Identification of a novel truncating PALB2 mutation and analysis of its contribution to early-onset breast cancer in French-Canadian women.

BACKGROUND: PALB2 has recently been identified as a breast cancer susceptibility gene. PALB2 mutations are rare causes of hereditary breast cancer but may be important in countries such as Finland where a founder mutation is present. We sought to estimate the contribution of PALB2 mutations to the burden of breast cancer in French Canadians from Quebec. METHODS: We screened all coding exons of PALB2 in a sample of 50 French-Canadian women diagnosed with either early-onset breast cancer or familial breast cancer at a single Montreal hospital. The genetic variants identified in this sample were then studied in 356 additional women with breast cancer diagnosed before age 50 and in 6,448 newborn controls. RESULTS: We identified a single protein-truncating mutation in PALB2 (c.2323 C>T, resulting in Q775X) in 1 of the 50 high-risk women. This variant was present in 2 of 356 breast cancer cases and in none of 6,440 newborn French-Canadian controls (P = 0.003). We also identified two novel new non-synonymous single nucleotide polymorphisms in exon 4 of PALB2 (c.5038 A>G [I76V] and c.5156 G>T [G115V]). G115V was found in 1 of 356 cases and in 15 of 6,442 controls (P = 0.6). The I76V variant was not identified in either the extended case series or the controls. CONCLUSION: We have identified a novel truncating mutation in PALB2. The mutation was found in approximately 0.5% of unselected French-Canadian women with early-onset breast cancer and appears to have a single origin. Although mutations are infrequent, PALB2 can be added to the list of breast cancer susceptibility genes for which founder mutations have been identified in the French-Canadian population.

Compliance with consensus recommendations for systemic therapy is associated with improved survival of women with node-negative breast cancer.

PURPOSE: The impact of consensus recommendations for systemic therapy on outcome of disease is unclear. We evaluated if compliance with guidelines for systemic adjuvant treatment is associated with improved survival of women with node-negative breast cancer. PATIENTS AND METHODS: The study population included women diagnosed with invasive node-negative breast cancer in Québec, Canada, in 1988 to 1989, 1991 to 1992, and 1993 to 1994. Information was collected by chart review, linkage with administrative databases, and queries to attending physicians. Guidelines from the 1992 St Gallen conference were used as standard of care. Survival was estimated by Kaplan-Meier and Cox proportional hazards analyses. RESULTS: Among 1,541 women, 358 died before December 1999. Median follow-up was 6.8 years. Seven-year event-free and overall survivals were 66% and 81%, respectively. Survival was 88%, 84%, and 74% in women at minimal, moderate, or high risk of recurrence. Virtually all women at minimal risk were treated according to the consensus (98.4% of 370). In comparison, adjusted hazard ratios of death were 1.0 (95% CI, 0.6 to 1.7) and 2.3 (95% CI, 1.3 to 4.0) among women at moderate risk treated according to the consensus or not, respectively. Among women at high risk, adjusted hazard ratios of death were 2.0 (95% CI, 1.4 to 2.8) and 2.7 (95% CI, 1.9 to 3.9), respectively. Both risk category (P <.0005) and compliance with guidelines (P <.0005) were independent significant predictors of survival. CONCLUSION: Treatment according to consensus recommendations is associated with improved survival of women with breast cancer in the community. Promoting the adoption of guidelines for treatment is an effective strategy for disease control.

International prospective evaluation of scintimammography with (99m)technetium sestamibi.

BACKGROUND: The purpose of this study is to evaluate the efficacy of scintimammography with (99m)Technetium-Sestamibi for the diagnosis of breast cancer. METHODS: This was a multicenter prospective cohort clinical trial. A total of 1,734 women were enrolled of whom 1,243 had complete data upon study completion. RESULTS: The mean +/- standard error age of the patients is 56 +/-12 years (with a range of 19 to 94). Mammographic results were classified by the Breast Imaging Reporting and Data System (BIRADS) as 199 (16%) BIRADS 5, 149 (12%) BIRADS 4, 199 (16%) BIRADS 3, and 696 (56%) BIRADS 2 or 1. Scintimammography was positive for 322 (26%) of the patients and negative for 921 (76%). Histopathology showed malignancy for 201 (16%) of the patients. Sensitivity and specificity of scintimammography was estimated 93% and 87% respectively. A positive predictive value (PPV) of 58% with a negative predictive value of 98% were calculated. CONCLUSIONS: The present study suggests that scintimammography with (99m)Technetium-Sestamibi is highly accurate for the detection of breast cancer.

Male breast carcinoma.

OBJECTIVE: To review the epidemiology, presentation, diagnosis, molecular genetics, treatment and prognosis of male breast cancer. DATA SOURCES: Articles, written in English or French, selected from the Medline database (1966 to January 2001), corresponding to the key words "male breast cancer," according to the following criteria: covering institutional experience or comparing diagnostic and treatment modalities, and epidemiologic or general reviews. STUDY SELECTION: Of 198 articles found 50 fulfilled the review criteria. DATA SYNTHESIS: Risk factors included advanced age, a positive family history, Jewish origin, black race, excess exposure to female hormones (Klinefelter's syndrome), environmental exposure (irradiation), alcohol, obesity, higher socioeconomic or higher educational status and childlessness. Gynecomastia remains a controversial factor, this term being used for both a histologic reality and a physical finding. Advanced disease is characterized by pain, bloody discharge and skin ulceration. There is no definitive diagnostic algorithm. Experience with male breast mammography is limited, and imaging is less informative for patients under 50 years of age. Fine-needle aspiration tends to overestimate the rate of malignancy. The commonest histologic finding is infiltrating ductal adenocarcinoma. Treatment includes modified radical mastectomy, followed by cyclophosphamide-methotrexate-5-fluorouracil or 5-fluorouracil-Adriamycin-cyclophosphamide chemotherapy for disease of stage II or greater. Radiotherapy does not seem to add any benefit. The disease is highly receptor-positive; however, many patients discontinue tamoxifen due to side effects. The most important prognostic factors are tumour size, lymphatic invasion and axillary node status. CONCLUSIONS: Because of the low incidence of male breast cancer, advances will be obtained mainly with the rapid transfer of newly gained knowledge in female mammary neoplasia. The increased use of adjuvant chemotherapy combined with tamoxifen postoperatively may have a positive impact on survival. Public education should be oriented toward men at higher risk to reduce the interval between appearance of symptoms and consultation. Rigorous data collection will allow for thorough reporting of risk factors and thus the possibility of characterizing the etiology of this disease.

Surgical margins in cutaneous melanoma (2 cm versus 5 cm for lesions measuring less than 2.1-mm thick).

BACKGROUND: This study addressed the question of whether limited surgery for primary malignant melanoma with a 2-cm margin is as good as a 5-cm margin. An update of a 16-year follow-up is provided. METHODS: Nine European Centers, over a period of 5 years, prospectively randomized 337 patients with melanoma measuring less than 2.1 mm in thickness to undergo a local excision with either a 2-cm or a 5-cm margin. Three hundred twenty-six patients were eligible for statistical analysis. Excluded from the trial were patients older than 70 years; those with melanomas from the toe, nail, or finger; and those with acral-lentiginous melanoma. A separate randomization was performed to independently test an adjuvant treatment with a nonspecific immunostimulant, isoprinosine, compared with observation. The median follow-up time was 192 months (16 years) for the estimation of survival and disease recurrences. RESULTS: There were 22 tumor recurrences in the 2-cm arm and 33 in the 5-cm arm. The median time to disease recurrence was 43 months and 37.6 months, respectively. The 10-year disease-free survival rates were 85% for the group with a 2-cm margin and 83% for the group with a 5-cm margin. There was no difference in the 10-year overall survival rates (87% vs. 86%). Isoprinosine did not demonstrate any activity in this setting. CONCLUSIONS: The authors concluded that for melanoma less than 2.1-mm thick, a margin of excision of 2 cm is sufficient. A larger margin of 5 cm does not appear to have any impact on either the rate or the time to disease recurrence or on survival.