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Triple-negative breast cancer (TNBC) represents approximately 10-20% of Breast Cancer (BC) diagnosed worldwide and in accordance with the current guideline it is defined by the absence of expression of the of expression of the estrogen receptor (ER=60yThe majority of BC was diagnosed at an early stage. All TNBCs present ductal histotype, mostly with high proliferation rate and grading 3. Characteristics of tumors are shown in Table 1. In our cohort, PALB2 mutations were the most frequent PVs in non-BRCA genes, in line with several previous studies. Interesting, we identified RAD51C/D mutations as second PVs non-BRCA genes, in support of certain studies that suggest an association with an increased risk for TNBC and OC. In conclusion, our results support the MGP using, opening the question about the 60-year cut off for genetic testing in TNBC, regardless of family history. Table 1.Characteristics of TNBC tumors in patients carrying other than BRCA gene mutationsPALB2RAD51C/DATMMUTYHBRIPPMS2PTENNBNBARD1CHECK2TP53Number of patients165332111111Mean age at diagnosis (y)61.4 (44-94)48 (33-62)52.3 (49-54)44.3(40-50)42.5 (36-49)394958485036Ki 67 (%)=406(54.5%)4(100%)1(50%)1 (50%)1(100%)100100unknown51111000011GradingG1-23 (25%)0000001000G39 (75%)4 (100%)3 (100%)3(100%)2(100%)110101Unknown41000000010Histotypeductal14 (100%)4(100%)3(100%)3(100%)2(100%)110111others00000001000unknown21000000000Stage at diagnosisI7 (63.6%)3 (60%)01 (100%)1 (100%)010000II4 (36.4%)1 (20%)2 (100%)00001000III01 (20%)000300000unknown50121000111 Citation Format: Laura Cortesi, Marta Venturelli, Angela Toss, Claudia Piombino, Elena Barbieri, Elisabetta Razzaboni, Luca Moscetti, Federico Piacentini, Claudia Omarini, Federica Domati, Massimo Dominici. Characteristics of TNBC patients carrying other than BRCA gene mutations [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P2-09-14.

Triple-negative breast cancer (TNBC) patients who do not obtain pathologic complete response (pCR) after neoadjuvant chemotherapy (NACT) present higher rate of relapse and worse overall survival. Risk factors for relapse in this subset of patients are poorly characterized. This study aimed to identify predictive factors for relapse in TNBC patients without pCR after NACT. Women with TNBC treated with NACT from January 2008 to May 2020 at the Modena Cancer Center were included in the analysis. We identified 142 patients with median follow-up of 55 months. After NACT, 62 patients obtained pCR (43.9%). Young age at diagnosis (< 50 years) and high ki-67 (>20%) were significantly associated to pCR. Lack of pCR after NACT resulted in worse 5-year EFS and OS. Factors independently predicting EFS in patients without pCR were the presence of multifocal disease (HR 3.22; 95% CI, 1.28–8.11; P 0.01) and Residual Cancer Burden (RCB) III (HR 3.8; 95% CI, 1.12–12; P 0.03). These data can be used to stratify patients and potentially guide treatment decision-making, identifying appropriate candidates for treatment intensification especially in neo/adjuvant setting.

Objective: As prostate cancer (PrC) shows a BRCA mutation rate as high as 30%, it becomes crucial to find the optimal selectioncriteria for genetic testing. The primary objective of this study was to evaluate the BRCA mutation rate in families with PrC associatedwith breast and/or ovarian cancers; secondary aims were to compare the characteristics of families and BRCA-related PrC outcomeamong BRCA1 and BRCA2 carriers. Methods: Following the Modena criteria for the BRCA test, we evaluated the mutation rate in families with breast and/or ovariancancer with a Gleason score ≥7 PrCs, by testing breast or ovarian cases and inferring the mutation in the prostate cases. Thecharacteristics of families and BRCA-related PrC outcomes were measured using the chi-square (χ2) test and Kaplan–Meier methods,respectively. Results: Among 6,591 families, 580 (8.8%) with a Gleason score ≥ 7 PrCs were identified, of which 332 (57.2%) met the Modenaselection criteria for BRCA testing. Overall, 215 breast or ovarian cancer probands (64.8%) were tested, of which 41 resulted positivefor BRCA and one for CHEK2 genes (19.5%). No statistically significant differences were found in BRCA-related PrC prognosis andin the characteristics of families among BRCA1, BRCA2 and non-tested patients. Ten of 23 (44%) mutations in the BRCA2 gene fellin the prostate cancer cluster region (PCCR) at the 3′ terminal of the 7914 codon. Conclusions: It appears the Modena criteria are very useful for BRCA testing selection in families with breast and/or ovarian cancerand PrC. A trend toward a worse prognosis has been found in BRCA2 carriers.

BackgroundAdult body fatness is a convincing risk factor for postmenopausal breast cancer. With the aim to compare the different breast cancer (BC) features in Northern and Southern Italy, we investigated the relationship between BMI and BC characteristic in two groups of patients referred in the Modena and Lecce breast units.Materials and MethodsA retrospective analysis of a continuous series of BC patients referred to the Città di Lecce Hospital and the Modena Cancer Center, from January 2019 to December 2020 was performed. We identified four groups of BMI at BC diagnosis: underweight, BMI 2; normal weight, BMI ≥ 18.5–24.9 kg/m2; overweight, BMI ≥ 25.0–29.9 kg/m2; obese, BMI ≥30.0 kg/m2. BC characteristics and clinical outcomes were analyzed by the Kolmogorov-Smirnov test and Mann-Whitney U test; categorical data were compared using Pearson’s chi-square test, and dicotomic data were compared by odds ratio.ResultsNine hundred seventy-seven BC patients were included in the analysis. Overall, 470 were from Modena and 507 from Lecce. No differences were observed in the mean age of BC patients of Modena (61,42) and Lecce (62,08). No statistical differences between the two populations were shown in terms of tumor characteristics and pathological stage. Conversely, a statistical difference of BMI between the BC patients coming from Modena and Lecce (25.87 and 27.81, respectively; p = 0.000001) was found. BC patients diagnosed in Lecce at age ≥70 years had higher median BMI compared with the ones from Modena (p = 0.000002). The increased BMI in this aged population was also associated to larger tumor size (p = 0.040).ConclusionThe rate of overweight and obesity was higher in BC women living in Southern Italy, despite the presumed nutrition according to the so-called Mediterranean type dietary pattern. Unexpectedly, an increased BMI rate and a relationship with larger tumor size were found in Southern BC patients aged ≥70 years. Our findings strongly support the need for promoting a healthier lifestyle model in Italy, with the aim of reducing the rate of the obesity and, consequently, the increased risk of BC.

Mutation carriers (Mut+) in DNA mismatch repair genes are predisposed to cancer of various organs and to adenomatous polyps; however, they may remain asymptomatic and cancer or polyp-free for several years. We purposed to analyse the clinical follow-up of individuals carrying constitutional mutations in the MLH1, MSH2 or MSH6 genes who were unaffected by benign polyps or malignant tumours at diagnosis.Mut + subjects (n.81) were members of Lynch syndromes in whom mutations were detected between 1993 and 2015; all were asymptomatic at diagnosis. They were informed of the cancer risk and surveillance was suggested. As controls, 113 nongene carriers (Mut-) in the same Lynch families were identified.About one-fourth of the mutation carriers developed polyps, mostly adenomas; polyps were less (12%, p .05) in Mut - subjects, and hyperplastic lesions were the prevalent histology. More polyps were detected in MLH1 vs. MSH2 mutation carriers. In Mut+, 21 malignant tumours developed in 14 carriers vs. 4 tumours in 3 patients among Mut- (p .001). Tumours were mostly of the Lynch spectrum; however, three glioblastomas were developed, together with neoplasms of various organs (duodenum, thyroid, skin, lung and cervix). Mean age of tumour occurrence was 43.0 years in Mut + vs. 53.0 among Mut-.Cancer developed more often in Mut+, with no consistent difference between MLH1 and MSH2 carriers. More polyps (mostly adenomas) were detected in MLH1 carriers. The majority (13 of 21) of malignant tumours occurred in organs for which there is no recommended surveillance, and were lethal in three patients.

Relatively little is known on the genotype-phenotype correlations between SMAD4 gene mutations, juvenile polyposis of the intestine and Hereditary Hemorrhagic Teleangectasia. We describe a family in which the proband (a 46-year old woman) had massive polyposis of the stomach-leading to surgery-with high-grade dysplasia at histology. Molecular analysis was carried out using Next Generation sequencing techniques with Miseq Illumina Platforms and a minimal coverage of 40 reads. In the proband, the analysis showed the presence of a truncating mutation in the SMAD4 gene (c.1213dupC, a variant previously associated with juvenile polyposis and Hereditary Hemorrhagic Teleangectasia). The same mutation was detected in two other members of the family (father and brother of the proband), who showed massive polypoid involvement of the stomach at gastroscopy. By taking the family history, subtle evidence of Hereditary Teleangectasia was found (nasal bleeding and arterovenous malformations) in the three gene carriers. Colonoscopy showed polyp occurrence in all three affected members with SMAD4 mutation, with prevalence of adenomatous lesions in one (father), of hamartomas in the brother, and of a mix of histological types in the proband. The main features of the family can be summarized as follows: (A) In hereditary juvenile polyposis, lesions of different histology can be detected at colonoscopy; (B) In the gene carriers of SMAD4 mutations, lesions of the stomach require careful surveillance and, when necessary, surgical interventions; (C) Signs and symptoms of Hereditary Hemorrhagic Teleangectasia should be suspected (and searched) in individuals with SMAD4 constitutional mutations.

Aims The clinical outcome of patients with locally advanced rectal cancer who undergo neoadjuvant chemoradiotherapy (CRT) is influenced by the tumour response to treatment, which is reflected by tumour regression grade and post-treatment (y) TNM stage. Little is known about the prognostic value of pretreatment histopathological features of the tumour that may be useful to discriminate potential non-responders and to design tailored therapeutic strategies. In this study, we aimed to investigate the prognostic role of poorly differentiated clusters (PDCs) of neoplastic cells in pretreatment biopsies of patients with rectal cancer treated with neoadjuvant CRT. Methods and results Grading based on PDC counting was retrospectively applied to 204 pretreatment endoscopic biopsies of rectal carcinomas from patients treated with neoadjuvant CRT and surgery. Interobserver agreement in the assessment of PDC grade was good. High PDC grade was significantly associated with high yT stage (P = 0.044), yM+ status (P = 0.0004), and unchanged TNM stage or TNM upstaging (P = 0.032). In addition, high PDC grade was a significant and independent prognostic factor for cancer-specific survival. Conclusions PDC grade may be assessed in preoperative biopsies of rectal cancer with good reproducibility. High PDC grade in a pretreatment tumour is significantly associated with a poor response to therapy. Hence, we suggest that PDC grading might be used as a significant predictive and prognostic factor in patients with locally advanced rectal cancer who are treated with neoadjuvant CRT, and to identify high-risk patients who need surgery and adjuvant chemotherapy.

Attenuated polyposis could be defined as a variant of familial adenomatous polyposis (FAP) in which synchronous polyps of the large bowel range between 10 and 99. We analysed all cases of attenuated polyposis observed over the last 30 years with the objectives: (A) to classify the disease according to different type and proportion of polyps; (B) To ascertain the contribution of APC and MutYH genes; (C) to discover features which could arise the suspicion of mutations; (D) To obtain indications for management and follow-up. 84 individuals in 82 families were studied. Polyps were classified into four groups as adenoma, hyperplastic, other serrated lesions or others; APC and MutYH mutations were assessed. Mean age at diagnosis was 54 ± 14 years in men and 48 ± 13 in women (P = 0.005). Polyps were more numerous in women (37 ± 26 vs 29 ± 22). Sixty % of patients underwent bowel resection, mainly for cancer; the remaining were managed through endoscopy. A total of 2586 polyps were detected at diagnostic endoscopy: 2026 (80 %) were removed and analysed. Adenomas were diagnosed in 1445 (70 %), hyperplastic polyps in 541 (26 %), other serrated lesions in 61 (2.9 %). Adenomas and hyperplastic lesions were detected in the majority of patients. In 68 patients (81 %) in whom studies were executed, APC mutations were found in 8 and MutYH mutations in 10. Genetic variants were more frequent in women (12 vs 6, P = 0.039). Taking into consideration the prevalent (>50 %) histology and presence of mutations, patients could be subdivided into four groups: (1) APC mutated polyposis (AFAP), when adenomas were >50 % and APC mutations detected (no. 8, 10 %); (2) MutYH mutated polyposis (MAP), adenomas >50 % and biallelic MutYH mutations (no. 10, 12 %); (1) attenuated polyposis without detectable mutations, prevalence of adenomas, 48 cases (57 %); (1) hyperplastic-serrated polyposis, with prevalence (>50 %) of hyperplastic/other serrated lesions and no constitutional mutation (no. 18, 21 %). Aggregation of tumors, cancer in probands, distribution of polyps and other clinical characteristics showed no difference among the four groups. In conclusions, AFAP and MAP, the polyposis labeled by constitutional mutations, represented about 25 % of all attenuated polyposis. Mutation-associated cases showed an earlier age of onset of polyps and were more frequent in the female sex.

The aim of the study was to investigate the clinical features, including survival, of patients with colorectal malignancies developed at a very early age (≤40 years), together with possible factors involved in the pathogenesis of these rare neoplasms. The study took advantage of the existence of a specialized colorectal cancer Registry active from 1984. 57 patients met the criteria of early onset cancer; main epidemiological data, morphology, stage, familial aggregation, possible role of inheritance and survival were analyzed. Despite the relevant increase over time of all registered patients, joiningpoint analysis of crude incidence rate of early onset colorectal neoplasms revealed a certain stability of these tumors (EAPC: 2.4, CI 14–22) with a constant prevalence of the male sex. Stage at diagnosis did not show significant variations between early onset and maturity onset colorectal neoplasms. Hereditary as well as familial cases were significantly (P < 0.005 and 0.03) more frequent among patients with early onset tumors, although in the majority of them no specific etiological factor could be identified. Survival was more favorable in patients with early onset tumors, though this had to be attributed to the higher presence of some histological types in early onset cases. Survival was significantly more favorable for patients of all ages registered in the last decade. Incidence of early onset colorectal cancer was relatively stable between 1984 and 2008. A male preponderance was evident through the registration period. Hereditary and familial cases were significantly more frequent among early onset case. A well defined etiology could be observed in 16 % of the cases (versus 2–3 % in older individuals). Five-year survival showed a significant improvement over time.

e13674 Background: BRCA germline (gBRCA) mutations occur in 11-15% of women with unselected ovarian cancers (OC), whereas somatic BRCA (sBRCA) mutations occur in approximately 5-7% of cases. The impact of sBRCA mutations on OC outcome is still debated. Methods: With the aim to explore the prognostic role of sBRCA mutations, the BRCA mutational status of 149 non-mucinous and non-borderline OC and their clinical-pathological features were evaluated. BRCA1 and BRCA2 mutational profiles, either for sequence variants or copy number alterations, were evaluated by amplicon next-generation sequencing (NGS) technology. Results: 29 (19.5%) patients carried a gBRCA mutation (12.7% BRCA1 and 6.7% BRCA2). 26 (17.5%) patients presented a sBRCA mutation (6.7% BRCA1, 10% BRCA2, 0.6% BRCA1+BRCA2). Patients carrying a gBRCA mutation were slightly younger (57 years) than the others (60 years). The FIGO stage at the diagnosis was III-IV in 77.2% of cases, with no significant difference among subgroups. The most frequent histotype was serous for all the subgroups (93.1% in gBRCA, 84.6% in sBRCA, 77.7% in BRCA-negative, p = 0.08). 80.7% of sBRCA mutation carriers, 62.1% of gBRCA mutation carriers and 62.7% of BRCA-negative patients underwent upfront surgery (p = 0.46). 29.1% of sBRCA mutation carriers, 17.8% of gBRCA mutation carriers and 25.6% of BRCA-negative patients presented macroscopic residual disease after surgery (p = 0.68). Although non-statistically significant, gBRCA-associated OC were more likely to be platinum-sensitive (96.6%) than the other patients (92% in sBRCA and 87.1% in BRCA-negative patients). Overall, the median platinum-free interval (PFI) resulted shorter in sBRCA mutation patients compared to gBRCA and BRCA-negative patients (p = 0.051). No patient took PARP inhibitors as maintenance after the first line therapy. Also progression free survival 2 (PFS2) resulted shorter for sBRCA mutation patients (p = 0.008). Three sBRCA and 5 gBRCA mutation carriers took a PARP inhibitor as maintenance after the second line therapy. Finally, sBRCA mutated patients showed worse overall survival (OS) compared to the other subgroups (p = 0.014). Conclusions: Overall, 19.5% of OC patients presented a gBRCA mutation, while 17.5% of patients showed sBRCA mutations. sBRCA-related OC did not show significantly differences in clinical-pathological features (stage at diagnosis, histotype, time to surgery and residual after surgery). To our knowledge this is the first study showing shorter PFI, PFS2 and OS in patients carrying sBRCA mutations.