these stay free from pain. However, the precise contribution from radiotherapy may be unclear because of difficulties in assessing the numbers of people achieving relief, the extent of relief and its duration, and the influence of other contemporaneous interventions, such as analgesics. OBJECTIVES: To assess pain relief from: 1. localised bone metastases achieved by radiotherapy, comparing the efficacy of different fractionation schedules 2. more generalised metastatic disease achieved by radiotherapy or radioisotopes. SEARCH STRATEGY: Studies were identified by searching Medline (1966 to August 1998), Embase (1980 to 1998), the Cochrane Library (1998 Issue 3) and the Oxford Pain Relief Database (1950 to 1994). SELECTION CRITERIA: The inclusion criteria used were: full journal publication, patients with pain due to bone metastases, and random allocation to a radiotherapeutic intervention (either external irradiation or administration of radioisotopes). DATA COLLECTION AND ANALYSIS: The number of patients achieving complete pain relief and at least 50% at one month were compared with an assumed natural history of 1 in 100 patients achieving pain relief without treatment to obtain the number-needed-to-treat (NNT). Summed pain relief or pain intensity difference over four to six hours was extracted, converted into dichotomous information yielding the number of patients with at least 50% pain relief, and used to calculate the relative benefit and the NNT for one patient to achieve at least 50% pain relief. MAIN RESULTS: Twenty trials reported on 43 different radiotherapy fractionation schedules and eight studies of radioisotopes. Radiotherapy produced complete pain relief at one month in 395/1580 (25%) patients, and at least 50% relief in 788/1933 (41%) patients at some time during the trials. There were no differences in the proportions of patients achieving these outcomes between single or multiple fraction schedules. The number-needed-to-treat (NNT) to achieve complete relief at one month (compared with an assumed natural history of 1 in 100 patients whose pain resolved without treatment) was 4.2 (95% CI 3.7-4.7). No pooled estimates of speed of onset of relief, or of its duration, could be obtained. In the largest trial (759 patients) 52% of those who had complete relief had achieved it within four weeks, and the median duration of complete relief was 12 weeks. For more generalised disease, radioisotopes produced similar analgesic results to external irradiation. Adverse effect reporting was poor. There were no obvious differences between the various fractionation schedules in the incidence of nausea and vomiting, diarrhoea or pathological fractures. REVIEWER'S CONCLUSIONS: Radiotherapy is clearly effective at reducing pain from painful bone metastases. There was no evidence of any difference in efficacy between different fractionation schedules, nor indeed of a dose-response with total dose of radiation. For treatment of generalised bone pain both hemibody irradiation and radioisotopes can reduce the number of painful new sites.

24. Bisphosphonates for the relief of pain secondary to bone metastases.
Wong R, Wiffen PJ.Cochrane Database Syst Rev. 2002;(2):CD002068.
BACKGROUND: Bisphosphonates form part of standard therapy for hypercalcemia and the prevention of skeletal events in some cancers. However, the role of bisphosphonates in pain relief for bony metastases remains uncertain. OBJECTIVES: To determine the effectiveness of bisphosphonates for the relief of pain from bone metastases. SEARCH STRATEGY: MEDLINE (1966-1999), EMBASE (1980-1999), CancerLit (1966-1999), the Cochrane library (Issue 1, 2000) and the Oxford Pain Database were searched using the strategy devised by the Cochrane Pain, Palliative and Supportive Care Group with additional terms 'diphosphonate', 'bisphosphonate', 'multiple myeloma' and 'bone neoplasms'. (Last search: January 2000). SELECTION CRITERIA: Randomized trials of bisphosphonates compared with open, blinded, or different doses/types of bisphosphonates in cancer patients were included where pain and/or analgesic consumption were outcome measures. Studies where pain was reported only by observers were excluded. DATA COLLECTION AND ANALYSIS: Article eligibility, quality assessment and data extraction were undertaken by both reviewers. The proportions of patients with pain relief at 4, 8 and 12 weeks were assessed. The proportion of patients with analgesic reduction, the mean pain score, mean analgesic consumption, adverse drug reactions, and quality of life data were compared as secondary outcomes. MAIN RESULTS: Thirty randomized controlled studies (21 blinded, four open and five active control) with a total of 3682 subjects were included. For each outcome, there were few studies with available data. For the proportion of patients with pain relief (eight studies) pooled data showed benefits for the treatment group, with an NNT at 4 weeks of 11[95% CI 6-36] and at 12 weeks of 7 [95% CI 5-12]. In terms of adverse drug reactions, the NNH was 16 [95% CI 12-27] for discontinuation of therapy. Nausea and vomiting were reported in 24 studies with a non-significant trend for greater risk in the treatment group. One study showed a small improvement in quality of life for the treatment group at 4 weeks. The small number of studies in each subgroup with relevant data limited our ability to explore the most effective bisphosphonates and their relative effectiveness for different primary neoplasms. REVIEWER'S CONCLUSIONS: There is evidence to support the effectiveness of bisphosphonates in providing some pain relief for bone metastases. There is insufficient evidence to recommend bisphosphonates for immediate effect; as first line therapy; to define the most effective bisphosphonates or their relative effectiveness for different primary neoplasms. Bisphosphonates should be considered where analgesics and/or radiotherapy are inadequate for the management of painful bone metastases.

Isolated locoregional recurrences should be treated with locoregional therapy as appropriate.Hormone therapy improves DFS in ER+ve locoregional recurrences.Radiotherapy provides excellent palliation in bone,brain and choroidal metastasis.Bisphosphonates are useful in lytic bone metastasis


BREAST CANCER -
Screening for breast cancer
7
EBM

25. Efficacy of screening mammography. A meta-analysis.
Kerlikowske K, Grady D, et al. JAMA 1995 Jan 11;273(2):149-54

OBJECTIVE. To determine the efficacy of screening mammography by age, number of mammographic views per screen, screening interval, and duration of follow-up. DESIGN. Literature review and meta-analysis. DATA IDENTIFICATION AND ANALYSIS. Literature search of English-language studies reported from January 1966 to October 31, 1993, using MEDLINE, manual literature review, and consultation with experts. A total of 13 studies were selected, and their results were combined using meta-analytic techniques based on the assumption of fixed effects. MAIN RESULTS. The overall summary relative risk (RR) estimate for breast cancer mortality for women aged 50 to 74 years undergoing screening mammography compared with those who did not was 0.74 (95% confidence interval [CI], 0.66 to 0.83). The magnitude of the benefit in this age group was similar regardless of number of mammographic views per screen, screening interval, or duration of follow-up. In contrast, none of the summary RR estimates for women aged 40 to 49 years was significantly less than 1.0, irrespective of screening intervention or duration of follow-up. The overall summary RR estimate in women aged 40 to 49 years was 0.93 (95% CI, 0.76 to 1.13); the summary RR estimate for those studies that used two-view mammography was 0.87 (95% CI, 0.68 to 1.12) compared with 1.02 (95% CI, 0.73 to 1.44) for those studies that used one-view mammography, and for those studies with 7 to 9 years of follow-up, the summary RR estimate was 1.02 (95% CI, 0.82 to 1.27) compared with 0.83 (95% CI, 0.65 to 1.06) for those studies with 10 to 12 years of follow-up. CONCLUSION. Screening mammography significantly reduces breast cancer mortality in women aged 50 to 74 years after 7 to 9 years of follow-up, regardless of screening interval or number of mammographic views per screen. There is no reduction in breast cancer mortality in women aged 40 to 49 years after 7 to 9 years of follow-up. Screening mammography may be effective in reducing breast cancer mortality in women aged 40 to 49 years after 10 to 12 years of follow-up, but the same benefit could probably be achieved by beginning screening at menopause or 50 years of age.

26. Breast Screening: the case for physical examination without mammography. Mittra I. Lancet; 1994, 343 : 342-344.

Many studies have shown that screening for breast cancer can reduce mortality from the disease. Mammography has come to be regarded as the screening method of choice, but evidence suggests that physical examination (PE) is at least as effective in reducing mortality. Mammography detects many non-infiltrating and small, non-palpable tumours, but we do not know whether these would ever cause symptoms or threaten the woman's life. It is doubtful whether the time gained by early mammographic detection confers any survival benefit over PE detection. PE has substantial advantages over mammography in terms of human and economic costs. The question we should be asking is not how to refine mammographic screening but whether we need it at all.

27. Randomized trial of breast self-examination in Shanghai: Final results. Thomas DB, Gao DL, Ray RM, et al: J Natl Cancer Inst; 2002;94:1445-57.

BACKGROUND: Among women who practice breast self-examination (BSE), breast cancers may be detected when they are at an earlier stage and are smaller than in women who do not practice BSE. However, the efficacy of breast self-examination for decreasing breast cancer mortality is unproven. This study was conducted to determine whether an intensive program of BSE instruction will reduce the number of women dying of breast cancer. METHODS: From October 1989 through October 1991, 266,064 women associated with 519 factories in Shanghai were randomly assigned to a BSE instruction group (132,979 women) or a control group (133,085 women). Initial instruction in BSE was followed by reinforcement sessions 1 and 3 years later, by BSE practice under medical supervision at least every 6 months for 5 years, and by ongoing reminders to practice BSE monthly. The women were followed through December 2000 for mortality from breast cancer. Cumulative risk ratios of dying from breast cancer were estimated using Cox proportional hazards models. All statistical tests were two-sided. RESULTS: There were 135 (0.10%) breast cancer deaths in the instruction group and 131 (0.10%) in the control group. The cumulative breast cancer mortality rates through 10 to 11 years of follow-up were similar (cumulative risk ratio for women in the instruction group relative to that in the control group = 1.04, 95% confidence interval = 0.82 to 1.33; P =.72). However, more benign breast lesions were diagnosed in the instruction group than in the control group. CONCLUSIONS: Intensive instruction in BSE did not reduce mortality from breast cancer. Programs to encourage BSE in the absence of mammography would be unlikely to reduce mortality from breast cancer. Women who choose to practice BSE should be informed that its efficacy is unproven and that it may increase their chances of having a benign breast biopsy.

 

 

 

 

 

 

 

 

 

Screening mammography alone is effective in saving lives in postmenopausal women. There is direct evidence that physical examination is as effective as mammogram in a single randomised trial. In premenopausal women, screening by mammography and or physical examination is debatable.



BREAST CANCER -
Familial Breast Cancer
8
EBM

28. Risks of cancer in BRCA1-mutation carriers.
Ford D, et al: Breast Cancer Linkage Consortium.
Lancet 1994;343:692-5
Germline mutations in a gene on chromosome 17q known as BRCA1 are responsible for a large proportion of inherited predispositions to breast and ovarian cancer. In 33 families with evidence of linkage to BRCA1, we estimated the risks of breast and ovarian cancer from the occurrence of second cancers in individuals with breast cancer, and examined the risks of other cancers in BRCA1 carriers. 26 contralateral primary breast cancers occurring more than 3 years after a first breast cancer were observed before age 70, giving an estimated cumulative risk of breast cancer in gene carriers of 87% by age 70.23 primary ovarian cancers occurred in women with a previous breast cancer, resulting in an estimated cumulative risk of ovarian cancer of 44% by age 70.87 cancers other than breast or ovarian cancer were observed in individuals with breast or ovarian cancer and their first-degree relatives compared with 69.3 expected, based on national incidence rates. Significant excesses were observed for colon cancer (estimated relative risk [RR] to gene carriers 4.11 [95% CI 2.36-7.15]) and prostate cancer (3.33 [1.78-6.20]). No significant excesses (or deficits) were noted for cancers of other sites. Our study provides estimates of breast and ovarian cancer risks, which are useful for counseling BRCA1-mutation carriers. It also shows that carriers are at increased risk of colon and prostate cancer, which may be of clinical significance in certain families if the risks are associated with specific mutations.

29. The risk of cancer associated with specific mutations of BRCA1 and BRCA2 among Ashkenazi Jews.
Struewing JP, et al N Engl J Med 1997;336:1401-8

BACKGROUND: Carriers of germ-line mutations in BRCA1 and BRCA2 from families at high risk for cancer have been estimated to have an 85 percent risk of breast cancer. Since the combined frequency of BRCA1 and BRCA2 mutations exceeds 2 percent among Ashkenazi Jews, we were able to estimate the risk of cancer in a large group of Jewish men and women from the Washington, D.C., area. METHODS: We collected blood samples from 5318 Jewish subjects who had filled out epidemiologic questionnaires. Carriers of the 185delAG and 5382insC mutations in BRCA1 and the 6174delT mutation in BRCA2 were identified with assays based on the polymerase chain reaction. We estimated the risks of breast and other cancers by comparing the cancer histories of relatives of carriers of the mutations and noncarriers. RESULTS: One hundred twenty carriers of a BRCA1 or BRCA2 mutation were identified. By the age of 70, the estimated risk of breast cancer among carriers was 56 percent (95 percent confidence interval, 40 to 73 percent); of ovarian cancer, 16 percent (95 percent confidence interval, 6 to 28 percent); and of prostate cancer, 16 percent (95 percent confidence interval, 4 to 30 percent). There were no significant differences in the risk of breast cancer between carriers of BRCA1 mutations and carriers of BRCA2 mutations, and the incidence of colon cancer among the relatives of carriers was not elevated. CONCLUSIONS: Over 2 percent of Ashkenazi Jews carry mutations in BRCA1 or BRCA2 that confer increased risks of breast, ovarian, and prostate cancer. The risks of breast cancer may be overestimated, but they fall well below previous estimates based on subjects from high-risk families.

 

 

Genetic testing provides information in a research setting but its use in routine practice needs much evaluation, social debate & counseling.A negative genetic testing does not completely eliminate breast cancer risk, and a positive test cannot be remedied easily or prevented from being transmitted vertically.
 

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