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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.

Simple Summary BRCA1 and BRCA2 are two major high-penetrance breast/ovarian cancer predisposition genes, whose mutations can lead to high risk and early onset of breast and ovarian cancer. Numerous studies are focused on spectrum and prevalence of BRCA1/2 mutations worldwide. This is the first study that exclusively focused on native Apulian probands. We found that ten recurrent BRCA1/2 pathogenic variants account for more than half of the patients with proven HBOC syndrome from Apulia. Besides BRCA1 c.5266dupC, which is present in significant numbers in every Apulian province, the other PVs occur at a high frequency in some areas and not others. In-depth knowledge of the mutation spectrum of the target population and of the relatively small number of recurrent mutations is crucial to develop a specific cost-effective strategy for mutation screening and a program for breast–ovarian cancer control and prevention through more liberal, yet rational, genetic testing and counseling. Abstract BRCA1/2-associated hereditary breast and ovarian cancer is the most common form of hereditary breast and ovarian cancer and occurs in all ethnicities and racial populations. Different BRCA1/BRCA2 pathogenic variants (PVs) have been reported with a wide variety among populations. In this study, we retrospectively analyzed prevalence and geographic distribution of pathogenic germline BRCA1/2 variants in families from Apulia in southern Italy and evaluated the genotype–phenotype correlations. Data were collected from Oncogenetic Services present in Apulian hospitals and a shared database was built containing Apulian native probands (n = 2026) that had undergone genetic testing from 2004 to 2019. PVs were detected in 499 of 2026 (24.6%) probands and 68.5% of them (342 of 499) were in the BRCA1 gene. We found 65 different PVs in BRCA1 and 46 in BRCA2. There were 10 most recurrent PVs and their geographical distribution appears to be significantly specific for each province. We have assumed that these PVs are related to the historical and geopolitical changes that occurred in Apulia over time and/or to a “founder effect”. Broader knowledge of BRCA1/2 prevalence and recurring PVs in specific geographic areas could help establish more flexible genetic testing strategies that may enhance our ability to detect high-risk subjects.

Background Considering the high proportion of tumor-infiltrating lymphocytes (TILs) in BRCA-related breast cancer, we expect that PD-1 pathway is highly expressed and PD-1 antagonist pembrolizumab could provide clinical activity in this kind of tumor. Furthermore, BRCA-related breast cancers are known to be more sensitive to platinum-derived drugs. Thus the association between Pembrolizumab and Carboplatin in metastatic BRCA-related breast cancer seems to be active in this setting of patients. This study will evaluate the safety and the efficacy of Pembrolizumab associated with Carboplatin in BRCA mutated or with unknown mutations metastatic breast cancer patients. Study and Statistical DesignThis is a national multicenter two-stage single arm phase II study, enrolling BRCA mutated or with unknown mutations metastatic breast cancer patients. The sample size has been estimated by using the two-stage Simon’s design. In the first stage, 20 subjects will be enrolled. If, after first stage ≤11 responses (r1) will be observed, accrual will terminate and the experimental regimen will be rejected. Otherwise if 12 or more responses will be seen then the accrual will continue to the second stage of an additional 33 subjects (total, 53 subjects). At the second stage if 33 or less responses out of 53 subjects will be observed the treatment will be rejected. With the null hypothesis (p0) being equal 0.55 with a type I (alfa) error of 0.10 (10%) and a type II (beta) error of 0.20 (power=80%) and the alternative hypothesis (p1) is 0.70, (response rate 70%), we expect to reach an overall response rate (ORR) ≥ 70% by the combination of Pembrolizumab plus Carboplatin. We also expect to reach a median Time to Progression (TTP) and Overall Survival (OS) of five and fifteen months respectively. The Disease Control Rate (DCR) will be expected as ≥ 80% by the combination of Pembrolizumab plus Carboplatin Study TreatmentCarboplatin at area under the time-concentration curve 6 (AUC 6) intravenously once every 3 weeks in combination with Pembrolizumab 200 mg intravenously every 3 weeks will be administered for six courses and then only Pembrolizumab alone will continue until occurrence of unacceptable toxicities or disease progression. Eligibility CriteriaIn order to be eligible for participation in this trial, the subject, aged ≥ 18 years, must have metastatic confirmed breast cancer, with a disease progression by radiological techniques within 12 months prior to signing informed consent, and a documented mutation in BRCA1 or BRCA2 genes that is predicted to be deleterious or suspected deleterious or with unknown significance. The subject must have measurable disease based on RECIST 1.1 and have a performance status of 0 or 1 on the Eastern Cooperative Oncology Group (ECOG) Performance Scale. Prior chemotherapy with anthracyclines and taxanes has to be administered in neoadjuvant or adjuvant setting. In case of luminal tumors hormonal treatments for advanced disease can be administered before. The life expectancy must be greater than 3 months and the subject must demonstrate adequate organ function by screening labs performed within 10 days of treatment initiation. Objectives and HypothesisThe primary end-point will be the ORR, evaluated according to RECIST criteria. Secondary objectives will be the TTP, the duration of response (DOR ), the DCR, and the OS. The safety of the combination will be evaluated according to the worst toxicity grade reported throughout the whole treatment period.The Exploratory Objective will be the evaluation of ORR, TTP, DOR, and DCR based on irRECIST. Biological parameters of CD8/TILs and PD-L1 will be considered in the metastatic biopsy. Target AccrualThe first subject was enrolled in January 2019 and recruitment is ongoing. Enrollment of the first 20 subjects is expected to complete in Q2 2021. Citation Format: Laura Cortesi, Marta Venturelli, Federica Caggia, Luigi Marcheselli, Annita Gozzi, Alberto Zambelli, Valentina Guarneri, Antonino Musolino, Elena Fiorio, Giancarlo Bisagni, Andrea Rocca, Valentina Arcangeli, Elisabetta De Matteis, Sergio Rizzo, Andrea Michelotti. A phase II study to evaluate the efficacy and safety of pembrolizumab plus carboplatin in BRCA-related metastatic breast cancer: PEMBRACA trial [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr OT-31-01.

Reproductive history and exogenous hormonal exposures are acknowledged risk factors for breast cancer in the general population. In women at increased breast cancer risk for genetic predisposition or positive family history, data regarding these risk factors are limited or conflicting, and recommendations for these categories are unclear. We evaluated the characteristics of reproductive life in 2522 women at increased genetic or familial breast cancer risk attending our Family Cancer Center. Breast cancers in BRCA mutation carriers were more likely to be hormone receptor negative, diagnosed at 35 years or before and multiple during the lifetime than tumors in women at increased familial risk, while the distribution of invasive cancers and HER2 positive tumors was similar in the different risk groups. At least one full-term pregnancy (HR 0.27; 95% CI 0.12-0.58; p = 0.001), breastfeeding either less (HR 0.24; 95% CI 0.09-0.66; p = 0.005) or more (HR 0.25; 95% IC 0.08-0.82; p = 0.022) than one year and late age at menopause (HR 0.10; 95% CI 0.01-0.82; p = 0.033) showed to be protective factors in BRCA mutation carriers, while in women at increased familial risk early age at first full-term pregnancy (HR 0.62; 95% IC 0.38-0.99; p = 0.048) and late menarche (HR 0.61; 95% CI 0.42-0.85; p = 0.004) showed to be the main protective factors. Finally, for the entire population, combined hormonal contraceptives demonstrated to do not increase breast cancer risk. The results of our study suggest that women at high familial risk and mutation carries develop tumors with different clinical-pathological characteristics and, consequently, are influenced by different protective and risk factors.

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.

Aim: This retrospective analysis focused on the effect of treatment with EVE/EXE in a real-world population outside of clinical trials. We examined the efficacy of this combination in terms of PFS and RR related to dose intensity (5 mg daily versus 10 mg daily) and tolerability. Methods: 163 HER2-negative ER+/PgR+ ABC patients, treated with EVE/EXE from May 2011 to March 2016, were included in the analysis. The primary endpoints were the correlation between the daily dose and RR and PFS, as well as an evaluation of the tolerability of the combination. Secondary endpoints were RR, PFS, and OS according to the line of treatment. Patients were classified into three different groups, each with a different dose intensity of everolimus (A, B, C). Results: RR was 29.8% (A), 27.8% (B) (p = 0.953), and not evaluable (C). PFS was 9 months (95% CI 7–11) (A), 10 months (95% CI 9–11) (B), and 5 months (95% CI 2–8) (C), p = 0.956. OS was 38 months (95% CI 24–38) (A), median not reached (B), and 13 months (95% CI 10–25) (C), p = 0.002. Adverse events were stomatitis 57.7% (11.0% grade 3–4), asthenia 46.0% (6.1% grade 3–4), hypercholesterolemia 46.0% (0.6% grade 3–4), and hyperglycemia 35.6% (5.5% grade 3–4). The main reason for discontinuation/interruption was grade 2–3 stomatitis. Conclusions: No correlation was found between dose intensity (5 vs. 10 mg labeled dose) and efficacy in terms of RR and PFS. The tolerability of the higher dose was poor in our experience, although this had no impact on efficacy.

Chemoprevention for women at risk for breast cancer has been shown to be effective, but in actual practice, women's uptake of chemoprevention has been poor. We explored factors that influence acceptability, adherence, and dropout in the International Breast (Prevention) Intervention Study during our first 3 years of activity at the Modena Familial Breast and Ovarian Cancer Center. We evaluated socio-demographic characteristics, health status, adherence, and side effect intensity. Semi-structured interviews analyzed reasons for accepting/refusing/stopping the trial. A total of 471 postmenopausal women were invited to participate, of which 319 declined to participate (68%), 137 accepted to participate (29%), and 15 participants did not make a final decision (3%). Breast cancer-related worries and trust in our preventive and surveillance programs were the most frequent reasons for accepting. Side effect-related worry was the most frequent reason for refusing. General practitioners' and family members' opinions played an important role in the decision-making process. Adherence significantly decreased after a 12-month follow-up, but it remained unchanged after 24- and 36-month follow-ups. Mild/moderate side effects reported by women did not change after 12 months of treatment. Forty percent of women withdrew from the study due to complaints of side effects. We concluded that chemoprevention trials are difficult medical experiments and that the process of deciding about whether or not to participate is based mainly on beliefs and values. This study has important clinical implications. During counselling with prospective participants, it is important to emphasize the potential benefits and to promote an informed choice. How participants make decisions, their belief systems, and their perception of risk are all factors that should be investigated in future research.

Since 1985, when first results were published on evaluation of female breast [1], MRI has been widely used for locating occult primary breast tumors, pre-surgical definition of breast tumors and assessment of treatment response to neo-adjuvant systemic therapy. Several single-center and multicenter studies evaluated MRI in pre-surgery setting, suggesting that breast MRI can modify treatment decisions. In patients having preoperative breast MRI, a correct change of treatment (different surgical access, wider excision, excision of another lesion in the same or contralateral breast) has been reported in 12–32% of patients although an incorrect one has been recorded in 3–30% [2–7]. Nevertheless, no data on current clinical using of MRI before surgery outside clinical trials have been reported so far. Therefore, this retrospective study was carried out to investigate the real using of breast MRI in the Province of Modena (Northern Italy), through a record linkage between the Modena Cancer Registry data base and the MRI facility in the same geographic area. Furthermore we searched for different surgical approaches in patients who underwent or not pre-surgery MRI.