Ira J. Bleiweiss

Frequency and Carrier Risk Associated with Common BRCA1 and BRCA2 Mutations in Ashkenazi Jewish Breast Cancer Patients

Based on breast cancer families with multiple and/or early-onset cases, estimates of the lifetime risk of breast cancer in carriers of BRCA1 or BRCA2 mutations may be as high as 85%. The risk for individuals not selected for family history or other risk factors is uncertain. We determined the frequency of the common BRCA1 (185delAG and 5382insC) and BRCA2 (6174delT) mutations in a series of 268 anonymous Ashkenazi Jewish women with breast cancer, regardless of family history or age at onset. DNA was analyzed for the three mutations by allele-specific oligonucleotide hybridization. Eight patients (3.0%, 95% confidence interval [CI] 1.5%-5.8%) were heterozygous for the 185delAG mutation, two (0.75%, 95% CI 0.20-2.7) for the 5382insC mutation, and eight (3.0%, 95% CI 1.5-5.8) for the 6174delT mutation. The lifetime risk for breast cancer in Ashkenazi Jewish carriers of the BRCA1 185delAG or BRCA2 6174delT mutations was calculated to be 36%, approximately three times the overall risk for the general population (relative risk 2.9, 95% CI 1.5-5.8). For the 5382insC mutation, because of the low number of carriers found, further studies are necessary. The results differ markedly from previous estimates based on high-risk breast cancer families and are consistent with lower estimates derived from a recent population-based study in the Baltimore area. Thus, presymptomatic screening and counseling for these common mutations in Ashkenazi Jewish women not selected for family history of breast cancer should be reconsidered until the risk associated with these mutations is firmly established, especially since early diagnostic and preventive-treatment modalities are limited.

Lumpectomy margins, reexcision, and local recurrence of breast cancer

BACKGROUND The diagnosis of breast cancer is often made by excisional biopsy without margin assessment for mammographic findings or palpable masses. Many patients treated with breast conservation undergo reexcision to obtain clear margins although the relationship between clear margins and local recurrence remains controversial. METHODS Patients undergoing breast conservation and adjuvant radiation therapy with complete follow-up over 5 years were studied. Factors associated with obtaining clear histopathologic margins and undergoing reexcision to obtain clear margins were studied in relation to the risk of local recurrence. RESULTS Clear biopsy margins were associated with diagnosis by fine-needle aspiration cytology (fine-needle aspiration 42%, spot localization 11%, excisional biopsy 10%; P <0.001). Reexcision was significantly related to diagnostic method (spot localization 63%, excisional biopsy 36%, fine-needle aspiration 10%; P <0.001), first margin status (clear 0%, close 11%, positive 46%, unknown 48%; P <0.001), patient age (54 years for reexcised patients and 58 for non-reexcised patients; P <0.001), and tumor size (mean tumor size 1. 4 cm for reexcised patients and 1.7 cm for non-reexcised patients; P = 0.003). Patients undergoing reexcision were significantly more likely to be diagnosed by spot localization, have nonnegative excisional biopsy margins, be younger, and have smaller tumors than patients not undergoing reexcision. Local recurrence was not significantly related to margin status (8% with clear margins, 7% with positive margins, 19% with close margins, and 11% with unknown margins) or reexcision (10% local recurrence rate for patients with negative final margins after reexcision and 12% with positive, close or unknown first margin without reexcision). Estrogen receptor status was the only variable related to local recurrence in Cox proportional hazards model (P = 0.009). Estrogen receptor negative patients with nonnegative margins experienced a 20% rate of local recurrence compared with 10% for estrogen receptor negative patients with negative margins and 7% for estrogen receptor positive patients regardless of margin status (P = 0.021). CONCLUSIONS Clear excision margins are facilitated by preoperative diagnosis by fine-needle cytology. For patients with nonnegative margins, reexcision was more commonly performed in young patients with small tumors diagnosed by spot localization biopsy. The relationship of local recurrence to margins and reexcision was not statistically significant. Estrogen receptor negative tumors with nonnegative margins had a significantly higher rate of local recurrence than estrogen receptor negative tumors with clear margins and estrogen receptor positive tumors regardless of margin status.

BRCA2 mutation-associated breast cancers exhibit a distinguishing phenotype based on morphology and molecular profiles from tissue microarrays

A distinct morphologic and molecular phenotype has been reported for BRCA1-associated breast cancers; however, the phenotype of BRCA2-associated breast cancers is less certain. To comprehensively characterize BRCA2-associated breast cancers we performed a retrospective case control study using tumors accrued through the Breast Cancer Family Registry. We examined the tumor morphology and hormone receptor status in 157 hereditary breast cancers with germline mutations in BRCA2 and 314 control tumors negative for BRCA1 and BRCA2 mutations that were matched for age and ethnicity. Tissue microarrays were constructed from 64 BRCA2-associated and 185 control tumors. Tissue microarray sections were examined for HER2/neu protein overexpression, p53 status and the expression of basal markers, luminal markers, cyclin D1, bcl2, and MIB1 by immunohistochemistry. The majority of BRCA2-associated tumors and control tumors were invasive ductal, no special-type tumors. In contrast to control tumors, BRCA2-associated cancers were more likely to be high grade (P<0.0001) and to have pushing tumor margins (P=0.0005). Adjusting for grade, BRCA2-associated tumors were more often estrogen receptor positive (P=0.008) and exhibited a luminal phenotype (P=0.003). They were less likely than controls to express the basal cytokeratin CK5 (P=0.03) or to overexpress HER2/neu protein (P=0.06). There was no difference in p53, bcl2, MIB1, or cyclin D1 expression between BRCA2-associated and control tumors. We have demonstrated, in the largest series of BRCA2-associated breast cancers studied to date, that these tumors are predominantly high-grade invasive ductal carcinomas of no special type and they demonstrate a luminal phenotype despite their high histologic grade.

Molecular subtypes of breast cancer in relation to paclitaxel response and outcomes in women with metastatic disease: Results from CALGB 9342

IntroductionThe response to paclitaxel varies widely in metastatic breast cancer. We analyzed data from CALGB 9342, which tested three doses of paclitaxel in women with advanced disease, to determine whether response and outcomes differed according to HER2, hormone receptor, and p53 status.MethodsAmong 474 women randomly assigned to paclitaxel at a dose of 175, 210, or 250 mg/m2, adequate primary tumor tissue was available from 175. Immunohistochemistry with two antibodies and fluorescence in situ hybridization were performed to evaluate HER2 status; p53 status was determined by immunohistochemistry and sequencing. Hormone receptor status was obtained from pathology reports.ResultsObjective response rate was not associated with HER2 or p53 status. There was a trend toward a shorter median time to treatment failure among women with HER2-positive tumors (2.3 versus 4.2 months; P = 0.067). HER2 status was not related to overall survival (OS). Hormone receptor expression was not associated with differences in response but was associated with longer OS (P = 0.003). In contrast, women with p53 over-expression had significantly shorter OS than those without p53 over-expression (11.5 versus 14.4 months; P = 0.002). In addition, triple negative tumors were more frequent in African-American than in Caucasian patients, and were associated with a significant reduction in OS (8.7 versus 12.9 months; P = 0.008).ConclusionNone of the biomarkers was predictive of treatment response in women with metastatic breast cancer; however, survival differed according to hormone receptor and p53 status. Triple negative tumors were more frequent in African-American patients and were associated with a shorter survival.

Lymphatic Invasion, Tumor Size, and Age Are Independent Predictors of Axillary Lymph Node Metastases in Women With T1 Breast Cancers

OBJECTIVE To identify characteristics of the primary tumor highly associated with lymph node metastases. SUMMARY BACKGROUND DATA Recent enthusiasm for limiting axillary lymph node dissection (ALND) in women with breast cancer may increase the likelihood that nodal metastases will be missed. Identification of characteristics of primary tumors predictive of lymph node metastases may prompt a more extensive surgical and pathologic search for metastases in patients with negative sentinel lymph nodes or limited ALND. METHODS The authors studied 850 consecutive patients who underwent ALND for T1 breast cancer. Age, tumor size, histopathologic diagnosis, tumor differentiation, presence of lymphatic invasion, and estrogen and progesterone receptor results were studied prospectively. Stepwise logistic regression was used to identify variables independently associated with axillary lymph node metastases. RESULTS Lymphatic invasion, tumor size, and age were independently associated with lymph node metastases. Fifty-one percent of the 181 patients with lymphatic invasion had axillary lymph node metastases, compared with 19% of the 669 patients without lymphatic invasion. Thirty-five percent of the 470 patients with tumors >1 cm had nodal involvement compared with 13% of the 380 patients with smaller cancers. Thirty-seven percent of the 63 women younger than age 40 had lymph node involvement compared with 25% of the 787 women older than age 40. Significant correlations were noted between lymphatic invasion and patient age and between lymphatic invasion and tumor size. The proportion of tumors with lymphatic invasion decreased progressively with increasing age and increased with increasing tumor size. CONCLUSIONS Axillary lymph node metastases are most significantly related to lymphatic invasion in the primary tumor, followed, in order of significance, by tumor size and patient age. Axillary nodal metastases should be suspected in the presence of lymphatic invasion of large tumors in young patients.

Mammographic Appearance of Nonpalpable Breast Cancer Reflects Pathologic Characteristics

ObjectiveTo study the relationship of mammographic appearance of nonpalpable breast cancer to the pathologic characteristics. Summary Background DataThe mammographic appearance of nonpalpable breast cancer may be associated with pathologic variables having prognostic significance, which could influence clinical management. MethodsThe authors correlated the mammographic appearance and pathologic characteristics of 543 nonpalpable malignancies diagnosed in a single institution between July 1993 and July 1999. Cancers were divided into four groups based on mammographic presentation: mass, calcification, mass with calcification, and architectural distortion. ResultsThe majority of masses (95%), masses with calcifications (68%), and architectural distortions (79%) were due to invasive cancers, whereas the majority of calcifications (68%) were due to ductal carcinoma in situ (DCIS). Among invasive cancers, calcifications were associated with more extensive intraductal carcinoma, more Her2/neu immunoreactivity, and more necrosis of DCIS. Lymphatic invasion was more common in cancers presenting as a mass with calcifications. Sixty-nine percent of DCIS associated with invasive cancers presenting as calcifications were of high grade according to the European Organization for Research and Treatment of Cancer. Calcifications in noninvasive tumors were associated with necrosis in DCIS. Two thirds of cancers presenting as architectural distortion had positive margins (65%) compared with 35% to 37% of other mammographic presentations. Mammographic presentation was not significantly related to tumor differentiation or estrogen or progesterone receptor status. The ratio of invasive to noninvasive malignancies increased progressively with increasing age from 1:1 in patients younger than 50 years of age to 3:1 in patients older than 70 years, whereas the proportion presenting as calcifications declined from 63% in patients younger than 50 years to 26% in patients older than 70 years. ConclusionsMalignancies presenting as calcifications on mammography are most commonly DCIS. When invasive malignancies presented as calcifications, the calcifications were associated with accompanying high-grade DCIS, and the invasive cancers were often Her2/Neu positive. Mammographic masses with calcifications were associated with lymphatic invasion. Excisional biopsy margins were most commonly positive with architectural distortions. The mammographic appearance of nonpalpable malignancies is related to pathologic characteristics with prognostic value, which varies with patient age and influences clinical management.

The consequence of undertreating breast cancer in the elderly.

BACKGROUND: Recent studies have noted that a large fraction of elderly patients do not receive conventional treatment for breast cancer. The consequences of undertreatment of the elderly have not been adequately assessed. STUDY DESIGN: The senior author’s database (PIT) was used to identify women undergoing potentially curative operations for breast cancer between 1978 and 1998. Risk factors, presentation, pathologic findings, treatment, and outcomes of 206 women aged over 70 years were compared with those of 920 younger patients. In addition, conventionally treated and “undertreated” elderly patients were identified, and their characteristics and outcomes were compared. RESULTS: Older patients’ cancers were more often visible on mammography, usually as a mass; younger patients’ mammograms were less frequently positive, presenting more often with calcifications (p = 0.002). Cancers of the elderly were better differentiated (p < 0.001) and more likely to be estrogen- and progesterone-receptor positive (p < 0.001; p = 0.007). Patients over 70 had fewer mastectomies (19% versus 33%; p < 0.001) and were also less likely to undergo axillary node dissection (71% versus 81%, p = 0.006), postoperative radiation (69% versus 92%, p < 0.001), and chemotherapy (18% versus 48%, p < 0.001). Fifty-seven percent of older patients were treated with tamoxifen compared with 36% of younger patients (p < 0.001). Elderly patients’ rates of local and distant recurrence were comparable to those of younger patients after both mastectomy and breast conservation. Ninety-eight patients (54%) over 70 were undertreated by conventional criteria. Undertreated elderly patients were significantly older (78 versus 76 years, p = 0.003), were diagnosed with excisional biopsy more often (69% versus 57%, p = 0.069) and with fine-needle aspiration less frequently (22% versus 38%, p = 0.069), and were more likely to have breast conservation (90% versus 73%, p = 0.004). Local and distant disease-free survival rates of both groups were comparable. Tamoxifen treatment significantly reduced the chance of developing distant metastasis in node-negative elderly patients with invasive tumors (p = 0.028). Omission of chemotherapy had no impact on disease control in the elderly. Axillary node status and estrogen-receptor status were significantly related to local disease-free survival, and axillary node status was significantly related to distant disease-free survival in multivariate analysis in the elderly. CONCLUSIONS: Elderly breast cancer patients are frequently treated with breast conservation, omitting axillary dissection, radiation therapy, and chemotherapy. Despite undertreatment by conventional criteria, the rates of local recurrence and distant metastasis are not increased in comparison with conventionally treated elderly patients. Tamoxifen should be administered to elderly breast cancer patients with invasive tumors because it significantly improves distant control.

Lobular neoplasia on core needle biopsy does not require excision

Lobular neoplasia (LN), encompassing atypical lobular hyperplasia (ALH) and lobular carcinoma in situ (LCIS), is often an incidental finding on core needle biopsies (CNBs) performed in instances of radiologic densities and/or calcifications. Because LN is generally considered a risk factor for breast carcinoma, the utility of subsequent excision is controversial.

Predictors of nonsentinel lymph node metastasis in breast cancer patients

BACKGROUND In order to define a future subset of breast cancer patients in whom the axilla may be staged by sentinel lymph node biopsy alone, the conditions under which nonsentinel axillary lymph node metastases occur must be delineated. METHODS A prospective database including 212 breast cancer patients who underwent sentinel lymph node biopsy followed by completion axillary dissection at our institution was reviewed. A multivariate, logistic, stepwise regression was performed to evaluate the relationship between nonsentinel lymph node metastasis and patient age, primary tumor size, presence of lymphatic invasion, use of radioisotope to identify the sentinel node and degree of metastasis in the sentinel node. RESULTS Tumor size greater than 2 cm, lymphatic invasion of the primary tumor, macrometastasis in the sentinel node, and use of radioisotope all positively correlated independently with metastasis in the nonsentinel lymph node (P = 0.0001, P = 0.0483, P = 0.0008, P = 0.0271, respectively). CONCLUSIONS Predictors of nonsentinel axillary node metastasis exist and are important in defining those patients in whom a sentinel lymph node biopsy alone may not be adequate.

The Consequence of Multiple Re-Excisions to Obtain Clear Lumpectomy Margins in Breast Cancer Patients

BackgroundMicroscopically clear lumpectomy margins are critical for optimizing local control with breast conservation for cancer. Re-excisions are often necessary to achieve clear surgical margins. Factors that contribute to nonnegative margins and necessitate re-excision may increase the risk of local recurrence.MethodsPatients who were treated with breast conservation for breast cancers were identified from a prospective database maintained by one of the authors. Factors associated with local recurrence were evaluated in 459 consecutive patients with attention to the number of re-excisions required to obtain clear margins.ResultsTwenty-eight patients (5%) developed local recurrences at a mean follow-up of 78 months. In multivariate analysis, local recurrence was most significantly associated with the omission of radiotherapy (19% vs. 5%; relative risk [RR], 3.64; 95% confidence interval, 1.6–8.2), followed by young age (52 vs. 58; 95% confidence interval, −.83 to −10.6 years) and the number of re-excisions required to obtain clear margins (none, 4%; one, 7% [RR, 2.05; 95% confidence interval, .86–4.89]; two or more, 17% [RR, 5.20; 95% confidence interval, 1.44–18.8]). Tumor size, the number of involved nodes, pathology, and adjuvant chemotherapy were not significantly related to local recurrence.ConclusionsThe risk of local recurrence after breast conservation for breast cancer increases progressively with the number of re-excisions needed to achieve clear margins. Patients in whom the cancer is fully excised with clear margins in the first excision will have less of a chance of local recurrence compared with patients who need further re-excision to achieve clear margins.