Isabella Marchi

Breast cancer screening in women at increased risk according to different family histories: an update of the Modena Study Group experience

BackgroundBreast cancer (BC) detection in women with a genetic susceptibility or strong family history is considered mandatory compared with BC screening in the general population. However, screening modalities depend on the level of risk. Here we present an update of our screening programs based on risk classification.MethodsWe defined different risk categories and surveillance strategies to identify early BC in 1325 healthy women recruited by the Modena Study Group for familial breast and ovarian cancer. Four BC risk categories included BRCA1/2 carriers, increased, intermediate, and slightly increased risk. Women who developed BC from January 1, 1994, through December 31, 2005 (N = 44) were compared with the number of expected cases matched for age and period. BRCA1/2 carriers were identified by mutational analysis. Other risk groups were defined by different levels of family history for breast or ovarian cancer (OC). The standardized incidence ratio (SIR) was used to evaluate the observed and expected ratio among groups. All statistical tests were two-sided.ResultsAfter a median follow-up of 55 months, there was a statistically significant difference between observed and expected incidence [SIR = 4.9; 95% confidence interval (CI) = 1.6 to 7.6; p < 0.001]. The incidence observed among BRCA carriers (SIR = 20.3; 95% CI = 3.1 to 83.9; P < 0.001), women at increased (SIR = 4.5; 95% CI = 1.5 to 8.3; P < 0.001) or intermediate risk (SIR = 7.0, 95% CI = 2.0 to 17.1; P = 0.0018) was higher than expected, while the difference between observed and expected among women at slightly increased risk was not statistically significant (SIR = 2.4, 95% CI = 0.9 to 8.3; P = .74).ConclusionThe rate of cancers detected in women at high risk according to BRCA status or strong family history, as defined according to our operational criteria, was significantly higher than expected in an age-matched general population. However, we failed to identify a greater incidence of BC in the slightly increased risk group. These results support the effectiveness of the proposed program to identify and monitor individuals at high risk, whereas prospective trials are needed for women belonging to families with sporadic BC or OC.

A rapid genetic counselling and testing in newly diagnosed breast cancer is associated with high rate of risk-reducing mastectomy in BRCA1/2-positive Italian women

BACKGROUND Risk-reducing mastectomy (RRM) decreases breast cancer (BC) risk in BRCA1/2 mutation carriers by up to 95%, but the Italian attitude towards this procedure is reluctant. PATIENTS AND METHODS This is an observational study with retrospective design, using quantitative and qualitative research methods, aimed at evaluating the attitude towards RRM by rapid genetic counselling and testing (RGCT), at the time of BC diagnosis, compared with traditional genetic counselling and testing (TGCT), after previous BC surgery. Secondary aims were to investigate patient satisfaction after RRM and the rate of occult tumour in healthy breasts. A total of 1168 patients were evaluated: 1058 received TGCT, whereas 110 underwent RGCT. RESULTS In TGCT, among 1058 patients, 209 (19.7%) mutation carriers were identified, with the rate of RRM being 4.7% (10 of 209). Conversely in RGCT, among 110 patients, 36 resulted positive, of which, 15 (41.7%) underwent bilateral mastectomy at the BC surgery time, showing an overall good satisfaction, measured by interpretative phenomenological analysis 12 months after the intervention. CONCLUSIONS Our study shows that RGCT in patients with a hereditary profile is associated with a high rate of RRM at the BC surgery time, this being the pathway offered within a multidisciplinary organization.

Favourable ten-year overall survival in a Caucasian population with high probability of hereditary breast cancer

BackgroundThe purpose of our study was to compare differences in the prognosis of breast cancer (BC) patients at high (H) risk or intermediate slightly (IS) increased risk based on family history and those without a family history of BC, and to evaluate whether ten-year overall survival can be considered a good indicator of BRCA1 gene mutation.MethodsWe classified 5923 breast cancer patients registered between 1988 and 2006 at the Department of Oncology and Haematology in Modena, Italy, into one of three different risk categories according to Modena criteria. One thousand eleven patients at H and IS increased risk were tested for BRCA1/2 mutations. The overall survival (OS) and disease free survival (DFS) were the study end-points.ResultsEighty BRCA1 carriers were identified. A statistically significantly better prognosis was observed for patients belonging to the H risk category with respect to women in the IS and sporadic groups (82% vs.75% vs.73%, respectively; p < 0.0001). Comparing only BRCA1 carriers with BRCA-negative and sporadic BC (77% vs.77% vs.73%, respectively; p < 0.001) an advantage in OS was seen.ConclusionsPatients belonging to a population with a high probability of being BRCA1 carriers had a better prognosis than those with sporadic BC. Considering these results, women who previously had BC and had survived ten years could be selected for BRCA1 analysis among family members at high risk of hereditary BC during genetic counselling. Since only 30% of patients with a high probability of having hereditary BC have BRCA1 mutations, selecting women with a long term survival among this population could increase the rate of positive analyses, avoiding the use of expensive tests.

Increased Incidence of Breast Cancer in Postmenopausal Women with High Body Mass Index at the Modena Screening Program

Purpose We conducted a study to evaluate the relationship between body mass index (BMI) and the risk of breast cancer (BC) and outcome in a population of 14,684 women aged 55 to 69 years eligible to participate in the Mammography Screening Program (MSP) in the Province of Modena, Italy. Methods The study population was drawn from women who underwent mammography screening between 2004 and 2006 in the Province of Modena. Women were subdivided into obese, overweight, and normal-weight categories according to BMI and followed until July 31, 2010, to evaluate the BC incidence. The clinicopathological characteristics of BC were also evaluated in different groups of patients classified according to BMI. After BC diagnosis, patients were followed for a median period of 65 (range, 2–104) months. Second events (recurrences and second tumors) were recorded, and the 5-year event-free survival (EFS) was calculated. Results After a period of 73 months, 366 cases of BC were diagnosed. Compared with normal-weight women, obese women had a significantly higher incidence of BC (relative risk [RR], 1.32; p=0.040) (RR=1), larger tumors (27% of tumors were larger than T2 size), and more nodal involvement (38.5% of tumors were node-positive). Furthermore, a significantly higher rate of total events was seen in obese women compared with overweight and normal-weight patients, respectively (17.9% vs. 11.4% vs. 10.8%, p=0.032). The 5-year EFS was 89.0%, 89.0%, and 80.0% for normal-weight, overweight, and obese patients, respectively. Conclusion We observed a significantly higher risk of BC in obese women among those eligible to participate in the MSP in the Province of Modena. Finally, obese women had more second events and poorer EFS compared to nono bese women.

BRCA1 p.His1673del is a pathogenic mutation associated with a predominant ovarian cancer phenotype

We have investigated the clinical significance of the BRCA1 variant p.His1673del in 14 families from the Emilia-Romagna region of Italy, including 20 breast and 23 ovarian cancer cases; four families displayed site-specific ovarian cancer. The variant, absent in human variation databases, has been reported three times in BRCA1 specific databases; all probands shared the same rare haplotype at the BRCA1 locus, consistent with a common ancestor. The multifactorial likelihood method by Goldgar, used to estimate the probability of the variant being causative, gave a ratio of 2,263,474:1 in favor of causality. Moreover, in silico modeling suggested that His1673-lacking BRCA1 protein may have a decreased ability to bind BARD1 and other related proteins. All six ovarian carcinomas and two out of four breast carcinomas available showed a loss of the BRCA1 wild-type allele, which in three out of four ovarian carcinomas analyzed by FISH was associated with duplication of the chromosome 17 containing the variant. Although the pathogenicity of the allele is strongly supported by the multifactorial ratio, we cannot exclude that p.His1673del is not itself deleterious, but is linked to another undetected mutation on the same ancestral allele.

Evaluation of Transvaginal Ultrasound plus CA-125 Measurement and Prophylactic Salpingo-Oophorectomy in Women at Different Risk Levels of Ovarian Cancer: The Modena Study Group Cohort Study

Objective: To evaluate the effectiveness of transvaginal ultrasound (TVU) and serum CA-125 measurement in women at different risk of developing ovarian cancer/fallopian tube cancer (OC/FTC) and the incidence of primary peritoneal cancer (PPC) after risk-reducing salpingo-oophorectomy (RRSO). Methods: Between 2002 and 2014, 661 women at different risk of OC/FTC/PPC due to a family history or BRCA1/2 gene mutation were offered TVU and CA-125 measurement or RRSO as prevention strategies. The detection rate of OC/FTC/PPC was evaluated, and the sensitivity and specificity for CA-125 measurement and TVU were calculated. Survival and event analysis was performed for diagnosed patients. Results: After a median follow-up of 112 months, 12 OC/FTC/PPC cases were detected (2.6/1,000 persons/year). The screening sensitivity was 70%, with 73% for BRCA carriers. Six (50%) of 12 cancers were stage I or II. Among 41 women who underwent RRSO, 2 BRCA1 carriers developed a PPC (4.9%). At 61-month follow-up, overall and event-free survival were 75 and 64%, respectively. Conclusions: The cancer detection rate in women with BRCA mutation or a strong family history supports the effectiveness of our surveillance program for early diagnosis. Screening for women at lower risk of OC/FTC is not recommended. A residual risk of PPC after RRSO remains for BRCA1 carriers.

Breast ultrasonography (BU) in the screening protocol for women at hereditary-familial risk of breast cancer: has the time come to rethink the role of BU according to different risk categories?: Ultrasound in hereditary-familial breast cancer

This article evaluates the breast cancer (BC) screening efficacy of biannual ultrasound (US) in three different risk categories. In a single‐center, prospective, nonrandomized comparison study, BRCA mutation carriers and women with high risk (HR) or intermediate risk (IR) received mammography (MMG), ultrasound, (US) and Magnetic Resonance Imaging (MRI), scheduled according to the risk categories. Single and combined sensitivity were evaluated in specific groups of risk and the US performance at six‐monthly interval was notably considered. Among 2,313 asymptomatic women at different risk (136 mutation carriers, 1,749 at HR and 428 at IR) 211 developed a BC, of which 193 (91.5%) were screen detected BC (SDBC) and 18 (8.5%) were interval BC (IBC). The SDBC detection rate (DR) was 11.2 per 1.000 person‐years (37.9, 8.5 and 16.1 for BRCA, HR and IR, respectively); 116 BC were detected by MMG (DR = 6.6 × 1,000 persons‐years), 62 by US (DR = 3.6 × 1,000 persons‐years) and 15 by MRI, that was applied only in 60 BRCA women (DR = 37 × 1,000 persons‐years). At the six‐monthly US, 52 BC were detected (DR = 3.0 × 1,000 persons/years), of which 8 were BRCA‐related. The most sensitive technique was MRI (93.7%) followed by MMG (55%) and US (29.4%). Combined sensitivity for MMG plus US was 100% in HR and 80.4% for IR women (p < 0.01). In BRCA mutated patients, MRI alone with annual US performed after six months, could be offered. In HR patients, MMG plus biannual US provide the most sensitive diagnosis and for IR group an annual MMG could be sufficient.

Abstract 161: Effect of Simvastatin and Nimesulide on inflammation and cardiovascular risk biomarkers in a phase II breast cancer prevention trial.

Background: Almost one-third of breast cancers (BC) will not be influenced by hormonal interventions because of the absence of ER expression. Thus, there is an urgent need to confirm in the clinical setting the potential efficacy of new compounds in contrasting hormone non-responsive BC, which are often marked by higher biological aggressiveness, early onset and worse prognosis. Over expression of COX-2 and HMG-CoA pathway seems to be involved in breast carcinogenesis and several studies have shown the ability of NSAIDs and statins to reduce the incidence of BC. Material and Methods: We conducted a randomized phase II, double blind, placebo controlled trial with simvastatin (20 mg/day) and nimesulide (100 mg/day) for 1 year in 150 high risk women for ER negative BC in a 1:1:1 fashion. Participants were treated for one year and followed-up for an additional year. The primary endpoint was the change in prevalence of atypical cells obtained by ductal lavage or ultrasound guided fine needle aspirate and cellular proliferation (measured by Ki-67), while the secondary objective was to analyze the efficacy of these drugs in modifying the levels of circulating inflammatory and cardiovascular risk biomarkers. Circulating concentrations of high-sensitivity C-reactive protein (hsCRP), triglycerides, total cholesterol, LDL-cholesterol, HDL-cholesterol, antithrombin III and fibrinogen were measured on morning fasting blood samples drawn at baseline and after 12 and 24 months. Results: Analysis of the primary endpoint is ongoing and here we present results on circulating biomarkers. After 12 months of treatment, simvastatin was associated to a statistically significant mean decrease of hsCRP compared to the placebo arm (0,90 mg/L vs 3,57 mg/L; p=0.008), while an attenuated effect of nimesulide was observed (1.61 mg/L vs 3.57 mg/L; p=0.077). As expected, simvastatin significantly decreased LDL and total cholesterol levels with respect to placebo (89.1 vs 130 mg/dL and 176.8 vs 218 mg/dL respectively; both p Conclusions: Our findings demonstrate a favourable anti-inflammatory effect of both agents on circulating levels of hsCRP, although simvastatin achieved a greater decrease. These results will be correlated with the main endpoint to further assess the potential role of simvastatin and nimesulide in breast carcinogenesis and the potential use of hsCRP as a surrogate endpoint biomarker. Citation Format: Valentina Aristarco, Davide Radice, Harriet Joahnsson, Debora Macis, Serena Mora, Massimiliano Cazzaniga, Laura Cortesi, Isabella Marchi, Maria Teresa Sandri, Bernardo Bonanni. Effect of Simvastatin and Nimesulide on inflammation and cardiovascular risk biomarkers in a phase II breast cancer prevention trial. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 161. doi:10.1158/1538-7445.AM2013-161