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Adjuvant therapy; Breast cancer; Olaparib Terapia adyuvante; Cáncer de mama; Olaparib Teràpia adjuvant; Càncer de mama; Olaparib Background The randomized, double-blind OlympiA trial compared 1 year of the oral poly(adenosine diphosphate-ribose) polymerase inhibitor, olaparib, to matching placebo as adjuvant therapy for patients with pathogenic or likely pathogenic variants in germline BRCA1 or BRCA2 (gBRCA1/2pv) and high-risk, human epidermal growth factor receptor 2-negative, early breast cancer (EBC). The first pre-specified interim analysis (IA) previously demonstrated statistically significant improvement in invasive disease-free survival (IDFS) and distant disease-free survival (DDFS). The olaparib group had fewer deaths than the placebo group, but the difference did not reach statistical significance for overall survival (OS). We now report the pre-specified second IA of OS with updates of IDFS, DDFS, and safety. Patients and methods One thousand eight hundred and thirty-six patients were randomly assigned to olaparib or placebo following (neo)adjuvant chemotherapy, surgery, and radiation therapy if indicated. Endocrine therapy was given concurrently with study medication for hormone receptor-positive cancers. Statistical significance for OS at this IA required P < 0.015. Results With a median follow-up of 3.5 years, the second IA of OS demonstrated significant improvement in the olaparib group relative to the placebo group [hazard ratio 0.68; 98.5% confidence interval (CI) 0.47-0.97; P = 0.009]. Four-year OS was 89.8% in the olaparib group and 86.4% in the placebo group (Δ 3.4%, 95% CI −0.1% to 6.8%). Four-year IDFS for the olaparib group versus placebo group was 82.7% versus 75.4% (Δ 7.3%, 95% CI 3.0% to 11.5%) and 4-year DDFS was 86.5% versus 79.1% (Δ 7.4%, 95% CI 3.6% to 11.3%), respectively. Subset analyses for OS, IDFS, and DDFS demonstrated benefit across major subgroups. No new safety signals were identified including no new cases of acute myeloid leukemia or myelodysplastic syndrome. Conclusion With 3.5 years of median follow-up, OlympiA demonstrates statistically significant improvement in OS with adjuvant olaparib compared with placebo for gBRCA1/2pv-associated EBC and maintained improvements in the previously reported, statistically significant endpoints of IDFS and DDFS with no new safety signals. Funding for this work, which was conducted as a collaborative partnership among the Breast International Group, NRG Oncology, Frontier Science, AstraZeneca, and Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, U.S.A. (MSD), was provided by the National Institutes of Health (grant numbers: U10CA 180868, UG1CA 189867, and U10CA 180822) and by AstraZeneca as part of an alliance between AstraZeneca and MSD. Provision of olaparib and placebo was from AstraZeneca.

Hematopoietic stem cell transplantation (HSCT) is a curative option for patients with Fanconi anemia (FA) and hematological manifestations but it does not prevent solid tumors, especially squamous cell carcinomas (SCC). Retrospective study in 22 FA patients who had received HSCT and had been followed up beyond 2 years after HSCT. The median follow-up was 15 years. Six patients developed head-and-neck SCC after transplantation. The cumulative incidence of SCC at 15 and 30 years from the HSCT was 14.2% and 71.2%, respectively. One patient was diagnosed in stage IV and the rest, who were being followed up in cancer screening programs, in stage I. Treatment of SCC consisted of surgery in all patients; radiotherapy and chemotherapy were used in two patients and were poorly tolerated. FA patients have high risk of head-and-neck SCC. Multi-disciplinary programs for early cancer detection are of special relevance in these patients.

Background: To prevent ovarian cancer in BRCA1/2 mutation carriers, risk reducing salpingo-oophorectomy (RRSO) is recommended around age 40. In women with no prior history of cancer, there are conflicting data regarding the impact of RRSO on breast cancer risk. Our aim was to explore the association between premenopausal RRSO and BC risk by using a methodology that maximally reduced potential biases. Methods: Prospective multicenter cohort study of BRCA1/2 carriers who underwent genetic testing under age 51, had no history of bilateral salpingo-oophorectomy, mastectomy or cancer prior to genetic testing and during the first six months of surveillance (to avoid cancer-induced testing bias and prevalent cancer bias). Observation period started six months after genetic testing (to avoid event-free time bias), and ended at BC or other cancer diagnosis except for non-melanoma skin cancer and cervical cancer in situ, risk reducing mastectomy (RRM), last follow-up or death. We calculated person-years of observation (PYO) starting at age 30 and RRSO was only accounted for when performed before age 51 (considered premenopausal). Cox proportional hazards models with RRSO as a time-dependent covariate (to avoid immortal person time bias) were used to calculate the BC risk reduction. Sensitivity analysis, censoring at age 51, was performed to calculate the impact of RRSO on the premenopausal BC. Results: We included 853 (444 BRCA1 and 409 BRCA2) women. Median age was 36.2 (30-50.9) years, 337 (39.5%) women underwent RRSO prior to age 51 with a median age at RRSO of 42.8 (30.5-50.9) and 240 (28.1%) women performed RRM at a median age of 40.7 (30-61.7) years. After a mean follow-up period of 4.3 years, 96 women (11.3%) were diagnosed with BC (54 BRCA1 and 42 BRCA2). Overall, women who underwent RRSO had a significant reduction in BC risk with hazard ratio (HR) of 0.57 (95% CI= 0.32 to 1; p=0.05); in BRCA1 carriers we found HR of 0.45 (95% CI= 0.22 to 0.92; p=0.03), while BRCA2 carriers had HR of 0.77 (95% CI= 0.35 to 1.67; p=0.51). When follow-up was censored at age 51, the HR estimates remained similar with overall HR of 0.54 (95% CI= 0.29 to 1; p=0.05); BRCA1 carriers had HR of 0.35 (95% CI= 0.15 to 0.82; p=0.02), while BRCA2 carriers had HR of 0.88 (95% CI= 0.39 to 1.96; p=0.75). Conclusions: This robust bias-reducing analysis in a large prospective cohort supports a role of premenopausal RRSO for BC risk reduction in BRCA1 carriers. A longer follow-up may be needed to estimate the potential benefit of the intervention in BRCA2 carriers. Citation Format: Stjepanovic N, Villacampa G, Nead K, Torres S, Gomez L, Nathanson KL, Teule A, Brunet J, Ramon y Cajal T, Llort G, Dienstmann R, Rue M, Domchek S, Balmana J. Impact of premenopausal RRSO on breast cancer risk in BRCA1/2 mutation carriers: Maximizing bias-reduction [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P5-09-04.

Background Current genetic and genomic tests measuring homologous recombination deficiency (HRD) show limited predictive value. This study compares the performance of an immunohistology-based RAD51 test with genetic/genomic tests to identify patients with HRD primary triple-negative breast cancer (TNBC) and evaluates its accuracy to select patients sensitive to platinum-based neoadjuvant chemotherapy (NACT). Patients and methods This is a retrospective, blinded, biomarker analysis from the GeparSixto randomized clinical trial. TNBC patients received neoadjuvant paclitaxel plus Myocet®-nonpegylated liposomal doxorubicin (PM) or PM plus carboplatin (PMCb), both arms including bevacizumab. Formalin-fixed paraffin-embedded (FFPE) tumor samples were laid on tissue microarrays. RAD51, BRCA1 and γH2AX were quantified using an immunofluorescence assay. The predictive value of RAD51 was assessed by regression models. Concordance analyses were carried out between RAD51 score and tumor BRCA (tBRCA) status or genomic HRD score (Myriad myChoice®). Associations with pathological complete response (pCR) and survival were studied. Functional HRD was predefined as a RAD51 score ≤10% (RAD51-low). Results Functional HRD by RAD51-low was evidenced in 81/133 tumors (61%). RAD51 identified 93% tBRCA-mutated tumors and 45% non-tBRCA mutant cases as functional HRD. The concordance between RAD51 and genomic HRD was 87% [95% confidence interval (CI) 79% to 93%]. In patients with RAD51-high tumors, pCR was similar between treatment arms [PMCb 31% versus PM 39%, odds ratio (OR) 0.71, 0.23-2.24, P = 0.56]. Patients with RAD51-low tumors benefited from PMCb (pCR 66% versus 33%, OR 3.96, 1.56-10.05, P = 0.004; interaction test P = 0.02). This benefit maintained statistical significance in the multivariate analysis. Carboplatin addition showed similar disease-free survival in the RAD51-high [hazard ratio (HR) 0.40, log-rank P = 0.11] and RAD51-low (0.45, P = 0.11) groups. Conclusions The RAD51 test identifies tumors with functional HRD and is highly concordant with tBRCA mutation and genomic HRD. RAD51 independently predicts clinical benefit from adding Cb to NACT in TNBC. Our results support further development to incorporate RAD51 testing in clinical decision-making.

Background Talazoparib (1 mg/day) exhibited promising efficacy and safety in patients with advanced breast cancer during ABRAZO (NCT02034916); this study evaluated patient-reported outcomes (PROs). Patients and methods ABRAZO is a two-cohort, two-stage, phase 2 study of talazoparib in patients with advanced breast cancer after a response to prior platinum-based therapy (cohort 1 [C1], n = 49) or ≥3 platinum-free cytotoxic-based regimens (cohort 2 [C2], n = 35). PROs were assessed on day 1 (baseline), every 6 weeks for an initial 24 weeks, and every 12 weeks thereafter until progression, using the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (QLQ-C30) and its breast cancer module, QLQ-BR23. Results Global health status/quality of life (GHS/QoL) was maintained from baseline across all time points for both C1 and C2. For C1 and C2, median time to deterioration (TTD) of GHS/QoL (95% confidence interval [CI]) was 2.8 (2.1, 3.0) and 5.5 (4.2, 5.7) months, respectively. Median TTD for all QLQ-C30 functional scales for C1 and C2 ranged 2.1–3.1 months and 4.2–5.6 months, respectively; median TTD for all QLQ-BR23 symptom scales ranged 2.6–4.0 months and 4.2–5.6 months, respectively. There were no statistically significant differences in estimated overall change from baseline in the GHS/QoL scale for both cohorts (C1: −2.6 [95% CI, −7.8, 2.5]; C2: 1.2 [95% CI, −5.5, 8.0]). Significant overall improvements in the breast symptoms and arm symptoms and the future perspective of patients in C1 and C2 were observed, despite the statistically significant and clinically meaningful overall deterioration among patients regarding their role functioning (in C1) and dyspnoea symptoms (in C2). Conclusion Despite the statistically significant and clinically meaningful overall deterioration among patients regarding their role functioning (in C1) and dyspnoea symptoms (in C2), patients in both C1 and C2 reported significant overall improvements in their breast symptoms, arm symptoms and future perspective, and their GHS/QoL was maintained from baseline.

Mama hereditaria; Cáncer de ovarios; Directrices SEOM Mama hereditària; Càncer d'ovaris; Directrius SEOM Hereditary breast; Ovarian cancer; SEOM guidelines Mutations in BRCA1 and BRCA2 high penetrance genes account for most hereditary breast and ovarian cancer, although other new high-moderate penetrance genes included in multigene panels have increased the genetic diagnosis of hereditary breast and ovarian cancer families by 50%. Multigene cancer panels provide new challenges related to increased frequency of variants of uncertain significance, new gene-specific cancer risk assessments, and clinical recommendations for carriers of mutations of new genes. Although clinical criteria for genetic testing continue to be largely based on personal and family history with around a 10% detection rate, broader criteria are being applied with a lower threshold for detecting mutations when there are therapeutic implications for patients with breast or ovarian cancer. In this regard, new models of genetic counselling and testing are being implemented following the registration of PARP inhibitors for individuals who display BRCA mutations. Massive sequencing techniques in tumor tissue is also driving a paradigm shift in genetic testing and potential identification of germline mutations. In this paper, we review the current clinical criteria for genetic testing, as well as surveillance recommendations in healthy carriers, risk reduction surgical options, and new treatment strategies in breast cancer gene-mutated carriers.

Background: Talazoparib (TALA; 1 mg/d) was well tolerated and exhibited promising antitumor activity in ABRAZO, a 2-cohort, 2-stage, open-label phase 2 study (NCT02034916) in patients (pts) with locally advanced or metastatic breast cancer and gBRCA1/2 mutations following platinum-based therapy (cohort 1 [C1]) or ≥3 platinum-free cytotoxic-based regimens (cohort 2 [C2]). This analysis evaluates health-related quality of life (QoL) for both cohorts. Methods: QoL was assessed on day 1 (baseline) and every 6 weeks for the initial 24 weeks and every 12 weeks thereafter, or sooner if progression was clinically suspected, using the EORTC QLQ-C30 and its breast cancer module, QLQ-BR23. For all scales, results were summarized using descriptive statistics for each cohort and at each time point, based on Characters (max 3400 including title, body and table [including spaces]): 3363 No abbreviations in title; title sentence case; define acronyms; no figures Category: Psychosocial, QOL, and Educational Aspects – Other 2 observed values and changes from baseline (clinically meaningful defined as ≥10-point change from baseline). Time to deterioration (TTD; defined as ≥10-point decrease in global health status [GHS]/functional scales or increase in symptom scales) analyses using survival analysis methods were carried out on the GHS/functional scales of QLQ-C30 and symptom scales of QLQ-BR23. Results:GHS was maintained from baseline across all time points for both C1 and C2 except at week 24 in C2, when a statistically significant but not clinically meaningful improvement in GHS was observed. In C1, statistically significant and clinically meaningful improvement was observed at specific time points in 4 functional scales (body image, week 6; sexual functioning, week 24; sexual enjoyment, week 36; and future perspective, weeks 6, 18, and 24) and in 3 symptom scales (dyspnea, week 24; insomnia, week 24; and breast symptoms, weeks 6 and 36). Statistically significant and clinically meaningful deterioration in C1 was observed in 2 functional scales (emotional functioning, week 12 and end of treatment, and role functioning, end of treatment) and in 1 symptom scale (fatigue, week 6). In C2, statistically significant and clinically meaningful improvement was observed at specific time points in 4 functional scales (role functioning, week 24; social functioning, week 24; sexual enjoyment, week 18; and future perspective, weeks 6, 12, and 18) and in 5 symptom scales (nausea/vomiting, week 18; pain, weeks 12, 18, and 24; insomnia, week 24; breast symptoms, weeks 12 and 18; and arm symptoms, week 48). For C2, no statistically significant and clinically meaningful deterioration was observed for any functional or symptoms scales across all time points, except in the dyspnea symptom scale at week 18. For C1 and C2, the median (95% confidence interval) TTD of GHS was 2.8 (2.1-3.0) and 5.5 (4.2-5.7) months, respectively. The median TTD for all QLQ-C30 functional scales for C1 and C2 ranged 2.1-3.1 and 4.2-5.6 months, respectively; the median TTD for all QLQ-BR23 symptoms scales ranged 2.6-4.0 and 4.2-5.6 months, respectively. Conclusions: The QoL of TALA-treated patients during ABRAZO was maintained. QoL is being evaluated among atients with germline BRCA1/2 mutated advanced BC treated with TALA vs physician's choice chemotherapy in the phase 3 EMBRACA trial (NCT01945775). Citation Format: Hurvitz SA, Turner NC, Telli ML, Rugo HS, Mailliez A, Ettl J, Grischke E-M, Mina LA, Balmaña J, Fasching PA, Tudor C, Quek RGW, Hannah AL, Robson ME, Wardley AM. Health-related quality of life during a phase 2 study of talazoparib in patients with advanced breast cancer and germline BRCA1/2 mutations (ABRAZO) [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P5-19-05.

Background: Talazoparib (TALA) is a dual-mechanism poly (ADP-ribose) polymerase (PARP) inhibitor that traps PARP on DNA. Efficacy results of this phase 2 trial were previously presented (Turner et al, ASCO 2017, abstract 1007). This study included sparse pharmacokinetic (PK) sampling for patients through cycle 4 of therapy. Exploratory analyses included assessment of exposure versus parameters of efficacy and safety. Methods: ABRAZO (NCT02034916) was a parallel-cohort, open-label phase 2 study of TALA (1 mg/d) following (i) platinum-based therapy (cohort 1) or (ii) ≥3 platinum-free cytotoxic-based regimens (cohort 2) in patients with locally advanced or metastatic breast cancer and germline BRCA1/2 mutation. Sparse PK sampling was performed on day 1 of cycles 1-4, consisting of a predose sample collected ≤60 minutes prior to dosing and 2 postdose samples collected ≥30 minutes after dosing (time of food ingestion prior to the dose was collected). The collection times of the 2 postdose samples were separated by ≥2 hours. Efficacy parameters included radiographic progression-free survival (rPFS) by central review and objective response rate (ORR). Safety parameters included incidence of overall adverse events (AEs) and grade ≥3 AEs. Individual AUCs (area under concentration-time curves) for exposure-response analyses were predicted by population PK analyses. Results: Patients were divided into AUC tertiles: low (median, 109.0 ng*hr/mL; n=27), intermediate (median, 170.8 ng*hr/mL; n=27), and high (median, 219.2 ng*hr/mL; n=27). Median rPFS was 5.3 months (95% confidence interval [CI], 3.1, 8.3) in the lowest AUC tertile, 5.6 months (95% CI, 3.7, 8.4) in the intermediate AUC tertile, and 5.3 months (95% CI, 3.9, 5.6) in the highest AUC tertile. The ORR was 22.2% (95% CI, 8.6, 42.3) in the lowest AUC tertile, 25.9% (95% CI, 11.1, 46.3) in the intermediate AUC tertile, and 37.0% (95% CI, 19.4, 57.6) in the highest AUC tertile. AEs of any grade were reported in 11 patients (40.7%) in the lowest AUC tertile, 21 patients (77.8%) in the intermediate AUC tertile, and 22 patients (81.5%) in the highest AUC tertile. Grade ≥3 AEs were reported in 8 patients (29.6%) in the lowest AUC tertile and in 18 patients (66.7%) in the intermediate and highest AUC tertiles. The most common AEs in all 3 exposure tertiles were anemia, thrombocytopenia, and neutropenia. Conclusions: Median rPFS did not change with increasing systemic exposure. There may be a trend to higher ORR in patients with highest systemic exposure. A larger percentage of patients experienced AEs with elevated systemic exposure. Increased response rates with greater exposure does not translate to improved rPFS. These results should be interpreted with caution due to the low patient numbers in each cohort. Citation Format: Telli ML, Turner NC, Mailliez A, Ettl J, Grischke E-M, Mina LA, Balmaña J, Hurvitz SA, Wardley AM, Fasching PA, Tudor C, Nguyen L, Hannah AL, Robson ME, Rugo HS. ABRAZO: Exposure-efficacy and -safety analyses of breast cancer patients with germline BRCA1/2 mutations receiving talazoparib in a phase 2 open-label trial [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P1-14-03.

Knowledge of genetic susceptibility to gastrointestinal cancers is constantly evolving with identification of new genes. Similarly, a better understanding of the genotype/phenotype relationship in patients with Lynch syndrome (LS) or familial adenomatous polyposis (FAP) is leading to more individualised surveillance recommendations. In addition, molecular profiling of patients with cancer has been shown to guide targeted therapies, such as immunotherapy. Specialists involved in the care of patients with gastrointestinal cancer should be familiar with the main hereditary cancer syndromes and refer patients to specialised cancer genetic units for adequate genetic counselling and to address specific concerns associated to each genetic susceptibility. These guidelines aim to summarise the evidence-based data on hereditary colorectal cancer (CRC), gastric cancer (GC) and pancreatic cancer (PC) and provide useful clinical recommendations for identification and management of patients with hereditary gastrointestinal cancers.

Background: PARP1/2 inhibitors (PARPi) are active anti-cancer agents in BRCA1 or BRCA2 mutation carriers (BRCA) with advanced breast or ovarian cancer. However, not all BRCA-tumors respond to PARP blockade, and eventually all develop acquired resistance. Little is known about clinically relevant mechanisms of PARPi resistance in BRCA-breast cancer. Here, we sought to identify biomarkers correlating with primary and acquired resistance to PARPi using PDX derived from both the early disease and the metastatic setting. Methods: We have developed a panel of PDX from patients harboring germline BRCA1 or BRCA2 mutations, namely from 12 primary and advanced breast cancer and 1 high-grade serous metastatic ovarian cancer (HGSOC). The antitumor activity of the PARP1/2 inhibitor olaparib as single agent (50 mg/kg) was assessed in all models. To study the mechanisms of acquired resistance, the olaparib-sensitive PDXs were exposed to olaparib for >100 days, until individual tumors regrew. The tumor's capacity to repair DNA double strand breaks was estimated by quantification of the BRCA1 and RAD51 nuclear foci in the S-phase of the cell cycle. We investigated the correlation between the tumor's BRCA1/RAD51 foci formation and sensitivity to olaparib, and also identified potential genetic modifiers of PARPi sensitivity by targeted sequencing. Results: Four out of 13 PDX (31%) treated with single agent olaparib exhibited tumor regression or disease stabilization. Nuclear BRCA1/RAD51 foci formation correlated with PARPi resistance in six BRCA1 PDX models investigated, either with primary or acquired resistance. No reversions in BRCA1/2 mutations were identified as the mechanism of olaparib resistance. We identified four potential genetic modifiers of PARPi sensitivity and the corresponding validating studies will be presented. Conclusions: Among our BRCA PDX, reactivation of HR functionality is a frequent event that is associated with PARPi resistance and seems to occur through mechanisms other than secondary mutations in BRCA1/2 in contrast to what it has been reported for HGSOC. Citation Format: Cruz C, Bustos Ld, Gris A, Palafox M, Castroviejo M, Llop A, Morancho B, Diez O, Gutiérrez S, Caratú G, Prudkin L, Bruna A, Caldas C, O'Connor MJ, Rubio IT, Arribas J, Baselga J, Cortes J, Serra V, Balmaña J. PARP inhibition in breast and ovarian patient-derived tumor xenografts (PDX) harboring germline BRCA1/2 mutations unveils mechanisms of primary and acquired resistance that restore homologous recombination (HR). [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P4-07-05.

Background: Metastatic breast cancer (MBC) is a clinically heterogeneous disease in which selective approaches are needed to identify patients (pts) who will benefit the most from available therapies and avoid unnecessary toxicities. Lurbinectedin (PM01183) is a new anticancer drug that binds to the DNA minor groove inducing double-strand breaks and blocking transcription. It has significant in vitro and in vivo antitumor activity, particularly in breast cancer models. PM01183 is more active against homologous recombination-deficient cell lines. Hence, MBC pts with deleterious germline BRCA mutations might be more sensitive to PM01183 than those with sporadic tumors. PM1183 activity was shown in different tumor types in clinical trials, especially in pts with platinum-resistant ovarian cancer (objective response rate [ORR]: 30%). Methods: MBC pts < 75-years-old with ductal or lobular carcinoma pretreated with ≤ 3 chemotherapy regimens for MBC, measurable disease per RECIST v1.1, performance status (PS) ≤1 and adequate major organ function are being treated with PM01183 7.0 mg flat dose i.v. every 3 weeks. The primary aim is to evaluate the clinical efficacy of PM01183 in two cohorts of MBC pts: cohort A: BRCA+ (known germline BRCA1/2 mutation) and cohort B: unselected (BRCA1/2 wild type or unknown mutation status). The primary endpoint is confirmed ORR by RECIST v1.1. A futility analysis was planned when 20 and 30 pts were recruited in cohort A and B, respectively. If at least 4 pts in cohort A and 3 pts in cohort B, achieve a response, recruitment in that cohort will continue up to 53 and 64 total pts, respectively. Results: As of June 2014, 56 pts had been enrolled. Cohort A/B (n: 21/35): Median age 40/52-years-old; Cohort A(%)/B(%): PS 0: 48/66; >2 metastatic sites: 58/40; most common sites of metastasis: lymph node 79/33, liver 48/60 and bone 42/48; triple negative: 57/46; hormonal receptor +: 38/49; prior anthracyclines: 95/91, taxanes: 100/94, platinum: 52/26, PARPi: 29/0; cohort A: BRCA 1/2 (%): 52/48. Cohort A-BRCA 1/2+ (n=21)Cohort B-unselected (n=35)Median cycles (range)4 (1-20)3 (1-14)Best overall response(n= 17 evaluable)(n= 34 evaluable)CR1 (6%)0PR6 (35%)3 (9%)SD6 (35%)16 (47%)PD4 (24%)15 (44%)ORR (95%CI)41% (18-67%)9% (1.9-23.7%)Median duration of response Monts (95%CI)5.0 (0.1-12.8)3.3 (1.4-5.1) In an exploratory analysis, ORR in cohort A was higher in PARPi naïve pts: 64% (7/11 pts). Grade (G) 3-4 related adverse events occurred in >5% pts were myelosuppression (neutropenia 69%, febrile neutropenia 7%, thrombocytopenia 14%); G3 fatigue 7%, transient transaminase increase 19% (G4: 2%), nausea 6% and dyspnea 6% (3 pts, 2 of them due to pneumonitis). One patient with massive liver involvement and impaired function died on C1D4 due to multiorgan failure possibly related to the study drug. Conclusions: PM01183 has promising activity in pretreated MBC pts with BRCA mutation. Safety profile appears to be mostly predictable and with non-cumulative toxicity. Treatment-related neutropenia was manageable with G-CSF and/or dose reduction. After futility analysis, targeted activity has been met in cohort A (BRCA+), and recruitment will continue up to 53 evaluable BRCA+ pts. Citation Format: Judit Balmaña, Cristina Cruz, Judy Garber, Jose A Perez Fidalgo, Ana Lluch, Nadine Tung, Silvia Antolin, Cristian Fernandez, Carmen Kahatt, Sergio Szyldergemajn, Arturo Soto Matos, Sonia Extremera, Jose Baselga, Steven J Isakoff. Lurbinectedin (PM01183) activity in BRCA1/2-associated or unselected metastatic breast cancer. Interim results of an ongoing phase II trial [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P3-13-01.

Background: Cancer cells with deleterious mutations in breast cancer susceptibility genes 1 and 2 (BRCA1/2) are deficient in the DNA double-strand break repair mechanism, rendering them highly dependent on the single-strand break repair pathway, which is initiated by poly-(ADP-ribose) polymerase (PARP) [1-3]. In cells with deleterious BRCA1/2 mutations, PARP inhibition is synthetically lethal because of accumulation of irreparable DNA damage [1-3]. Talazoparib (BMN 673) exhibits a novel two-pronged approach in treating BRCA1/2-mutant tumors: 1) potent catalytic inhibition of the PARP enzyme; and 2) trapping of PARP at sites of DNA damage [4-7]. The capacity to trap PARP-DNA complexes varies widely across PARP inhibitors and is not correlated with catalytic inhibition potency [4-7]. In preclinical models, trapping PARP on DNA is more potent at inducing cancer cell death than enzymatic inhibition of PARP alone [4,7]. Talazoparib is the most potent clinical-stage PARP inhibitor tested to date with the highest efficacy at trapping PARP-DNA complexes [7]. Talazoparib has shown single-agent antitumor efficacy in several solid tumor types and was generally well tolerated in a phase 1/2 clinical study [8]. Methods: This 2-stage, 2-cohort, phase 2 international study (ABRAZO) evaluates the safety and efficacy of talazoparib in patients with a deleterious germline BRCA1 or BRCA2 mutation with locally advanced and/or metastatic breast cancer. Eligible subjects will be assigned to one of two cohorts based on prior chemotherapy for metastatic disease. Cohort 1 (n=70) includes patients with a complete response (CR) or partial response (PR) to platinum-containing regimens for metastatic disease. Cohort 2 (n=70) includes patients who have received >2 prior chemotherapy regimens in the metastatic setting but have not had prior platinum therapy for locally advanced or metastatic disease (prior adjuvant or neoadjuvant therapy with a platinum is allowed). The primary objective is objective response rate (ORR). Secondary objectives include clinical benefit response (CBR) rate, duration of response (DOR), progression-free survival (PFS), and overall survival (OS). Health-related quality of life (QoL) assessments are an exploratory objective. Eligible subjects will receive oral talazoparib (1 mg/day, 21-day cycles) until disease progression or unacceptable toxicity. This trial is currently enrolling patients from the United States and Europe (NCT02034916). This study is funded by BioMarin Pharmaceutical Inc. References: 1. Ashworth A. J Clin Oncol. 2008;26:3785-3790; 2. Jalve M, Curtin NJ. Ther Adv Med Oncol. 2011;3:257-267; 3. Helleday T. Mol Oncol. 2011;5:387-393; 4. Murai J et al. Cancer Res. 2012;72:5588-5599; 5. Rouleau M et al. Nat Rev Cancer. 2010;10:293-301; 6. Shen Y et al. Clin Cancer Res. 2013;19:5003-5015; 7. Murai J et al. Mol Cancer Ther. 2014;13:433-443; 8. Wainberg ZA et al. J Clin Oncol. 2014;32(suppl):5. Abstract 7522. Citation Format: Turner NC, Balmaña J, Fasching PA, Hurvitz SA, Rugo HS, Telli ML, Visco F, Wardley AM, Yang X, Lokker NA, Lounsbury DL, Robson ME. ABRAZO: An international phase 2 (2-stage, 2-cohort) study of the oral PARP inhibitor talazoparib (BMN 673) in BRCA mutation subjects with locally advanced and/or metastatic breast cancer. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr OT1-03-17.

Lynch syndrome (LS) is an autosomal dominant cancer-susceptibility disease caused by inactivating germline mutations in mismatch repair (MMR) genes. Variants of unknown significance (VUS) are often detected in mutational analysis of MMR genes. Here we describe a large family fulfilling Amsterdam I criteria carrying two rare VUS in the MLH1 gene: c.121G > C (p.D41H) and c.2128A > G (p.N710D). Collection of clinico-pathological data, multifactorial analysis, in silico predictions, and functional analyses were used to elucidate the clinical significance of the identified MLH1 VUS. Only the c.121G > C variant cosegregated with LS-associated tumors in the family. Diagnosed colorectal tumors were microsatellite unstable although immunohistochemical staining revealed no loss of MMR proteins expression. Multifactorial likelihood analysis classified c.2128A > G as a non-pathogenic variant and c.121G > C as pathogenic. In vitro functional tests revealed impaired MMR activity and diminished expression of c.121G > C. Accordingly, the N710 residue is located in the unconserved MLH1 C-terminal domain, whereas D41 is highly conserved and located in the ATPase domain. The obtained results will enable adequate genetic counseling of c.121G > C and c.2128A > G variant carriers and their families. Furthermore, they exemplify how cumulative data and comprehensive analyses are mandatory to refine the classification of MMR variants.

Background: MBC is a clinically heterogeneous disease that cannot be cured with currently available treatment options. Selective approaches are needed to identify patient subgroups with different tumor sensitivities who will benefit the most from available therapies for MBC. PM01183 (P), also known as lurbinectedin, is a new anticancer drug that binds to the DNA minor groove inducing both double-strand breaks and transcription blocking. It has significant in vitro and in vivo activity against several tumor models, particularly breast cancer. P is more active against homologous recombination (HR)-deficient cell lines; hence, MBC patients (pts) with deleterious germline BRCA mutations might be more sensitive to P than sporadic tumors. Methods: A multicenter, open-label, phase II study of P (7.0 mg fixed dose) as 1-hour intravenous infusion every 3 weeks in pts with MBC with or without known BRCA1/2 mutation at study entry. To be enrolled, pts must be women 18-75 years old with confirmed MBC pretreated with 1-3 chemotherapy regimens for MBC (including at least one prior trastuzumab-containing regimen for HER-2 overexpressing pts), measurable disease as per RECIST v1.1, performance status (PS) of 0-1 and adequate major organ function. Pts are excluded if pretreated with P, trabectedin, or radiotherapy (RT) on >35% of bone marrow; if they have prior/concurrent malignant disease not in complete remission for >5 years, clinically unstable central nervous system involvement, and other diseases/situations that might increase patient's risk; if they are pregnant or lactating women; or if they require RT. Aims: The primary aim is to determine the antitumor activity of P, in terms of overall response rate (ORR), in two cohorts of MBC pts: BRCA+ (with known BRCA1/2 mutation), and unselected (with BRCA1/2 wild type or unknown mutation status). Secondary aims are to determine duration of response, clinical benefit (response or stable disease > 3 months), PFS and one-year overall survival; to evaluate whether presence of BRCA1/2 mutation predicts response to P in MBC; to explore the activity of P in specific MBC subpopulations, safety, pharmacokinetics (PK), PK/pharmacodynamic correlations, and pharmacogenomics. Planned enrollment is 117 evaluable pts: 53 in the BRCA+ cohort and 64 in the unselected cohort. P will be considered effective if confirmed objective response is achieved in ≥ 17 BRCA+ pts and ≥ 12 unselected patients. An ORR-based futility analysis will be conducted when 20 and 30 evaluable pts have been recruited in each cohort, respectively. If Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr OT1-4-01.

BRCA1-associated breast cancers have been associated to a triple-negative phenotype. The prevalence of BRCA1 germline mutations in young onset TNBC based on informativeness of family history has not been reported. From January 2008 to May 2009 were collected blood and tumor samples from patients with TNBC younger than 50 years and without a family history of breast and ovarian cancer in first- and second-degree relatives. Analysis of BRCA1 germline mutations was made. Age at diagnosis and informativeness of family history (presence of female in first- and second-degree relatives alive until age 45) was collected in all cases. Immunohistochemistry of basal-like features was performed centrally in all available tumors. Seven pathogenic mutations were detected in 92 patients (7.6 %), two of them in patients younger than 35 years (28.6 %) (Fisher's exact test, p = 0.631). Three non-classified variants were detected (3.2 %). Family history was informative in two patients with a pathogenic mutation (28.6 %) and not informative in five (71.4 %) (Fisher's exact test, p = 0.121). Of the seven patients with a pathogenic mutation, four had a basal-like phenotype. Patients with apparently sporadic TNBC younger than 50 years and a non-informative family history are candidates for germline genetic testing of BRCA1.

Management of the axilla in early breast cancer (EBC) patients has dramatically evolved in recent years from more radical to increasingly conservative approaches. Classically, the EBC patients with a clinically positive axilla are offered axillary lymph node dissection (ALND) and those with a clinically negative axilla (cN0) are offered sentinel lymph node (SLN) biopsy, which obviates the complications related to ALND and provides adequate surgical staging and comparable locoregional control and survival. The need for performing ALND when the SLN is positive and contemporary adjuvant treatment is delivered has been questioned in recent years. On the other hand, ongoing trials are testing whether node-positive patients can be spared chemotherapy, based on intrinsic primary tumor biology. Because the integration of novel surgical management and tumor biology is needed, this article provides an overview of the current challenges that a more detailed knowledge of tumor biology has brought to EBC staging and treatment. We propose that breast cancer oncologists (surgeons, radiation therapists, and medical oncologists) should focus their efforts on offering therapy tailored to each patient's needs in such a way that no matter which treatment is used, no overtreatment occurs.

Background: Symptomatic BMinv occurs in a minor proportion of metastatic BC patients (pts). Few data exist regarding its clinical presentation, prognosis and optimal treatment (Tx). ZA has shown to interrupt metastatic “vicious cycle” in bone and to “clear” micrometastastic BMinv in early BC, but its role in symptomatic BMinv remains unclear. We reviewed our series of pts with proven symptomatic BMinv, focusing on Tx delivered and prognosis according to BC subtype and ZA use. Methods: Pts with histologic/cytologic evidence of BMinv from Jan2000 to Feb2012 and with any associated cytopenia were retrospectively identified from Pathology Department files. Results: Twenty-nine pts were identified. Ductal histology: 62%, lobular 24%; Luminal (Lum = HR+/HER2−):76%; HER2+:7%, Triple negative (TN):17%. Stage: II 28%, III 34.5%, IV 24%; median (M) disease free interval: 39.6 months (m) (1.3–113.4). Time BC relapse to BMinv (M): 11.5 m (0–127). At time of BMinv onset: M age 54.7 years (34.3–77.6); M systemic Tx for metastatic disease 2 (0–7). BMinv was present at time of metastatic relapse in 11 pts, including 3 without overt bone metastasis (BM1). Other involved sites at BMinv onset: bone 90% (55% prior to BMinv), nodes 28%, liver 24% and pleuropulmonar 21%. Anemia was the most prominent hematologic sign (97%) followed by thrombocytopenia (Th) (76%) and neutropenia (35%). Tx efficacy in terms of blood count improvement (BCI) and tumor response (TR) outside BM are summarized in table 1. Most pts received non-mielotoxic regimens (endocrine therapy, weekly chemotherapy or capecitabine). ZA was administered in 22 pts (with or without overt BM1). Overall survival (OS)(M) for the whole group was 5.6m (0.3–72.9); M OS in Lum, and TN groups were 9.3 (0.4–72.9) & 0.4m (0.3–20.9+), respectively, while in the 2 HER2+ pts OS was 5.6 & 44.9+ m (p = 0.023). BC subtype, ECOG (0–1 vs 2–3), ZA use after BMinv onset and Th grade (0–1 vs ≥2) were related with OS in the univariate analysis for the whole population. ZA use after BMinv onset, Th grade and presence of BMinv at time of metastatic relapse were also significantly associated with OS in the Lum subgroup. In multivariate analysis, Th remained as an independent factor for OS both in the whole group and Lum subset. ZA use after BMinv onset showed a strong prognostic trend in the Lum group (p = 0.07). Conclusions: BMinv has to be considered in BC pts with BM1 and otherwise unexplained cytopenia. Lum subtype correlates with 9 m M OS, while prognosis in TN subset appears to be particularly dismal. Severe th ( Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P6-13-03.

Background: Objectives: Characterize 1) the frequency of mutations in patients with clinical criteria for HBOC using a 25-gene panel in a Spanish population (FAMOSA study). 2) The psychological impact of these tests and patient''s counseling preferences. Methods: Patients with breast or ovarian cancer who met the NCCN criteria for genetic testing with a) prior testing for BRCA genes with NO mutation identified; or b) recently diagnosed (

This abstract was withdrawn by the authors.

Background: Germline mutation screening of BRCA1 and BRCA2 genes is performed in suspected familial breast cancer cases, but a causative mutation is found in only 30% of patients. The development of additional methods to identify good candidates for BRCA1 and BRCA2 analysis would therefore increase the efficacy of diagnostic mutation screening. With this in mind, we developed a study to determine molecular signatures of BRCA1—or BRCA2—mutated breast cancers. Materials and Methods: Array-cgh (comparative genomic hybridization) and transcriptomic analysis were performed on a series of 103 familial breast cancers. The series included 7 breast cancers with a BRCA1 mutation and 5 breast cancers with a BRCA2 mutation. The remaining 91 cases were obtained from 73 families selected on the basis of at least 3 affected first-degree relatives or at least 2 affected first-degree relatives with breast cancer at an average age of 45 years. Array-cgh analyses were performed on a 4407 BAC-array (CIT-V8) manufactured by IntegraGen. Transcriptomic analyses were performed using an Affymetrix Human Genome U133 Plus 2.0 chip. Results: Using supervised clustering analyses we identified two transcriptomic signatures: one for BRCA1-mutated breast cancers consisting of 600 probe sets and another for BRCA2-mutated breast cancers also consisting of 600 probes sets. We also defined cgh-array signatures, based on the presence of specific genomic rearrangements, one for BRCA1-mutated breast cancers and one for BRCA2-mutated breast cancers. Conclusions: This study identified molecular signatures of breast cancers with BRCA1 or BRCA2 germline mutations. Genes present in these signatures could be exploited to find new markers for such breast cancers. We also identified specific genomic rearrangements in these breast cancers, which could be screened for in a diagnostic setting using fluorescence in situ hybridization, thus improving patient selection for BRCA1 and BRCA2 molecular genetic analysis.

Data reduction is often desired in the development of a prediction model, for example for effects of age and family history in the identification of subjects having a genetic mutation. We aimed to evaluate a strategy for model simplification by robust coding of related predictors. We considered 898 patients suspected of having Lynch syndrome, which is caused primarily by mutations in the mismatch repair genes, MLH1 or MSH2. The presence of colorectal cancer (CRC) and endometrial cancer in patients and their relatives was related to mutation prevalence with logistic regression analysis. The performances of simplified and more complex models were quantified with a concordance statistic (c), which was corrected for optimism by cross-validation and bootstrapping. External validation was performed in 1016 patients. The first challenge was the coding of age at diagnosis of CRC, where we forced effects to be identical in patients, in 1st degree and in 2nd degree relatives, by taking the sum of the ages at diagnosis. As a further simplification, CRC diagnosis in 2nd degree relatives was weighted half that of 1st degree relatives. These data reduction approaches were also followed for endometrial cancer. The simplified model used 7 instead of 17 degrees of freedom (df) for a more complex model incorporating individual predictor effects. The optimism-corrected c was higher (0.79 instead of 0.77), but the external c was similar (0.78 for the simplified and more complex models). A stepwise selected model performed slightly worse (external c=0.77). In conclusion, a prediction model could be developed with relatively few df that captured effects of age at diagnosis across patients and relatives per type of cancer in the family. Such robust coding may especially be relevant for modeling in relatively small data sets.

Approximately, 7 % of all breast cancers (BC) and 11–15 % of ovarian cancers (OC) are associated with inherited predisposition, mainly related to germline mutations in high penetrance BRCA1/2 genes. Clinical criteria for genetic testing are based on personal and family history to estimate a minimum 10 % detection rate. Selection criteria are evolving according to new advances in this field and the clinical utility of genetic testing. Multiplex panel testing carries its own challenges and we recommend inclusion of genes with clinical utility. We recommend screening with annual mammography from age 30 and breast MRI from age 25 for BRCA1 and BRCA2 mutation carriers. Bilateral salpingo-oophorectomy should be offered to women with a BRCA1 or BRCA2 mutation, between 35 and 40 years and after completion of childbearing, or individualise based on the earliest age of ovarian cancer diagnosed in the family. Bilateral risk-reducing mastectomy is an option for healthy BRCA1 and BRCA2 mutation carriers, as well as contralateral mastectomy for young patients with a prior BC diagnosis. BRCA genetic testing in patients with BC and OC may influence their locoregional and systemic treatment.

Background: Women with BRCA1/2 germline mutations who undergo bilateral salpingo-oophorectomy (BSO) are left with a residual risk of peritoneal serous carcinoma (PSC). We aimed to identify the incidence and risk factors for the development of PSC after BSO in BRCA1/2 mutation carriers. Methods: One-hundred-seventeen BRCA1/2 mutation carriers who underwent BSO were evaluated for further development of PSC. The BSO specimens were evaluated for occult Fallopian tube carcinoma (FTC), ovarian carcinoma (OVC) and serous tubal intraepithelial carcinoma (STIC) in all patients. P53-signature was available in 58 patients. Clinical data was obtained from patients’ charts. We calculated the association between clinical, pathological and molecular risk factors of PSC after BSO. Results: Analysis of BSO specimens revealed occult FTC in 1 woman (0.8%), STIC in 2 women (1.7%), and 6/58 women (10.3%) had a positive “p53 signature”. Older age at menopause (p=0.007) and shorter oral contraceptive use (p

Iniparib is an investigational agent with antitumor activity of controversial mechanism of action. Two previous trials in advanced triple-negative breast cancer (TNBC) in combination with gemcitabine and carboplatin showed some evidence of efficacy that was not confirmed. This phase II randomized neoadjuvant study was designed to explore its activity and tolerability with weekly paclitaxel (PTX) as neoadjuvant treatment in TNBC patients. 141 patients with Stage II-IIIA TNBC were randomly assigned to receive PTX (80 mg/m(2), d1; n = 47) alone or in combination with iniparib, either once-weekly (PWI) (11.2 mg/kg, d1; n = 46) or twice-weekly (PTI) (5.6 mg/kg, d1, 4; n = 48) for 12 weeks. Primary endpoint was pathologic complete response (pCR) in the breast. pCR rate was similar among the three arms (21, 22, and 19 % for PTX, PWI, and PTI, respectively). Secondary efficacy endpoints were comparable: pCR in breast and axilla (21, 17, and 19 %); best overall response in the breast (60, 61, and 63 %); and breast conservation rate (53, 54, and 50 %). Slightly more patients in the PTI arm presented grade 3/4 neutropenia (4, 0, and 10 %). Grade 1/2 (28, 22, and 29 %), but no grade 3/4 neuropathy, was observed. There were no differences in serious adverse events and treatment-emergent adverse events leading to treatment discontinuation among the three arms. Addition of iniparib to weekly PTX did not add relevant antitumor activity or toxicity. These results do not support further evaluation of the combination of iniparib at these doses plus paclitaxel in early TNBC.

textabstractContext: Lynch syndrome is caused primarily by mutations in the mismatch repair genes MLH1 and MSH2. Objectives: To analyze MLH1/MSH2 mutation prevalence in a large cohort of patients undergoing genetic testing and to develop a clinical model to predict the likelihood of finding a mutation in at-risk patients. Design, Setting, and Participants: Personal and family history were obtained for 1914 unrelated probands who submitted blood samples starting in the year 2000 for full gene sequencing of MLH1/MSH2. Genetic analysis was performed using a combination of sequence analysis and Southern blotting. A multivariable model was developed using logistic regression in an initial cohort of 898 individuals and subsequently prospectively validated in 1016 patients. The complex model that we have named PREMM1,2 (Prediction of Mutations in MLH1 and MSH2) was developed into a Webbased tool that incorporates personal and family history of cancer and adenomas. Main Outcome Measure: Deleterious mutations in MLH1/MSH2 genes. Results: Overall, 14.5% of the probands (130/898) carried a pathogenic mutation (MLH1, 6.5%; MSH2, 8.0%) in the development cohort and 15.3% (155/1016) in the validation cohort, with 42 (27%) of the latter being large rearrangements. Strong predictors of mutations included proband characteristics (presence of colorectal cancer, especially ≥2 separate diagnoses, or endometrial cancer) and family history (especially the number of first-degree relatives with colorectal or endometrial cancer). Age at diagnosis was particularly important for colorectal cancer. The multivariable model discriminated well at external validation, with an area under the receiver operating characteristic curve of 0.80 (95% confidence interval, 0.76-0.84). Conclusions: Personal and family history characteristics can accurately predict the outcome of genetic testing in a large population at risk of Lynch syndrome. The PREMM1,2 model provides clinicians with an objective, easy-to-use tool to estimate the likelihood of finding mutations in the MLH1/MSH2 genes and may guide the strategy for molecular evaluation.

This phase II multicentric study evaluates a modified preoperative chemoradiotherapy schedule.Patients75 years with potentially resectable neoplasm were eligible. Treatment included an initial course of CDDP 100 mg/m2 (Day 1) and 5-FU CI 5000 mg/m2 (Days 1-5) followed by 45 Gy (Days 28-63) and 5-FU CI 5000 mg/m2 (Days 28-33), CDDP 75 mg/m2 (Day 56) and 5-FU CI 3750 mg/m2 (Days 56-61). Regional lymph nodes were irradiated.Nineteen patients were studied. Oesophagectomy was performed in 17. Clear margins were achieved in 16 of these. Eight patients showed a pathologic complete response (pCR). One patient died of infection during the preoperative treatment and four died due to acute surgical complications. The study was closed prematurely because of excessive mortality. Median follow-up was 19 months. Local and regional relapse occurred in one and three patients, respectively. Median time and actuarial 3-year of overall survival and progression free rates were 18.6 months and 28%, and 12.7 months and 10.4%, respectively.This schedule showed a high pCR, resectability and local control rate. Treatment-related mortality limits its clinical applicability, but further investigations are warranted.

Lynch syndrome (LS) is an autosomal dominant cancer-susceptibility disease caused by inactivating germline mutations in mismatch repair (MMR) genes. Variants of unknown significance (VUS) are often detected in mutational analysis of MMR genes. Here we describe a large family fulfilling Amsterdam I criteria carrying two rare VUS in the MLH1 gene: c.121GC (p.D41H) and c.2128AG (p.N710D). Collection of clinico-pathological data, multifactorial analysis, in silico predictions, and functional analyses were used to elucidate the clinical significance of the identified MLH1 VUS. Only the c.121GC variant cosegregated with LS-associated tumors in the family. Diagnosed colorectal tumors were microsatellite unstable although immunohistochemical staining revealed no loss of MMR proteins expression. Multifactorial likelihood analysis classified c.2128AG as a non-pathogenic variant and c.121GC as pathogenic. In vitro functional tests revealed impaired MMR activity and diminished expression of c.121GC. Accordingly, the N710 residue is located in the unconserved MLH1 C-terminal domain, whereas D41 is highly conserved and located in the ATPase domain. The obtained results will enable adequate genetic counseling of c.121GC and c.2128AG variant carriers and their families. Furthermore, they exemplify how cumulative data and comprehensive analyses are mandatory to refine the classification of MMR variants.

Summary Background: It is estimated that about 5%-10% of breast cancer (BC) cases is due to inherited predisposition. Early works reported that 45%-50% of site-specific BC families had BRCA1 mutations and 25%-35% BRCA2 mutations. However, these percentages could have been overestimated and likely vary among the populations studied. Patients and methods: We analysed the BRCA2 gene in 87 Spanish breast/ovarian cancer families in which the BRCA1 mutation screening was negative. Results: We detected 15 (17.2%) disease-causing mutations and 11 polymorphisms and unclassified variants. Four mutations were recurrent, and five were novel. Seven (47%) mutations were found in site-specific female BC families, five (33%) in families with OC cases, and three (20%) mutations in families with male BC cases. There was incomplete penetrance of the mutations in some families, and considerable phenotypic variations with respect to the age of diagnosis and cancer types. Conclusions: The percentage of mutations detected reinforces the possibility that some of these families have mutations in genes other than BRCA1 or BRCA2 that confer lower BC risks.

It is believed that 5% of all cancers are hereditary, on being caused by mutations in the germinal line in cancer susceptibility genes. The hereditary pattern in the majority of cases is autosomal dominant. Genetic tests are only recommended to individuals whose personal or family history is highly suggestive of a hereditary cancer. The appropriate assessment of these individuals and their families must be performed in Cancer Genetic Counselling Units (UCGC).Representatives of the Spanish Medical Oncology Society (Sociedad Española de Oncología Médica [SEOM]) and the three primary care scientific societies: Spanish Society of Family and Community Medicine (Sociedad Española de Medicina de Familia y Comunitaria [SEMFyC]), Spanish Society of Primary Care Physicians (Sociedad Española de Médicos de Atención Primaria [SEMERGEN]) and the Spanish Society of General and Family Doctors (Sociedad Española de Médicos Generales y de Familia [SEMG]), met to prepare this consensus document on hereditary cancer. The consensus identified the three main aspects: how to identify subjects at risk of hereditary cancer; how to refer to a UCGC; and the usefulness of the assessment and genetic studies.A document, with the text fully agreed by all the participants, has been prepared. It contains a summary of the principal characteristics of the care for individuals with hereditary cancer. It shows how to; identify them, assess them, refer them to a UCGC. How to assess their genetic risk, perform genetic studies, as well as prevention measures and reduction of the risk is also presented.This consensus document is a landmark in the relationships with several Scientific Societies that represent the professionals who provide care to individuals with cancer and their families, and will help to improve care in hereditary cancer in Spain.

Biallelic inactivation of ATM gene causes the rare autosomal recessive disorder Ataxia-telangiectasia (A-T). Female relatives of A-T patients have a two-fold higher risk of developing breast cancer (BC) compared with the general population. ATM mutation carrier identification is laborious and expensive, therefore, a more rapid and directed strategy for ATM mutation profiling is needed. We designed a case-control study to determine the prevalence of 32 known ATM mutations causing A-T in Spanish population in 323 BRCA1/BRCA2 negative hereditary breast cancer (HBC) cases and 625 matched Spanish controls. For the detection of the 32 ATM mutations we used the matrix-assisted laser desorption/ionization time-of-flight mass spectrometry technique. We identified one patient carrier of the c.8264_8268delATAAG ATM mutation. This mutation was not found in the 625 controls. These results suggest a low frequency of these 32 A-T causing mutations in the HBC cases in our population. Further case-control studies analyzing the entire coding and flanking sequences of the ATM gene are warranted in Spanish BC patients to know its implication in BC predisposition.