Context Most hereditary ovarian cancers are associated with germline mutations in BRCA1 or BRCA2. Attempts to define the clinical significance of BRCA mutation status in ovarian cancer have produced conflicting results, especially regarding survival.Objective To determine whether hereditary ovarian cancers have distinct clinical and pathological features compared with sporadic (nonhereditary) ovarian cancers. Design and SettingRetrospective cohort study of a consecutive series of 933 ovarian cancers diagnosed and treated at our institution, which is a comprehensive cancer center as designated by the National Cancer Institute, over a 12-year period (December 1986 to August 1998). PatientsThe study was restricted to patients of Jewish origin because of the ease of BRCA1 and BRCA2 genotyping in this ethnic group. From the 189 patients who identified themselves as Jewish, 88 hereditary cases were identified with the presence of a germline founder mutation in BRCA1 or BRCA2. The remaining 101 cases from the same series not associated with a BRCA mutation and 2 additional groups (Gynecologic Oncology Group protocols 52 and 111) with ovarian cancer from clinical trials (for the survival analysis) were included for comparison.Main Outcome Measures Age at diagnosis, surgical stage, histologic cell type and grade, and surgical outcome; and response to chemotherapy and survival for advancedstage (III and IV) cases. ResultsHereditary cancers were rarely diagnosed before age 40 years and were common after age 60 years, with mean age at diagnosis being significantly younger for BRCA1-vs BRCA2-linked patients (54 vs 62 years; P= .04). Histology, grade, stage, and success of cytoreductive surgery were similar for hereditary and sporadic cases. The hereditary group had a longer disease-free interval following primary chemotherapy in comparison with the nonhereditary group, with a median time to recurrence of 14 months and 7 months, respectively (PϽ.001). Those with hereditary cancers had improved survival compared with the nonhereditary group (P=.004). For stage III cancers, BRCA mutation status was an independent prognostic variable (P = .03). ConclusionsAlthough BRCA-associated hereditary ovarian cancers in this population have surgical and pathological characteristics similar to those of sporadic cancers, advancedstage hereditary cancer patients survive longer than nonhereditary cancer patients. Age penetrance is greater for BRCA1-linked than for BRCA2-linked cancers in this population.

Prognostic factors have been examined in 644 patients with tumor-node-metastasis (TNM) stage T1 breast carcinoma treated by mastectomy and followed for a median of 18.2 years. Overall, 148 patients (23%) died of recurrent breast carcinoma. Eighteen (3%) were alive with recurrent disease and 478 (74%) were alive or died of other causes without recurrence. Unfavorable clinicopathologic features were larger tumor size (1.1 to 2.0 cm v less than or equal to 1 cm), perimenopausal menstrual status, the number of axillary lymph node metastases, poorly differentiated grade, presence of lymphatic tumor emboli (LI) in breast tissue near the primary tumor, blood vessel invasion (BVI), and an intense lymphoplasmacytic reaction around the tumor. Median survival after recurrence for the entire series was 2 years. This was not significantly influenced by tumor size, the number of axillary nodal metastases, the type of treatment for recurrence, or the interval to recurrence. The proportions surviving 5 and 10 years after recurrence were 17% and 5%, respectively. Among T1N0M0 cases, the chance of a local recurrence was 2.8% within 20 years. Median survival of T1N0M0 cases after local recurrence (4.5 years) was significantly longer than after systemic recurrence (1.5 years). A similar trend (3.7 v 2.0 years), not statistically significant, was seen in T1N1M0 patients, who had a 6.5% chance of local recurrence within 20 years. Median survival following systemic recurrence detected 10 or more years after diagnosis in T1N0M0 and in T1N1M0 patients was significantly longer than the median survival for systemic recurrences found in the first decade of follow-up. This difference did not apply following local recurrence in either T1N0M0 or T1N1M0 cases. It is evident that patients with T1 breast carcinoma can be subdivided into differing prognostic groups and this must be taken into account when considering the role of adjuvant chemotherapy for stage I disease. Systemic adjuvant treatment may prove to be beneficial for patients with unfavorable prognostic factors, while women with an especially low risk for recurrence (eg, T1N0M0 tumor 1.0 cm or less) might be spared such treatment.

This study was undertaken to investigate the long-term survival and the probability of "cure" in a group of 644 patients treated by mastectomy for T1 breast carcinoma. After a median follow-up of 18.2 years, 23% were dead of recurrent breast carcinoma, 3% were alive with recurrent disease, and 74% had not experienced a recurrence. The probability of recurrence was directly related to the initial extent of the disease. Overall, 16% of recurrences and 25% of deaths due to disease occurred in the second decade of follow-up. The proportion of recurrences detected in the second decade was inversely related to the stage of the primary tumor at diagnosis. When stratified by tumor size, T1N0M0 patients with tumors 1.0 cm or less in diameter had a significantly better 20-year recurrence-free survival (86%) than did T1N0M0 patients with tumors 1.1 to 2.0 cm (69%). When observed and expected survival curves were compared by the method of Brinkley and Haybittle, it appeared that 80% of T1N0M0 patients with tumors 1 cm or less might be cured at 20 years, whereas for those in the 1.1- to 2-cm group, the proportion cured was indeterminate, but might be as high as 70%. A potentially cured group could not be identified among T1N1M0 patients, but an estimated 52% of these patients did not have a recurrence within the nearly 20-year follow-up period. These data are important when one considers the proper role of adjuvant therapy for stage I disease. Patients with tumors larger than 1 cm and those with axillary lymph node metastases may have an improved recurrence-free survival as a result of systemic adjuvant treatment, while women in the T1N0M0 group with an especially favorable recurrence-free survival, particularly those with tumors 1 cm in diameter or smaller, might be spared adjuvant therapy.

Recurrence and survival data at 10 years were examined for 147 women with single axillary lymph node metastases found in a modified radical or standard radical mastectomy. The cases were identified through a review of all patients with primary operable breast cancer treated at Memorial Hospital from 1964 to 1970. The patients were stratified into groups according to size of the primary tumor and of the metastatic deposit (micro less than or equal to 2 mm; macro greater than 2 mm) as well as level of the positive node. In the entire series, there was a significantly poorer prognosis among those patients with single macrometastases (30/77 patients; 39% recurrence rate) when compared with those having micrometastases (17/70 patients: 24% recurrence rate). A major prognostic difference emerged after stratification by tumor size. Within the first six years of the follow-up period, T1 patients with negative nodes and those with single micrometastases had similar survival curves, significantly better than those with macrometastases. However, at 12 years, the survival rats of those patients with either a micro- or macrometastases was nearly identical, and significantly worse than for those patients with negative lymph nodes. On the other hand, among women with primary tumors 2.1-5.0 cm (T2), patients with negative lymph nodes or single micrometastases had survival curves that did not differ significantly throughout the course of the follow-up period. Both had an outcome significantly better than observed for patients with macrometastases. These findings have important implications for our understanding of the clinical behaviour of breast cancer and for the stratification of patients entered into randomized treatment trials.

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