The clinical utility of genetic testing in breast cancer kindreds: a prospective study in families without a demonstrable BRCA mutation.

We report prospectively observed risk for breast cancer in breast cancer kindreds without a demonstrable BRCA1/2 mutation. According to family history, the optimal available member(s) of each breast cancer kindred attending our clinic was tested for BRCA mutations. Women in families without a demonstrable BRCA mutation were subjected to annual mammography. BRCA mutations were demonstrated in 496/2,118 (23 %) breast cancer kindreds. In families without a demonstrable BRCA mutation, a total of 3,161 healthy women aged 25-59 years were prospectively followed for 24,808 observation years. Sixty-four cancers were observed, compared to 34.0 expected (p < 0.01), arriving at a 7.9 % cumulative risk at age 60 compared to 4.0 % in the population [relative risk (RR) = 2.0]. Women with one mother or sister affected ≤50 years and with no other close relatives with breast cancer did not have increased risk (0 cancers observed and 0.6 expected at age 40, 11 cancers observed and 7.9 expected at age 60, p > 0.05). Excluding these, cumulative risk at 60 years was 8.8 % (RR = 2.2). The highest cumulative risk at 60 years was 11.4 %, found in families with two cases ≤55 years (RR = 2.8). In breast cancer kindreds without a demonstrable BRCA mutation, the risk for breast cancer in female first degree relatives was about twice the risk in the general population. Women with one early affected relative only did not have increased risk for early onset breast cancer, while those with more than one young affected relative had close to three times population risk.

Survival of patients with BRCA1-associated breast cancer diagnosed in an MRI-based surveillance program.

We report the 5- and 10-year survival rate of women diagnosed with breast cancer in the context of an annual MRI-based surveillance program. In 2001, as part of a national initiative, women in Norway with a BRCA1 mutation were offered annual screening with breast MRI in addition to mammography. 802 women with a BRCA1 mutation were screened one or more times and followed for a mean of 4.2 years. As of December 2011, 68 of 802 women in the screening program were diagnosed with DCIS or invasive breast cancer (8.5 %), including eight prevalent, 50 incident screen-detected and eight interval cancers. Two latent cancers were detected at prophylactic mastectomy. Sixty-three of the cancers were invasive and five were in situ. The mean tumour size was 1.4 cm (range 0.2-4.5 cm), and 85 % of the patients were node-negative. Ten of the 68 patients died of cancer in the follow-up period. The 5-year breast cancer-specific survival for women with cancer was 75 % (95 % CI 56-86 %) and the 10-year survival was 69 % (95 % CI: 48-83 %). The 5-year survival for women with Stage 1 breast cancer was 82 % compared to 98 % in the population. The 5- and 10-year survival of women with a BRCA1-associated breast cancer detected in a national MRI-based screening program in BRCA1 mutation carriers Norway was less than anticipated. The benefit of annual MRI surveillance on reducing breast cancer mortality in BRCA1 mutation carriers remains to be proven.

High penetrances of BRCA1 and BRCA2 mutations confirmed in a prospective series.

Penetrances of BRCA1 and BRCA2 mutations have been derived from retrospective studies, implying the possibility of ascertainment biases to influence the results.We have followed women at risk for breast and/or ovarian cancer for two decades, and report the prospectively observed age-related annual incidence rates to contract breast or ovarian cancer for women with deleterious BRCA1 or BRCA2 mutations based on 4830 observation years. Patients were grouped according to mutation, age and having/not having had previous cancer.In women not having had previous cancer and aged 40-59 years, the annual incidence rate to contract breast or ovarian cancer in those having the most frequent BRCA1 founder mutations was 4.0%, for women in this age group and with less frequent BRCA1 mutations annual incidence rate was 5.9%, and for women with BRCA2 mutations 3.5%.The observed figures may be used for genetic counseling of healthy mutation carriers in the respective age groups. The results may indicate that less frequent BRCA1 mutations have higher penetrances than BRCA1 founder mutations.

Genetic epidemiology of BRCA mutations--family history detects less than 50% of the mutation carriers.

Ten BRCA mutations were demonstrated to be frequent in the Norwegian population. We present maps verifying the uneven distribution of prevalences according to municipality. We tested incident breast cancer cases treated in Mid-Norway from 1999 onwards for these mutations. Uptake of testing was 97% and 2.5% were demonstrated to be mutation carriers. Ten (77%) were outside families previously known to carry a mutation. Ten (77%) did not meet clinical criteria to be selected for mutation testing. We tested incident ovarian cancer cases in South-West Norway from 2001 onwards. Uptake of testing was 80% and 23% were mutation carriers. Twenty-one (88%) were outside families previously known. Twelve (67%) did not meet clinical criteria to be selected for testing. All patients with mutation collaborated actively to give our offer of predictive genetic testing to their relatives. No complaint on the activity was received.

Sensitivity of MRI versus conventional screening in the diagnosis of BRCA-associated breast cancer in a national prospective series.

We wanted to compare the sensitivities of breast magnetic resonance imaging (MRI) and the conventional screening programme consisting of mammography (XRM) +/- ultrasound for early diagnosis of breast cancer in BRCA1/2 mutation carriers. BRCA1/2 mutation carriers were examined prospectively by both breast MRI and XRM +/- ultrasound. Eight hundred and sixty-seven MRI examinations were carried out in 445 BRCA1 and 46 BRCA2 mutation carriers. A total of 25 cancers were observed, five (20%) as interval cancers. At the time of diagnosis, sensitivity to detect cancer was 19/22=86% for MRI and 12/24=50% for XRM. Twenty-one were examined by both methods at the time of diagnosis. In the19 BRCA1 mutation carriers among them, MRI had a sensitivity of 1/3(33%) to diagnose DCIS and 15/16 (94%) among the invasive cancers. For XRM the sensitivities were 1/3(33%) for DCIS, 3/7(42%) for pT1b, 3/6(50%) for pT1c, and 3/3/100%) for pT2. In the two BRCA2 mutation carriers, both were demonstrated by breast MRI, neither was detected by XRM. Breast MRI had increased sensitivity compared to XRM to diagnose all cancers staged less than pT2.