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Brazil is the largest country in South America and the most genetically heterogeneous. The aim of the present study was to determine the prevalence of germline pathogenic variants (PVs) in Brazilian patients with breast cancer (BC) who underwent genetic counseling and genetic testing at a tertiary Oncology Center. We performed a retrospective analysis of the medical records of Brazilian patients with BC referred to genetic counseling and genetic testing between August 2017 and August 2019. A total of 224 unrelated patients were included in this study. Premenopausal women represented 68.7% of the cohort. The median age at BC diagnosis was 45 years. Multigene panel testing was performed in 219 patients, five patients performed single gene analysis or family variant testing. Forty-eight germline PVs distributed among 13 genes were detected in 20.5% of the patients (46/224). Eighty-five percent of the patients (91/224) fulfilled NCCN hereditary BC testing criteria. Among these patients, 23.5% harbored PVs (45/191). In the group of patients that did not meet NCCN criteria, PV detection rate was 3% (1/33). A total of 61% of the patients (28/46) harbored a PV in a high-penetrance BC gene: 19 (8.5%) BRCA1/2, 8 (3.5%) TP53, 1 (0.5%) PALB2. Moderate penetrance genes (ATM, CHEK2) represented 15.2% (7/46) of the positive results. PVs detection was statistically associated (p<0.05) with BC diagnosis before age 45, high-grade tumors, bilateral BC, history of multiple primary cancers, and family history of pancreatic cancer. According to the current hereditary cancer guidelines, 17.4% (39/224) of the patients had actionable variants. Nine percent of the patients (20/224) had actionable variants in non-BRCA genes, it represented 43.5% of the positive results and 51.2% of the actionable variants. Considering the observed prevalence of PVs in actionable genes beyond BRCA1/2 (9%, 20/224), multigene panel testing may offer an effective first-tier diagnostic approach in this population.

Breast cancer (BC) is the most prevalent malignancy in women with Li-Fraumeni syndrome (LFS). The literature on BC in LFS is limited due to its rarity worldwide. A TP53 founder pathogenic variant (c.1010G&gt;A; p.R337H) is responsible for the higher prevalence of this syndrome among women of Brazilian ancestry.PurposeThe aim of the study was to describe the BC phenotype expressed by Brazilian female LFS carriers and compare the data between p.R337H and other TP53 germline pathogenic/likely pathogenic variants (non-p.R337H carriers).MethodsWe searched for cases of TP53 germline pathogenic/likely pathogenic variant carriers affected by BC included between 2015 and 2020 in the BLiSS (Brazilian Li-Fraumeni Study) registry at the Sírio-Libanês Hospital.ResultsAmong 163 adult female carriers from the registry, 91 (56%) had received a BC diagnosis, including 72 p.R337H carriers. BC was the first cancer diagnosed in 90% of cases. Early onset BC (age ≤45 years) was diagnosed in 78.2% of cases (11.5% &lt;31 years; 66.7% 31–45 years; 21.8% &gt;45 years). The median age of BC diagnosis for p.R337H carriers was 39.5 years (range 20–69 years) compared to 34 years (range 21–63 years) for non-p.R337H carriers (p = 0.009). In total, 104 breast tumors were observed in 87 women. Bilateral BC was observed in 29.3% of cases. Histology was available for 96 tumors, comprising 69 invasive breast carcinomas, which were mostly invasive ductal carcinomas (95.6%), 25 ductal in situ carcinomas and 2 soft-tissue sarcomas. Overall, 90.5% of invasive breast carcinomas were hormone receptor (HR)-positive, 39.5% were human epidermal growth factor receptor 2 (HER2)-positive, and 32.8% showed HR and HER2 co-expression. In addition, 55.4% of patients opted for contralateral prophylactic mastectomy after a first BC diagnosis. There were no significant differences in the risk of developing contralateral BC or in the immunohistochemical profile between p.R337H and non-p.R337H groups.ConclusionsThe expressed phenotype of p.R337H is similar to that of other TP53 pathogenic/likely pathogenic variants, except for an average older age at the onset of disease; however, this is still younger than the general population.

Background: Even though breast cancer is uncommon in women ≤ age 35, women in this group are more likely to present aggressive cancer subtypes, advanced clinical stage at diagnosis and pathogenic variants (PV) in cancer susceptibility genes. Higher recurrence and mortality rates in very early-onset breast cancer patients may be related to differences in tumor biology, mutation status, clinical or treatment features. Management of those women should comprehend dedicated approach and standard care that are often not available on cancer care centers at low-middle income countries. We aim to describe the clinical and pathological factors associated with very early-onset breast cancer patients and the challenges associated with treatment of those women in a public health facility in Brazil. Methods: Retrospective review of 748 patients diagnosed and treated at the biggest surgical center for breast cancer in Brasilia - Brazil between 2015 and 2020 was performed and 54 patients with cancer diagnosis ≤ age 35 were identified. Pathological and clinical characteristics as well as treatment information were collected from medical and electronic patients’ records. Bivariate and multivariate analyzes were performed. Findings: Median age at diagnosis was 31.9 years old (23 to 35). 44% had a positive familial history for HBOC. 20% presented first period &lt;12 years of age and 61% and 53% had first childbirth &lt; 30 years and breastfed for over 6 months, respectively. Only 10% had a BMI index over 30, and 37% were overweight. The distribution of BC stage at diagnosis was I (9.3%), II (51.9%), III (29.6%) and IV (3.7%). The most common were invasive carcinoma of no special type (98%) and malignant phyllodes (2%) and 10.9%, 50.9% and 27.3% were grades 1, 2 and 3, respectively. BC subtypes were as follows: Luminal A 18.5%, Luminal B 31.5%, HER2 positive 24.1% and Triple negative 25.9%. With a mean follow-up of 31.94 months, the overall survival rate was 93%, with a recurrence-free survival rate of 72.1%.Although all patients met the criteria for germline testing, only 25.9% had access, with two BRCA1, four BRCA 2, one CHECK2 and one TP53 PV detected. 27.8% had BCS as surgical treatment and 53.7% e 13% had unilateral and bilateral mastectomy. There was an increased rate of bilateral mastectomy on the last 8 years. 73.6% were treated with neoadjuvant chemotherapy (NC) and mean interval between NC and surgery was 61.1 days (19-370). 63% had radiotherapy and the mean interval between previous treatment (chemotherapy or surgery) and radiotherapy was 93.8 days (56-150). None of the HER2 positive patients were exposed to dual HER2 blockade and there was no adjuvant treatment with T-DM1 or capecitabine when pCR was not achieved. Only 22% of the women with hormone receptor tumors were exposed to ovarian suppression alongside hormone therapy. Of the 54 patients, 27.9% relapsed, 18.6% distant recurrence, 9.3% local. The most common sites of metastasis was bone and liver (6.8% each) followed by lung and central nervous system (3.4% and 1.7%). Conclusions: Previous studies showed that breast cancer is diagnosed at an earlier age among Brazilian patients. BC is often detected when symptomatic and therefore a significant proportion is diagnosed at more advanced clinical stages. These findings alongside the restrict acess to genetic counseling and the delay on treatment in the public healthcare system are a clear indication of the challenges for achieving standard care for those patients and could have a significant impact on survival outcomes. These data combined indicate the need for supportive care program for young women with breast cancer. Citation Format: Natasha Garcia Caldas, Karoline Evangelista Souza, Thais Karla Vivan, Vinicius Xavier Santana, Mauro Pinto Passos, Natalia Polidorio. Clinical and pathological features of very early-onset breast cancer and treatment challenges on public health care system at a cancer center in Brazil [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 PS7-81.

10623 Background: Risk-reducing mastectomy (RRM) is a common strategy for managing breast cancer (BC) risk in women with Li-Fraumeni syndrome (LFS). Data on uptake and health-related quality of life (HRQoL) in LFS are limited and often extrapolated from BRCA scenario, despite the lack of evidence on survival benefits in LFS. This study evaluated RRM uptake and its impact on HRQoL in women with LFS. Methods: TP53 PV female carriers from a Brazilian LFS cohort from January 2012 to December 2022 were eligible. After informed consent, 90 women reported oncological status, uptake of RRM, and completed BREAST-Q questionnaire. Scores were compared among different BC risk management strategies and minimal important difference (MID) of ≥ 4 was described. Multivariable analyses were performed to identify surgical factors related to HRQoL outcomes. Results: 71.7% (n=33) of women diagnosed with unilateral BC (n=46) underwent contralateral risk-reducing mastectomy (CRRM) at a median age of 39 years. Among unaffected BC women (n=44), 36.3% underwent bilateral risk-reducing mastectomy (BRRM) at a median age of 36 years. CRRM was associated with lower scores for psychosocial (64[±19] vs 93[±21], p=.05) and physical well-being (72[±16] vs 92[±18], p=.001). BRRM women had lower physical well-being scores (72[±19] vs 92[±13], p=.003). MID associated with worst HRQoL outcomes were seen in all four domains on CRRM women and on satisfaction with breasts and physical well-being of BRRM patients (table). Nipple-sparing mastectomy (NSM) presented better psychosocial (74[±20] vs 52[±19], p=.04) and sexual well-being (60[±20] vs 46[±20], p=.05) when compared to skin-sparing mastectomy (SSM) on CRRM patients and with higher sexual well-being (60[±20] vs 46[±20], p=.05) on BRRM patients. Women with BRRM > 2 years had better physical well-being (83[±14] vs 56 [±12], p<.001). There were no significant differences in scores of women with age £35 years at the time of BRRM, although MID ≥ 4 was observed on psychosocial and sexual well-being and satisfaction with breasts: -23.0, -14.4, and -20.0, respectively. Conclusions: We observed high rates of RRM in LFS women and those were associated with worse outcomes on breast HRQoL in comparison to surveillance. The potential benefits and harms of RRM should be carefully discussed with patients before performing it, especially in LFS women where the survival benefits of these interventions remain uncertain. [Table: see text]