Carriers Of Pathogenic Variants Research Articles

Incidences of colorectal adenomas and cancers under colonoscopy surveillance suggest an accelerated “Big Bang” pathway to CRC in three of the four Lynch syndromes

BackgroundColorectal cancers (CRCs) in the Lynch syndromes have been assumed to emerge through an accelerated adenoma-carcinoma pathway. In this model adenomas with deficient mismatch repair have an increased probability of acquiring additional cancer driver mutation(s) resulting in more rapid progression to malignancy. If this model was accurate, the success of colonoscopy in preventing CRC would be a function of the intervals between colonoscopies and mean sojourn time of detectable adenomas. Contrary to expectations, colonoscopy did not decrease incidence of CRC in the Lynch syndromes and shorter colonoscopy intervals have not been effective in reducing CRC incidence. The prospective Lynch Syndrome Database (PLSD) was designed to examine these issues in carriers of pathogenic variants of the mis-match repair (path_MMR) genes.Materials and methodsWe examined the CRC and colorectal adenoma incidences in 3,574 path_MLH1, path_MSH2, path_MSH6 and path_PMS2 carriers subjected to regular colonoscopy with polypectomy, and considered the results based on sojourn times and stochastic probability paradigms.ResultsMost of the path_MMR carriers in each genetic group had no adenomas. There was no association between incidences of CRC and the presence of adenomas. There was no CRC observed in path_PMS2 carriers.ConclusionsColonoscopy prevented CRC in path_PMS2 carriers but not in the others. Our findings are consistent with colonoscopy surveillance blocking the adenoma-carcinoma pathway by removing identified adenomas which might otherwise become CRCs. However, in the other carriers most CRCs likely arised from dMMR cells in the crypts that have an increased mutation rate with increased stochastic chaotic probabilities for mutations. Therefore, this mechanism, that may be associated with no or only a short sojourn time of MSI tumours as adenomas, could explain the findings in our previous and current reports.

HRD-negative high-grade carcinoma of the ovary in <i>BRCA2</i> pathogenic variant carrier

Background. Homologous recombination deficiency (HRD) is a valuable molecular marker for predicting response to platinum agents and poly(ADP-ribose)-polymerase (PARP) inhibitors. Germline and somatic alterations in the BRCA1 and BRCA2 genes are the major cause of HRD in ovarian cancer. However, in some cases, tumors arising in carriers of BRCA1 or BRCA2 pathogenic variants do not lose the normal copy of the corresponding gene and are not deficient for homologous recombination. Aim of the study was to present a case of high-grade ovarian carcinoma without HRD phenotype developed in a BRCA2 mutation carrier. Case report. A 48-year-old woman was diagnosed with multiple primaries: HER2-positive high-grade ovarian cancer and colorectal adenocarcinoma. analysis of the coding BRCA1/BRCA2 sequences revealed the germline BRCA2 c.658_659delgt [rs80359604] pathogenic variant. Given the unusual histological features, namely the absence of serous or endometrioid markers and high HER2 expression, we performed additional molecular analysis of the metastatic lesions in the lymph nodes. In all samples, the pattern of chromosomal instability did not match the HRD profile and there was loss of the mutant copy of the BRCA2 gene. Therefore, this tumor lacked the BRCAness phenotype. Conclusion. Tumors arising in HRR gene mutation carriers require additional molecular analysis for a comprehensive assessment of HRD.

High Frequency of BRCA2 c.5576_5579del Carriers in Kakogawa, Japan.

Certain germline pathogenic variants (PVs), known as founder mutations, have been frequently observed in specific regions and ethnic groups. In Japan, several pathogenic variants of BRCA1/2 have been identified as founder mutations, with their distribution varying across different regions. This retrospective study aimed to further investigate the detailed distribution and correlation between genotype and clinical features among breast cancer patients. This study was conducted at Kobe University Hospital and three collaborating institutions. It included breast cancer patients who underwent BRCA1/2 genetic testing between July 1, 2018, and March 31, 2021, and were found to have germline PVs. Clinical characteristics and breast cancer subtypes were compared between carriers of BRCA2 c.5576_5579del and those with other PVs. Additionally, the detection rate of BRCA2 c.5576_5579del was compared with that observed in a previous report. A total of 38 breast cancer patients were included; PVs in BRCA1 and BRCA2 were detected in 12 and 26 patients, respectively, 12 of whom were BRCA2 c.5576_5579del carriers. BRCA2 c.5576_5579del carriers were more likely to develop triple negative breast cancers among all BRCA2 PV carriers. BRCA2 c.5576_5579del accounted for 30.8% of the PVs detected, with a particularly high frequency of 72.7% at Kakogawa Central City Hospital. BRCA2 c.5576_5579del was detected with a particularly high frequency in Hyogo Prefecture, especially in Kakogawa city. In the future, a survey of the distribution of the BRCA2 c.5576_5579del carriers may provide more clarity regarding their localization.

Abstract PS10-02: Association between Germline Mutation Status and Overall Survival among Women with Breast Cancer in Population-based Studies in the United States

Abstract Background: The influence of germline pathogenic variants (PVs) in breast cancer predisposition genes on overall survival (OS) after breast cancer diagnosis is not well defined, particularly for PVs in genes other than BRCA1 and BRCA2, and in the context of estrogen-receptor (ER) positive breast cancer. Even for BRCA1/2, OS estimates in women with breast cancer have primarily been derived from high-risk women qualifying for genetic testing due to young age at diagnosis or family history of cancer, and OS estimates by germline PV status from population-based studies are lacking. Methods: The study included 16,797 prospectively followed women with locoregional breast cancer within the population-based CARRIERS study who underwent surgical resection of the primary tumor. OS was compared between germline PV carriers and non-carriers (negative for germline PVs in 12 breast cancer predisposition genes) from the time of breast cancer diagnosis in a multivariable Cox proportional hazard regression analysis adjusting for age and menopausal status at diagnosis, race/ethnicity, ER status, type of surgery, use of adjuvant radiation, chemotherapy and endocrine agents, and prophylactic oophorectomy. Further subset analyses by race/ethnicity ER status of the primary tumor and adjusting for relevant covariates were also performed. Results: Germline PVs in ATM, BRCA1, BRCA2, CHEK2, or PALB2 were detected in 5.6% of the women in the study [ATM: 142 (0.8%), BRCA1: 206 (1.2%), BRCA2: 260 (1.5%), CHEK2:167 (1.0%) and PALB2:116 (0.7%)]. Compared to non-carriers, a significant difference in OS was not observed for germline PV carriers in ATM, BRCA1, BRCA2, or CHEK2 in the overall study population. However, a trend towards worse OS was noted for PALB2 PV carriers compared to non-carriers although this was not statistically significant (Hazard Ratio (HR): 1.36, 95%CI: 0.98 – 1.89, p=0.06). Further subset analysis by race/ethnicity demonstrated that the OS was significantly worse among Black PALB2 PV carriers (HR: 3.11, 95%CI: 1.74 – 5.55, p< 0.001) but not in non-Hispanic White PALB2 PV carriers (HR: 1.00, 95%CI: 0.59 – 1.70, p=0.98) compared to non-carriers within the same race/ethnicity. Among 12,780 women with ER+ breast cancer, compared to non-carriers, OS was significantly worse in BRCA2 PV carriers (HR: 1.51, 95%CI: 1.06 – 2.16, p=0.02) and a trend towards worse OS was observed in BRCA1 PV carriers (HR:1.53, 95%CI:0.93 – 2.51, p=0.09). Among women with ER-negative breast cancer, a significant difference in OS was not observed between PV carriers in each of the five genes and non-carriers. Conclusions: The differences in OS by race/ethnicity in PALB2 PV carriers and by ER status of the tumor in BRCA2 PV carriers warrant further investigation of underlying tumor biology and assessment of endocrine sensitivity of breast cancer in germline PV carriers. Citation Format: Fergus Couch. Association between Germline Mutation Status and Overall Survival among Women with Breast Cancer in Population-based Studies in the United States [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PS10-02.

Abstract PO5-08-07: Ki-67 Expression in Breast Cancer associated with ATM, BRCA1, BRCA2, CHEK2 and PALB2 Pathogenic Variants

Abstract Background: Germline Pathogenic Variants (PVs) in ATM, BRCA1, BRCA2, CHEK2, and PALB2 are known to increase breast cancer (BCa) risk, but the effect of these PVs on tumor biology is not well-understood. Ki-67 is an established prognostic marker in hormone receptor (HR) positive breast cancer but the distribution of Ki-67 in breast cancer associated with germline PVs is not known. Methods: The study included patients with loco-regional (Stage I-III) HR-positive (ER+ or PR+), HER2-negative invasive ductal or lobular breast cancer evaluated at Mayo Clinic for curative intent treatment between 2012 and 2021. PV carrier status was ascertained in more than two-thirds of cases from germline whole exome sequencing (Regeneron) of patients who participated in a prospective registry at Mayo Clinic. Additional PV carriers were identified through a review of the results of clinical germline genetic testing in electronic medical records aided by natural language processing. Clinically performed Ki-67 values were abstracted from electronic medical records and analyzed as continuous and categorical variables (low: < 20% vs. high: ≥20%). Throughout the timeline of the study, a consistent method for assessment of Ki-67 was utilized at Mayo Clinic, Rochester: Immunohistochemical staining of the Ki-67 antigen in formalin-fixed paraffin-embedded tissue was performed using MIB-1 clone, the scanned slides were reviewed by a technologist and traced areas further analyzed for Ki-67 using Aperio Software. Patients who received neoadjuvant therapy prior to the assessment of Ki-67, with metastatic disease at diagnosis, with PVs in two or more genes of interest, or unknown germline PV or Ki-67 status were excluded from the analysis. Multiple primary tumors in the same patient diagnosed within one year of each other were analyzed independently. The control (non-carrier) group included randomly selected patients from the prospective registry who tested negative for PVs in the five genes over the same time period. Ki-67 values were compared between germline PV carriers and non-carriers in a multivariable logistic regression analysis adjusting for sex, race, age at diagnosis, stage at presentation, and histology of the tumor. Results: A total of 113 HR+/HER2- tumors from 111 PV carriers (ATM: 27, BRCA1: 24, BRCA2: 28, CHEK2: 22, and PALB2:12) along with 431 HR+/HER2- tumors from 422 randomly selected non-carriers were evaluated. The majority (>95%) of patients were non-Hispanic White. Germline PV carriers in each gene were diagnosed at a significantly younger age (P< 0.05) compared to non-carriers. The median Ki-67 value was 12 (Range: 1 to 93) for non-carriers, 16 (Range: 0 to 79) for ATM, 31 (Range: 4 to 86) for BRCA1, 30 (Range: 6 to 80) for BRCA2, 13 (Range: 1 to 38) for CHEK2, and 20 (Range: 3 to 46) for PALB2 PV carriers. In multivariable analysis, compared to non-carriers, we observed significantly higher odds of a high Ki67 value (≥20%) for tumors arising from germline PV carriers in BRCA1 (Odds Ratio (OR): 7.3, 95%CI: 2.3 – 23.3, p< 0.001), BRCA2 (OR: 3.0, 95%CI: 1.2 – 7.4, p=0.02) and PALB2 (OR: 3.9, 95%CI: 1.1 – 14.5, p=0.04). No such relationship was observed with either ATM (OR: 1.1, 95%CI: 0.4 – 2.9, p=0.81) or CHEK2 (OR: 0.8, 95%CI: 0.3 – 2.2, p=0.63). Conclusion: This study reveals that HR+/HER2- tumors in BRCA1, BRCA2, and PALB2 PV carriers have a significantly higher Ki-67 expression compared to non-carriers. These findings have implications for understanding prognosis and endocrine response PV with HR+ breast cancer. Further exploration of the relationships between Ki67 and germline PV status is necessary to personalize systemic therapy options in germline PV carriers. Acknowledgments: Thank you to Regeneron Genetics Center. The study was funded in part by the NIH Specialized Program of Research Excellence in Breast Cancer [P50CA116201] to Mayo Clinic, Mayo Clinic Department of Oncology Small Grants Program, and the Paul Calabresi Program at Mayo Clinic Citation Format: Robert Scheel, Grace Choong, Tara Rao, Nicholas Boddicker, Chunling Hu, Jie Na, Vinod Kaggal, Sean Murphy, Karthik Giridhar, Saba Yasir, Matthew Goetz, Fergus Couch, Siddhartha Yadav. Ki-67 Expression in Breast Cancer associated with ATM, BRCA1, BRCA2, CHEK2 and PALB2 Pathogenic Variants [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO5-08-07.

Abstract PO5-08-03: Breastfeeding and Breast Cancer Screening Among Carriers of Pathogenic Variants in BRCA 1 and BRCA 2 and Other High Penetrance Genes: Knowledge and Perspectives

Abstract Objectives: Carriers of pathogenic variants in high penetrance mutations, including BRCA 1 or BRCA 2 face higher lifetime risks of developing breast and tubo-ovarian cancers, and possibly endometrial cancers, than non-carriers. In particular, relative risks are higher among carriers than non-carriers at younger ages, suggesting the value of early initiation of breast cancer screening and the use of sensitive imaging methods, such as magnetic resonance imaging (MRI). Further, breastfeeding appears protective for these three cancers in the general population, and potentially among mutation carriers, albeit based on limited evidence. Given that data related to knowledge and perspectives of carriers about these issues are limited, we surveyed mutation carriers regarding breastfeeding, cancer risk, and the deferral of breast cancer screening coinciding with reproductive events. These data may guide future cancer prevention research and developing of targeted communication campaigns. Methods: Researchers at Mayo Clinic, in collaboration with Facing Our Risk of Cancer Empowered (FORCE) – a large, national non-profit organization that addresses the needs of people and families affected by inherited mutations linked to cancer – designed and conducted a survey using the Mayo Clinic’s external RedCap system. The survey covered genetic testing and results, history of live births and breastfeeding history for mothers, history of risk-reducing surgery, personal cancer history, sources of information about cancer screening, breastfeeding knowledge, and breast cancer screening at various times, including during pregnancy, while breastfeeding, and after weaning. The survey was disseminated through FORCE’s electronic newsletter, website, social media pages, and advocacy partners. Survey responses were collected anonymously and analyzed descriptively using standard descriptive statistics, including frequency and percentages for categorical responses and means (SD) or medians (IQR) for continuously scaled responses. The open-ended responses were analyzed qualitatively using standard qualitative methodology. Results: Respondents included 253 women, of whom 88.7% were U.S. residents and 92.9% were white. The mean age + SD was 47(13) years, 61.7% were parous, with a mean age at first birth of 22.58 (13.16) years. Approximately 60% of women were carriers of mutations in BRCA1 or BRCA2 or both genes and all but two of the remaining women reported mutations in other genes linked to increased cancer risk. At the time of the survey, 92% of women had undergone a mammogram, with first screen at a mean age of 35 (6.49) years, and 85.3% had undergone breast MRI, with first screen at a mean age of 43 (12.39) years. Among 34.3% of participants, their 1st postpartum mammogram occurred >3 years after the birth of their last child and 57% had 1st MRI 3 years postpartum. Preliminarily, our analysis shows that nearly 90% of women were unaware of their mutation status prior to pregnancy and approximately 1/3 did not undergo radiologic screening until 3 years postpartum. While 62.6% of respondents believed that breastfeeding lowers breast cancer risk, 74.2% of participants responded that nursing had no effect on tubo-ovarian cancer risk, and 78.2% considered that nursing did not impact endometrial cancer risk. Discussion and Conclusions: Preliminarily, we conclude that most women in the surveyed population were unaware of their mutation status when pregnant years earlier and many had not undergone screening until years after delivery. Many participants did not consider breastfeeding a potentially protective factor for women’s cancers. These data raise issues about the potential value of discussing genetic testing with women when considering family planning and mutation carriers, addressing complex issues about breast cancer screening while pregnant and breastfeeding. Citation Format: Laura Pacheco-Spann, Mark Sherman, Susan Friedman, Diane Rose, Miriam Levi, Alex Hochwald, Jennifer Ridgeway, Sophia Blumenfeld. Breastfeeding and Breast Cancer Screening Among Carriers of Pathogenic Variants in BRCA 1 and BRCA 2 and Other High Penetrance Genes: Knowledge and Perspectives [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO5-08-03.

Abstract PS10-04: The Landscape of Somatic Genetic Alterations in Breast Cancers from Carriers of Germline Pathogenic Variants in DNA-repair Genes

Abstract Background: Hereditary breast cancer in carriers of germline pathogenic or likely pathogenic variants (PVs) in ATM, BRCA1, BRCA2, CHEK2, and PALB2 have unique clinicopathological characteristics compared to sporadic breast cancer. However, very little is known about the underlying differences in somatic genetic alterations between hereditary and sporadic breast cancer. Methods: The study included 7,533 individuals with breast cancer subjected to Tempus xT tumor-normal matched sequencing (596-648 genes). The frequencies of the somatic genetic alterations in each gene were compared separately between tumors arising in individuals with incidental germline PVs (gATM, gBRCA1, gBRCA2, gCHEK2, gPALB2) and sporadic breast tumors. Sporadic tumors were identified as individuals with no detected incidental germline PVs in these 5 genes. Comparisons were made by either Pearson’s Chi-squared or Fisher’s exact test, with false discovery rate (FDR) correction for multiple testing. Breast cancer subtype was determined based on the record of IHC positivity for ER, PR, or HER2. Detection of ERBB2 (HER2) gene amplifications via DNA sequencing was also used to classify samples as HER2+ in the absence of available IHC data. Results: The median age at breast cancer diagnosis for the cohort was 56 years. More than two-thirds of the patients were White (73%) while 14% identified as Black or African American. The overall frequency of incidental germline PVs in each gene was 0.8% for gATM, 1.4% for gBRCA1, 2.1% for gBRCA2, 1.0% for CHEK2, and 0.7% for PALB2. A total of 3,648 (48.4%) tumors were ER+/PR+/HER2-, 1,297 (17.2%) were triple-negative (TNBC), 841 (11.2%) were HER2+ and 1,747 (23.2%) could not be classified due to missing ER, PR or HER2 status, or absence of detected ERBB2 amplifications. Among ER+/PR+/HER2- breast cancers, compared to sporadic tumors, ESR1 mutations were significantly enriched in gATM carriers (33% vs. 11%, q-value 0.05), TP53 alterations were significantly enriched in gBRCA1 PV carriers (69% vs. 30%, q-value < 0.001) but depleted in gATM (12% vs. 30%, q-value 0.4) and gCHEK2 PV carriers (5.4% vs. 30%, q-value 0.06), and PIK3CA (14% vs. 35%, q-value 0.001) and CCND1 (3.4% vs. 17%, q-value 0.02) alterations were significantly lower in gBRCA2 PV carriers. Among TNBC, TP53 alterations were also significantly higher in gBRCA1 PV carriers compared to sporadic tumors (96% vs. 69%, q-value 0.004). In HER2+ breast cancers, ERBB2 alterations were observed in approximately two-thirds of the tumors, and a significant difference was not observed between incidental hereditary and sporadic tumors. Among ER+/PR+/HER2- tumors, although not statistically significant, the frequency of ESR1 (3.1% vs. 11%, q-value >0.9), PIK3CA (12% vs. 35%, q-value 0.2) alterations were lower in incidental gBRCA1 versus sporadic tumors, FGFR1 alterations were lower in incidental gBRCA1 (6.2% vs. 13%, q-value >0.9) and incidental gBRCA2 (3.4% vs. 13%, q-value 0.13) but enriched in incidental gATM (33% vs. 13%, q-value 0.05). Conclusions: The observed differences in the frequencies of CCND1, ESR1, PIK3CA, TP53, and other key genetic alterations between incidental hereditary and sporadic breast cancer highlight the unique tumor biology of breast cancer in germline PV carriers and have significant implications for understanding tumorigenesis and identifying therapeutic strategies for the management of hereditary breast cancer. Citation Format: Minxuan Huang, Melissa Stoppler. The Landscape of Somatic Genetic Alterations in Breast Cancers from Carriers of Germline Pathogenic Variants in DNA-repair Genes [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PS10-04.

Abstract PO5-08-04: Characteristics of breast cancer in carriers of pathogenic variant in ATM in a large academic health center

Abstract Background: Pathogenic variants (PVs) in ATM are associated with an increased risk of breast, pancreas, and other cancers. The clinical and pathological characteristics of ATM-associated breast cancers have not been well defined. Methods: Patients who underwent multigene panel testing between December 2012 and May 2023 and were identified to harbor ATM PVs were included in the study. We analyzed demographics, germline findings, histopathology, genomic recurrence score, and management of ATM PV carriers with breast cancer. Results: A total of 222 individuals were identified to have PVs in ATM, of whom 184 (83%) were female. The majority were Caucasian (n = 179, 81%) and of those, 22 (12%) had Ashkenazi Jewish ancestry. The median age at genetic testing was 52y, with a range of 20-90y. A total of 111 patients (50%) had a personal cancer diagnosis, the most common of which was breast cancer (n = 70; 63%). The median age at breast cancer diagnosis was 53y, with a range of 25-84y. The most common histopathology was invasive ductal carcinoma (74%), followed by DCIS (21%), and invasive lobular carcinoma (5%). The majority of patients had breast tumors with stage 2 or 3 (78%), grade 2 or 3 (92%), ER and/or PR positive (92%) and HER2 negative (70%). One patient had triple-negative breast cancer. Forty-four percent of breast cancers were less than two centimeters, 23% were lymph node-positive, and 29% had lymphovascular invasion. Thirty-eight percent of patients underwent bilateral mastectomy, 54% received radiation therapy, 40% received adjuvant chemotherapy, 24% received neoadjuvant chemotherapy, and 70% received hormonal therapy. Of the 15 breast cancers with known 21-gene recurrence scores, 47% were intermediate (11-26), 33% were high (>=26) and 20% were low (< =10). Other notable cancers observed were pancreas (n = 9), colorectal (n = 6), prostate (n = 5), uterine (n = 4), melanoma (n = 4), and thyroid (n = 4). Conclusion: Our study outlines the clinical and pathological characteristics of ATM-associated breast cancer in a large academic center. The majority of breast cancers were invasive ductal type, early stage, intermediate or high grade, and hormone receptor-positive with an intermediate or high recurrence score. Despite the early stage, a significant proportion of patients underwent bilateral mastectomy. Further studies are needed to better elucidate the unique characteristics of breast cancer in ATM PV carriers in order to provide tailored management guidelines for this population. Citation Format: Ujjwal Karki, Tara Rangarajan, Dana Zakalik. Characteristics of breast cancer in carriers of pathogenic variant in ATM in a large academic health center [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO5-08-04.

Abstract PS10-01: Hormonal Contraception and Breast Cancer Risk for Carriers of Germline Pathogenic Variants in BRCA1 and BRCA2

Abstract BACKGROUND: Current use of hormonal contraception is associated with a 20-30% relative increase in the risk of breast cancer (BC) for women in the general population compared with never using. Longer duration of use is associated with higher risk, and the risk remains elevated above that of never users for at least 5 years after cessation. Most published data are for various formulations of the combined oral contraceptive pill, but associations are similar for progestogen-only contraceptives, including intrauterine devices. For women in the general population who use hormonal contraceptives in their 20s and 30s, when baseline BC risk for most women is low, these increased relative risks translate into only small increases in absolute risk. It is unclear whether use of hormonal contraceptives increases BC risk for women carrying a germline BRCA1 or BRCA2 pathogenic variant (PV). These women are at markedly higher risk of early-onset BC, so even slightly increased relative risks could translate to important increases in their absolute risk of BC. This study assessed the association between use of any hormonal contraception and BC risk for BRCA1 and BRCA2 PV carriers using individual participant data from four prospective cohorts. METHODS: Data from females born after 1920 with a PV in BRCA1 or BRCA2 and no history of cancer or bilateral mastectomy at cohort entry were analyzed. Cox regression models were used to estimate hazard ratios (HR) and 95% confidence intervals (CI) for BC (invasive disease or ductal carcinoma in situ) associated with use of hormonal contraceptives for at least 1 year, with age as the timescale, entry at cohort enrolment, and censoring at the earlier of bilateral mastectomy, death, diagnosis of another cancer or last follow-up. Analyses were adjusted for study, birth cohort, first-degree family history of BC, parity, premenopausal bilateral oophorectomy and menopausal status. Current use of hormonal contraceptives was defined as use within the previous year, to account for cessation of use due to BC symptoms or clinical investigation. RESULTS: Of 3,882 BRCA1 and 1,509 BRCA2 PV carriers, 53% and 71%, respectively had ever used hormonal contraceptives (for at least one year). The median cumulative duration of hormonal contraceptive use was 4.8 and 5.7 years, respectively. Overall, 488 BRCA1 and 191 BRCA2 PV carriers developed incident BC during a median of 5.9 and 5.6 years of follow-up, respectively. For BRCA1 PV carriers, use of hormonal contraceptives for at least 1 year was associated with increased BC risk (HR [95% CI]: 1.29 [1.04-1.60] p=0.019). BC risk increased with longer cumulative duration of hormonal contraceptive use (HR [95% CI]: 1.13 [0.88-1.45] p=0.35, 1.48 [1.11-1.96] p=0.007 and 1.56 [1.13-2.17] p=0.007 for 1-5, 6-10 and >10 years of use, respectively), with an estimated proportional increase in risk of 3% (1%-5%, p=0.002) for each additional year of use. For BRCA2 PV carriers, there was no evidence that current or past use, or cumulative duration of use, were associated with increased risk of BC, but confidence intervals on the HRs were wide. CONCLUSION: Hormonal contraceptive use is associated with an increased risk of BC for women carrying PVs in BRCA1 and risk increases with cumulative duration of use. Hormonal contraceptives are an important healthcare option for women; they provide excellent contraceptive efficacy and reduce risks of ovarian and endometrial cancer. Decisions about use of hormonal contraceptives in women at increased risk for BC due to BRCA1 PVs need to carefully weigh the risks and benefits; while shorter-term use may result in only small increases, prolonged cumulative use may result in larger increases in absolute BC risk that may not be acceptable to some women. Citation Format: Kelly-Anne Phillips, Joanne Kotsopoulos, Susan Domchek, James Chamberlain, Julie Bassett, Amber Aeilts, Irene Andrulis, Saundra Buys, Wanda Cui, Mary Daly, Andrea Eisen, William Foulkes, Michael Friedlander, Jacek Gronwald, John Hopper, Esther John, Beth Karlan, Raymond Kim, Jan Lubiński, Kelly Metcalfe, Katherine Nathanson, Christian F. Singer, Heather Symecko, Nadine Tung, Steven Narod, Mary Beth Terry, Roger Milne. Hormonal Contraception and Breast Cancer Risk for Carriers of Germline Pathogenic Variants in BRCA1 and BRCA2 [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PS10-01.

Abstract PO3-11-10: Second primary non-breast cancers in young breast cancer survivors

Abstract Adolescent and young adults (AYAs) (15-39 years) have a heightened risk of developing a second primary malignancy due to extended periods of survivorship, higher incidence of germline cancer predisposing variants, and increased susceptibility to treatment-induced malignancies. Research on survivors of specific AYA cancer types, including breast cancer (BC) survivors, is limited. Among BC survivors, while much survivorship research focuses on risk of locoregional recurrence or contralateral BC, little is known about overall risk, and risk factors, of developing second non-breast primaries. This prospective cohort study examined women diagnosed with BC from 2006-2016 at age ≤40 years enrolled in the Young Women’s BC Study (YWS) (N=1297). Women were excluded from the analytic cohort if initially diagnosed with Stage IV breast cancer (N=64). To enable investigation of how BC treatments may impact second primary risk, women were also excluded if they reported another cancer before primary BC diagnosis (N=3). Patient characteristics, treatment information, and clinical events were collected via serial surveys. Tumor characteristics and detailed treatment data were obtained from medical record review. Five- and 10-year risk of second non-breast primary was estimated via the cumulative incidence function after applying the Fine-Gray competing risks model with time starting at primary BC diagnosis. Death, metastasis, or diagnosis with a second primary BC were considered as competing events. Univariate and multivariate Fine-Gray sub-distribution models were used to estimate sub-distribution hazard ratios (sHRs) and 95% confidence intervals (CI) for second non-breast primary cancer risk. Risk factors considered included age, race, body mass index, smoking, alcohol use, income, family history of cancer, germline pathogenic variant (PV) carrier status, tumor stage, grade, and ER status, primary surgery type, and receipt of radiation, chemotherapy, or endocrine therapy (yes/no). Multivariate models tested individual associations with additional adjustment for radiation therapy and PV carrier status, as both are consistently associated with second primary in the literature. Over a median follow-up of 10.1 years (inter-quartile range (IQR) =7.9-12.1 y), 47 patients (4%) developed a second non-breast primary cancer. Median age at second non-breast primary was 43 years (IQR=39-46), and median time between primary BC and second non-breast primary was 7.3 years (IQR=4.1-9.3). Second primary types included melanoma (n=10), thyroid (n=10), ovarian (n=4), sarcoma (n=4), uterine (n=3), rectal (n=3), bladder (n=2), cervical (n=2), head and neck (n=2), lung (n=2), lymphoma (n=2), pancreatic (n=2), and kidney (n=1). During the study, 22 patients (2%) developed a second primary BC, 167 (19%) developed metastasis, and 15 (1%) died from causes other than BC. Among the patients who developed a second primary BC, two later developed another non-breast cancer (ovarian and brain cancer). When incorporating competing risks, five and 10-year cumulative incidence of second non-breast primary was 1.4% and 3.2%, respectively. No patient or treatment factors were statistically significantly associated with second non-breast primary in univariate or multivariate models, including radiation and PV carrier status. In this population of young BC survivors, 10-year cumulative incidence of second non-breast primary cancer was 3.2%, with the most common second cancers being melanoma and thyroid cancer. Incidence rates of all second primary cancer types in this cohort were higher than population-based incidence rates for healthy women under 50 years of age, highlighting the importance of long-term surveillance for other cancer events in this young population. While risk of second non-breast primary was not associated with primary BC treatment in this study, cases were limited, and the follow-up interval was relatively short. Citation Format: Bessie Zhang, Kristen Brantley, Shoshana Rosenberg, Gregory Kirkner, Laura Collins, Kathryn Ruddy, Rulla Tamimi, Lidia Schapira, Virginia Borges, Ellen Warner, Steven Come, Eric Winer, Ann Partridge. Second primary non-breast cancers in young breast cancer survivors [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO3-11-10.

Abstract PO4-11-10: Comparison of frozen embryo transfer cycle (FET) outcomes between young women with breast cancer (YWBC) with and without pathogenic variants (PV), and breast cancer-free PV carriers

Abstract BACKGROUND: In vitro fertilization (IVF) and preimplantation genetic testing for aneuploidy (PGT-A) and monogenic disorders (PGT-M) are valuable tools for YWBC with or without PV such as BRCA1/2, ATM, CHEK2, PMS2 to prevent variant transmission to offspring. However, to date, there is scarce data on the usability of these cryopreserved, tested embryos and on the outcomes of FET cycles within the cancer population. It has been suggested that PV may influence endometrial thickness which is associated with embryo implantation and ultimately FET success rates. Thus, this study aimed to compare reproductive outcomes of FET cycles between YWBC with an identified PV, breast cancer (BC) patients without a PV, and cancer-free PV-carriers who returned to use their cryopreserved oocytes or embryos derived from IVF ± PGT-A/M cycles. METHODS: Patients that underwent either fertility preservation (FP) prior to BC therapy or preventative IVF/PGT-A/M cycles from 2009-2023 were included. All IVF & PGT-A/M was performed at academic IVF centre. Genetic testing was conducted using high resolution next generation sequencing on the Illumina platform. We compared reproductive outcomes between 3 groups: 1) YWBC with a known PV (BCPV), 2) YWBC without a PV (BCNV), 3) Cancer-free patients who had a PV (CFPV). Primary outcomes measured were endometrial thickness, and FET success rates (i.e., ongoing pregnancy or live birth) analyzed by chi-square, t-tests and ANOVA. RESULTS: 185 patients underwent 202 cycles for either oocyte or embryo freezing. Mean age was 33.8±4.6 years (range 21-45) and mean BMI was 24.6±5.0 kg/m2 (range 15.7-42.7). 64 patients had a PV including BRCA1 (n=22), BRCA2 (n=20) and others (n=22): ATM, BARD1, BRIP1, CHEK2, MLH1, P53, PALB2, PDL2, PMS2, PTCH1, & RAD51D. When comparing the BCPV, BCNV & CFPV groups, no significant differences were found in the mean age (33.7 ± 4.9 vs. 36.8 ± 4.3 vs. 34.3 ± 4.4 years, p=0.52), mean BMI (26.2 ± 4.9 vs. 24.3 ± 4.8 vs. 24.3 ± 4.8 kg/m2, p=0.13), and the proportion of smokers (23.1% vs. 35.0% vs. 36.4%, p=0.72). Only 60% of BCNV performed PGT-A due to their lack of PV. As of June 2023, 44 patients (12 in BCPV, 20 in BCNV, and 12 in CFPV) returned to undergo 81 FET cycles (range 1-5/patient). 12/81(14.8%) FETs involved a surrogate. When comparing the BCPV, BCNV & CFPV who had FET, a significant difference was found in the mean age at oocyte retrieval between BCPV & BCNV (32.9±4.4 vs. 37.0±4.0 years, p=0.001) but not with CFPV (33.5±4.4 years). The endometrial thickness at the time of FET between the BCPV, BCNV, and CFPV groups was similar (10.2±1.6 vs. 10.6±2.6 vs. 9.3±1.9 mm, p=0.12), as was the proportion of smokers (25.0% vs. 36.8% vs. 33.3%, p=0.79). YWBC had a mean delay from egg retrieval to their first FET of 37 months. Estrogen receptor positive (ER+) YWBC had a longer delay than ER- patients (40.1±23.8 months vs. 29.6±11.6 months, p=0.25). 29/44 (65.9%) had at least one successful FET and another 5 YWBC conceived naturally or with intrauterine insemination (IUI); the cumulative pregnancy rate was 77.3% (34/44). The clinical pregnancy rate of 81 FETs was 44.4%. The BCPV group (73.7%) had a significantly higher successful outcome than the BCNV (35.3%) and CFPV (35.7%) groups (p=0.01). CONCLUSIONS: FP done at the time of a BC diagnosis is an effective tool to preserve fertility potential. 77% of patients had at least one baby from either IVF, IUI or conceived naturally. We did not find a difference in endometrial thickness in PV carriers. While all YWBC had a delay to their first FET from the time of their retrieval, those who were ER+ had a longer delay than ER- because of their need for endocrine therapy. The BCPV group had the highest FET success rate which is likely due to their younger age and use of PGT-A/M thereby eliminating FETs of abnormal embryos that would fail to implant. The BCNV were older with more untested embryos. The CFPV group transferred euploid embryos and thus the lower success rate is puzzling and needs further investigation. Citation Format: Maya Sharon-Weiner, Amanda Kauffman, Adina Tanen, Samantha Yee, Svetlana Madjunkova, Karen Glass. Comparison of frozen embryo transfer cycle (FET) outcomes between young women with breast cancer (YWBC) with and without pathogenic variants (PV), and breast cancer-free PV carriers [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO4-11-10.

Abstract PO1-09-02: Universal genetic testing for women with newly diagnosed breast cancer identified many mutations, impacted clinical management and caused no psychological distress to patients

Abstract Background: For newly diagnosed breast cancer (BC) patients, identification of pathogenic germline mutations in hereditary breast cancer (HBC) genes can inform clinical management and risk mitigation strategies and identify patients who would benefit from targeted therapy and clinical trials. Offering germline testing based on NCCN or other guidelines fails to identify all patients with germline HBC gene mutations, potentially with adverse consequences for patients and their families. As an integral part of the study, we have explored the acceptance of universal testing among patients and clinicians. Methods: This is the largest Australian multi-centre prospective study exploring the prevalence of hereditary pathogenic variants in the Australian BC population. 650 newly diagnosed consecutive, consented patients with non-metastatic breast cancer or high-grade DCIS were recruited from May 2020 to March 2023 in 2 phases. Phase 1 (n=157) offered a combination of germline and somatic sequencing. Germline testing was performed by whole genome sequencing on DNA from blood or saliva, and the data analyzed for actionable HBC gene mutations, including large genomic rearrangements. Germline variants were interrogated for pathogenic variants in BRCA1, BRCA2, PALB2, ATM, CHEK2, BARD1, BRIP1, RAD51B, RAD51C, RAD51D, MLH1, MSH2, MSH6, PMS2, CDH1, PTEN, STK11, TP53 and NTHL1.Tumour sequencing will be reported separately. Phase 2 (n=493) included germline exome sequencing with no somatic sequencing. The objectives were to assess the additional actionable HBC gene mutations identified by universal testing compared to algorithmic based (MANCHESTER and BOADICEA scores) and NCCN guidelines, the clinical impact of this identification and the prevalence of germline mutations in the general BC population. A 3-generation pedigree was constructed for every patient for accurate estimation of NCCN, MANCHESTER, and BOADICEA scores. Phase 1 patients completed surveys of perceptions of universal testing, psychological distress and cancer-specific worry pre- and post-testing. Results: 50 carriers of actionable germline mutations were identified: (7.7%). BRCA1 (n=10), BRCA2 (n=12), PALB2 (n=7), CHEK2 (n=10), ATM (n=4), PMS2 (n=2), MSH6 (n=1), RAD51C (n=2), and BARD1 (n=3). One carrier had both PALB2 and CHEK2 mutations. Updated NCCN guidelines (2023 version) identified 44/50 pathogenic germline variant carriers (88%). The BOADICEA and MANCHESTER scores only identified 22 carriers (44%). Immediate clinical management changed due to the discovery of HBC gene in 40/50 (80%). Among 105 participants, cancer-specific distress declined from pre- to post-testing. Anxiety, stress and depression did not change. 90/103 participants agreed that genetic testing should be routine, 100/104 reported their decision to undergo testing as correct. All (n=25) BC clinicians reported that genetic test results were helpful for important treatment decisions and none that testing was distressing to patients. Conclusion: HBC gene mutation prevalence was 7.7%. Universal germline HBC gene testing is the best method for detecting carriers. Current testing guidelines would have missed HBC genes which would have impacted clinical management. Updated NCCN guidelines were sensitive in the detection of HBC gene mutation, but more than half of HBC gene mutations were missed by Australian standards. Discovery of HBC gene mutations led to changed management in most cases. Universal testing is highly acceptable to clinicians and patients who reported no adverse impact on psychological distress or cancer-specific worry and no decision regret. Germline mutations identified and their impact on management Citation Format: Dilanka De Silva, Lesley Stafford, Anita Skandarajah, Michelle Sinclair, Lisa Devereux, Kirsten Hogg, Maira Kentwell, Allan Park, luxi Lal, Magnus Zethoven, Madawa Jayawardena, Fiona Chan, Paul James, Geoffrey Lindeman, Ian Campbell, Bruce Mann. Universal genetic testing for women with newly diagnosed breast cancer identified many mutations, impacted clinical management and caused no psychological distress to patients [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO1-09-02.

Abstract PO4-08-04: Comparison of Outcomes and Prognosis between BRCA Pathogenic Variant Carriers Undergoing Breast-Conserving Surgery versus Mastectomy for Breast Cancer

Abstract Introduction: While outcomes are similar following breast-conserving surgery (BCS) or mastectomy among patients with sporadic breast cancer, data are still controversial for germline BRCA pathogenic variant carriers. We previously compared outcome following BCS between BRCA pathogenic variant carriers and non-carriers, and reported higher ipsilateral breast recurrence and comparable prognosis in the carriers. The purpose of this current study was to compare outcomes among BRCA pathogenic variant carriers undergoing BCS versus mastectomy in long-term follow-up period. Methods: Women with a BRCA pathogenic variant and a stage 0-III breast cancer who underwent definitive surgery from 1987–2021 were retrospectively identified from institutional database. Factors including clinicopathologic information and treatment characteristics were identified. Subsequent local recurrence, regional recurrence, distant recurrence, contralateral breast cancer (CBC), breast cancer-specific survival (BCSS), and overall survival (OS) rates were compared between BCS and mastectomy using Kaplan-Meier method and log-rank test. The chi-square test and t-test were used to compare patient characteristics between the two groups. Results: A total of 232 BRCA mutation carriers with 257 cancers including 25 patients with synchronous bilateral breast cancer were identified. Surgical treatment included BCS for 82 cancers and mastectomy for 175 cancers including nipple-sparing mastectomy for 51 cancers. Patient age at surgery and cancer stage did not statistically differ between BCS and mastectomy groups. Comparing to patients choosing mastectomy, patients who underwent BCS were less likely to be aware of their genetic status before surgery and were more likely to receive radiation therapy (p < 0.001). Contralateral risk reducing mastectomy was performed in 22.5% (18/80) in the BCS group and 48.7% (74/152) in the mastectomy group (p < 0.001) concurrently or at any time after the first definitive surgery. Risk reducing salpingo-oophorectomy was performed in 40% (32/80) in the BCS group and 49% (75/152) in the mastectomy group (p = 0.17). At 7.5 years median follow-up, local recurrence rate was statistically higher in the BCS group than in the mastectomy group (20.0% in BSC vs. 4.6% in mastectomy, p = 0.043). In patients who underwent nipple-sparing mastectomy, 4.0% (2/51) had local subcutaneous recurrence and no nipple-areolar recurrence was observed. Median duration from the first definitive surgery to ipsilateral local recurrence was 10.0 years in the BCS group and 2.3 years in the mastectomy group. Regional lymph node recurrence (11.2% in BCS vs. 6.4% in mastectomy, p = 0.62), distant recurrence (13.7% vs. 9.2%, p = 0.84), CBC (15.0% vs. 8.6%, p = 0.70), BCSS (88.8% vs. 94.1%, p = 0.65) and OS (87.5% vs. 94.1%, p = 0.49) rates did not statistically differ between two groups. Conclusions: With 7.5 years median follow-up, higher local recurrence rate was observed in BCS than in mastectomy among BRCA pathogenic variant carriers. Our results found no statistical difference between BCS and mastectomy in regional recurrence, distant recurrence, CBC, and prognosis, indicating relatively higher risk in BCS. While BCS could be an option for BRCA pathogenic variant carriers willing to continue high-risk breast surveillance, shared decision making should be carefully performed based on the long-term local recurrence risk. Citation Format: Kumiko Kida, Junko Takei, Misato Suzuki, Megumi Okawa, Sakurako Kazama, Sakiko Kondo, Michiko Yamanaka, Atsushi Yoshida. Comparison of Outcomes and Prognosis between BRCA Pathogenic Variant Carriers Undergoing Breast-Conserving Surgery versus Mastectomy for Breast Cancer [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO4-08-04.

Abstract PO5-08-05: Breast Cancer in PMS2 related Lynch Syndrome: evidence of a possible association?

Abstract Background: Lynch syndrome (LS) is a hereditary cancer predisposition syndrome caused by pathogenic variants (PVs) in mismatch repair genes, MLH1, MSH2, MSH6, and PMS2. LS is associated with increased risk of colorectal, and endometrial cancers but breast cancer risk is uncertain, with some studies suggesting MSH6 and PMS2 PVs may have a higher risk for breast cancer. Our study outlines the incidence and clinical characteristics of breast cancer in PMS2-related LS identified at a large academic center. Methods: Patients with PMS2 PVs identified between July 2009 and May 2023 were selected from a database at the Nancy and James Grosfeld Cancer Genetic Center at Beaumont Health. Data on demographics, genetic testing, cancer types, and breast cancer characteristics were retrospectively analyzed. Results: A total of 108 patients from 74 families were found to carry a pathogenic or likely pathogenic variant in PMS2, of whom the majority were female (75%) and Caucasian (85%). The median age at genetic testing was 52y (19 to 95y). The most common variant was c.137G > T (p.Ser46Ile), seen in 15 of 74 (20%) families. Forty-seven patients (46%) had a personal history of cancer, with a median age at diagnosis of 58y. Of these forty-seven patients, sixteen (34%) had multiple malignancies, including one patient with six separate cancers. The most common malignancies were breast (19; 40%), colon (16; 34%), followed by uterine cancer (7), pancreas (4), and prostate (3). The median age at breast cancer diagnosis was 53y, with a range of 41-78y. The most common histopathology was invasive ductal carcinoma (54%), followed by DCIS (31%), and invasive lobular carcinoma (15%). The majority of patients had breast tumors with stage 0 or 1 (75%), grade 2 (63%), ER-positive (92%), PR positive (67%), and HER2-negative (88%). One patient had triple-negative breast cancer. Sixty-seven percent of breast cancers were less than two centimeters, and 92% were lymph node-negative. Fifty-nine percent received radiation therapy and 53% received chemotherapy. Conclusion: Our study outlines the incidence and clinical characteristics of breast cancer in PMS2-related LS. Breast cancer was the most common malignancy in our cohort of PMS2 PV carriers, accounting for 40% of all cancers, supporting a possible association between PMS2 and breast cancer. The majority of PMS2-related breast cancers were invasive ductal type, early stage, intermediate grade, and hormone receptor-positive. Further studies with larger diverse cohorts of patients with LS are needed to better characterize a possible association in order to provide tailored breast cancer screening and management guidelines for this population. Citation Format: Ujjwal Karki, Tara Rangarajan, Dana Zakalik. Breast Cancer in PMS2 related Lynch Syndrome: evidence of a possible association? [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO5-08-05.

Breast cancer screening in BRCA1/2 pathogenic sequence variant carriers during pregnancy and lactation

ObjectivesWomen harboring germline BRCA1/BRCA2 pathogenic sequence variants (PSVs) are at an increased risk for breast cancer. There are no established guidelines for screening during pregnancy and lactation in BRCA carriers. The aim of this study was to evaluate the utility of whole-breast ultrasound (US) screening in pregnant and lactating BRCA PSV carriers. MethodsData were retrospectively collected from medical records of BRCA PSV carriers between 2014 and 2020, with follow-up until 2021. Associations between imaging intervals, number of examinations performed and pregnancy-associated breast cancers (PABCs) were examined. PABCs and cancers diagnosed at follow-up were evaluated and characteristics were compared between the two groups. ResultsOverall 212 BRCA PSV carriers were included. Mean age was 33.6 years (SD 3.93, range 25–43 years). During 274 screening periods at pregnancy and lactation, eight (2.9 %) PABCs were diagnosed. An additional eight cancers were diagnosed at follow-up. Three out of eight (37.5 %) PABCs were diagnosed by US, whereas clinical breast examination (n = 3), mammography (n = 1) and MRI (n = 1) accounted for the other PACB diagnoses. One PABC was missed by US. The interval from negative imaging to cancer diagnosis was significantly shorter for PABCs compared with cancers diagnosed at follow-up (3.96 ± 2.14 vs. 11.2 ± 4.46 months, P = 0.002). ConclusionIn conclusion, pregnant BRCA PSV carriers should not delay screening despite challenges like altered breast tissue and hesitancy towards mammography. If no alternatives exist, whole-breast ultrasound can be used. For lactating and postpartum women, a regular screening routine alternating between mammography and MRI is recommended.

THE ADDED VALUE OF BLOOD GLUCOSE MONITORING IN HIGH-RISK INDIVIDUALS UNDERGOING PANCREATIC CANCER SURVEILLANCE.

The study aimed to investigate the added value of blood glucose monitoring in high-risk individuals (HRIs) participating in pancreatic cancer surveillance. HRIs with a CDKN2A/p16 germline pathogenic variant (PV) participating in pancreatic cancer surveillance were included in this study. Multivariable logistic regression was performed to assess the relationship between new-onset diabetes (NOD) and pancreatic ductal adenocarcinoma (PDAC). To quantify the diagnostic performance of NOD as a marker for PDAC, receiver operating characteristic curve with area under the curve (AUC) was computed. In total, 220 HRIs were included between 2000-2019. Median age was 61 (IQR 53-71) years and 62.7% of participants were female. During the study period, 26 (11.8%) HRIs developed NOD, of whom 5 (19.2%) later developed PDAC. The other 23 (82.1%) PDAC cases remained NOD-free. Multivariable analysis showed no statistically significant relationship between NOD and PDAC (OR 1.21; 95% CI, 0.39-3.78) and four out of five PDAC cases appeared to have NOD within three months before diagnosis. Furthermore, NOD did not differentiate between HRIs with- and without PDAC (AUC 0.54; 95% CI, 0.46-0.61). In this study we found no added value for longitudinal glucose monitoring in CDKN2A PV carriers participating in an imaging-based pancreatic cancer surveillance program.

The odyssee from surveillance to the detection of pancreatic cancer, total pancreatectomy, and its impact on life. insights from a p16-Leiden pathogenic variant carrier.

The odyssee from surveillance to the detection of pancreatic cancer, total pancreatectomy, and its impact on life. insights from a p16-Leiden pathogenic variant carrier.

Genetic Landscape and Clinical Features of Hyperphenylalaninemia in North Ossetia-Alania: High Frequency of P281L and P211T Genetic Variants in the PAH Gene.

This study, conducted in the Republic of North Ossetia-Alania (RNOA), aimed to explore the genetic landscape of hyperphenylalaninemia (HPA) and phenylketonuria (PKU) in the Ossetian population using data from newborn screening (NBS). Through comprehensive molecular genetic analysis of 29 patients with HPA from diverse ethnic backgrounds, two major genetic variants in the PAH gene, P281L and P211T, were identified, constituting 50% of all detected pathogenic alleles in Ossetian patients. Remarkably, these variants exhibited an exceptionally high frequency in the Ossetian population, surpassing global prevalence rates. This study unveiled a notable prevalence of mild forms of HPA (78%), underscoring the importance of genetic counseling for carriers of pathogenic variants in the PAH gene. Moreover, the findings emphasized the necessity for ongoing monitoring of patients with mild forms, as they may lack significant symptoms for diagnosis, potentially impacting offspring. Overall, this research offers valuable insights into the genetic landscape of HPA and PKU in the Ossetian population.

Prevalence of Homologous Recombination Deficiency Among Patients With Germline RAD51C/D Breast or Ovarian Cancer

RAD51C and RAD51D are involved in DNA repair by homologous recombination. Germline pathogenic variants (PVs) in these genes are associated with an increased risk of ovarian and breast cancer. Understanding the homologous recombination deficiency (HRD) status of tumors from patients with germline PVs in RAD51C/D could guide therapeutic decision-making and improve survival. To characterize the clinical and tumor characteristics of germline RAD51C/D PV carriers, including the evaluation of HRD status. This retrospective cohort study included 91 index patients plus 90 relatives carrying germline RAD51C/D PV (n = 181) in Spanish hospitals from January 1, 2014, to December 31, 2021. Genomic and functional HRD biomarkers were assessed in untreated breast and ovarian tumor samples (n = 45) from June 2022 to February 2023. Clinical and pathologic characteristics were assessed using descriptive statistics. Genomic HRD by genomic instability scores, functional HRD by RAD51, and gene-specific loss of heterozygosity were analyzed. Associations between HRD status and tumor subtype, age at diagnosis, and gene-specific loss of heterozygosity in RAD51C/D were investigated using logistic regression or the t test. A total of 9507 index patients were reviewed, and 91 patients (1.0%) were found to carry a PV in RAD51C/D; 90 family members with a germline PV in RAD51C/D were also included. A total of 157 of carriers (86.7%) were women and 181 (55.8%) had received a diagnosis of cancer, mainly breast cancer or ovarian cancer. The most prevalent PVs were c.1026+5_1026+7del (11 of 56 [19.6%]) and c.709C>T (9 of 56 [16.1%]) in RAD51C and c.694C>T (20 of 35 [57.1%]) in RAD51D. In untreated breast cancer and ovarian cancer, the prevalence of functional and genomic HRD was 55.2% (16 of 29) and 61.1% (11 of 18) for RAD51C, respectively, and 66.7% (6 of 9) and 90.0% (9 of 10) for RAD51D. The concordance between HRD biomarkers was 91%. Tumors with the same PV displayed contrasting HRD status, and age at diagnosis did not correlate with the occurrence of HRD. All breast cancers retaining the wild-type allele were estrogen receptor positive and lacked HRD. In this cohort study of germline RAD51C/D breast cancer and ovarian cancer, less than 70% of tumors displayed functional HRD, and half of those that did not display HRD were explained by retention of the wild-type allele, which was more frequent among estrogen receptor-positive breast cancers. Understanding which tumors are associated with RAD51C/D and HRD is key to identify patients who can benefit from targeted therapies, such as PARP (poly [adenosine diphosphate-ribose] polymerase) inhibitors.

Abstract P70: HIGH-THROUGHPUT IMAGING-BASED PHENOTYPIC PROFILING OF IMMUNE CELLS FROM BRCA2 VARIANT CARRIERS AND NON-CARRIERS

Abstract Mutated germline alleles in the DNA damage repair (DDR) genes BRCA1/2 are major risk factors for breast and ovarian cancers. Recent studies have found that BRCA1-mutant tumors tend to have higher abundance of immune cells within the tumor microenvironment, but much better response was observed from the BRCA2-mutant tumors when given immune-checkpoint inhibitors, suggesting possible functional and phenotypic effects of germline BRCA2 mutations on the immune cells. However, most existing studies focus on investigating the genomic instability and phenotypes of hereditary mutations in breast and ovarian cancer cells. Thus, the impact of these mutations on immune cells’ phenotypes and functions remains largely unknown. Here, we report a study of immune cells with and without BRCA2 mutations using High-throughput Imaging-based Phenotypic Profiling (HIPP), which can identify changes in cellular morphology and protein subcellular localization patterns that are not obvious from other traditional functional assays. We performed HIPP on immune cells from nine BRCA2 pathogenic variant carriers and eight non-carriers. Automatic quantification of ~200 phenotypic features from each single cell revealed that CD8+ T cells from BRCA2 variant carriers have distinct and quantifiable changes in their morphological features (such as cytoskeleton structures) and immunological features (such as Granzyme B expressions). Moreover, we found that BRCA2-mutant CD8+ T cells proliferate faster than normal CD8+ T cells. Our results suggest that BRCA2 mutations affect the functions and phenotypes of immune cells. Some of these phenotypic features and markers may be used to classify BRCA2 variants and predict the pathogenicity of variants of uncertain significance (VUS). Our study provides new insight into the immune phenotyping of cancer patients at individual level and may help to stratify patients, leading to the development of more effective therapeutic strategies. This method can potentially extend to other germline variants and overcome the challenge of VUS interpretation in clinical management. Citation Format: Guorui Zhong, Oscar Fu, Claresta Yeo, Siao Ting Chong, Sock Hoai Chan, Joanne Ngeow, Lit-Hsin Loo. HIGH-THROUGHPUT IMAGING-BASED PHENOTYPIC PROFILING OF IMMUNE CELLS FROM BRCA2 VARIANT CARRIERS AND NON-CARRIERS [abstract]. In: Proceedings of Frontiers in Cancer Science; 2023 Nov 6-8; Singapore. Philadelphia (PA): AACR; Cancer Res 2024;84(8_Suppl):Abstract nr P70.