Testing In Breast Cancer Patients Research Articles

Mainstream Germline Genetic Testing with Expanded Eligibility for Early Breast Cancer Patients in a Large Integrated Health System.

This study evaluated a new mainstream genetic testing pathway for hereditary cancer, with expanded eligibility for early-stage breast cancer patients. The study compared multigene panel (62 genes) germline testing uptake and results for breast cancer patients at 4 pilot sites (n = 502 patients) and 10 non-pilot sites (n = 1792 patients) within Kaiser Permanente Northern California from December 2020, to June 2021. At the pilot sites, breast care coordinators (BCCs) offered and consented patients for testing, with eligibility expanded to include all patients age 65 years or younger. At the non-pilot sites, eligible patients were referred to genetics for pre-test counseling, ordering, and follow-up evaluation with the standard guideline that included all patients age 45 years or younger. Demographic and disease characteristics were similar at the pilot and non-pilot sites. At the pilot verses non-pilot sites, a higher percentage of patients was tested overall (61.6% vs 31.7%) and across all age groups. The median time from breast biopsy to test result also was reduced (22 vs 33 days, respectively). A higher percentage of patients at the pilot sites was identified as having a pathogenic/likely pathogenic variant (PV/LPV) in a breast cancer-related gene (3.6% vs 1.6%). Although the percentage of total patients tested was nearly twofold higher at the pilot sites than at the non-pilot sites, the percentage of total patients seen by genetics was estimated to be similar (33.7% vs 31.7%). Mainstream genetic testing of breast cancer patients facilitated by BCCs makes it feasible for a large health care system to expand germline genetic testing to early breast cancer patients age 65 years or younger.

314P The impact of changes in tumor mutational landscape during neoadjuvant therapy on tumor-informed ctDNA testing in breast cancer patients

314P The impact of changes in tumor mutational landscape during neoadjuvant therapy on tumor-informed ctDNA testing in breast cancer patients

Genetic Testing of Breast Cancer Patients with Very Early-Onset Breast Cancer (≤30 Years) Yields a High Rate of Germline Pathogenic Variants, Mainly in the BRCA1, TP53, and BRCA2 Genes.

Early-onset breast cancer constitutes a major criterion for genetic testing referral. Nevertheless, studies focusing on breast cancer patients (≤30 years) are limited. We investigated the contribution and spectrum of known breast-cancer-associated genes in 267 Greek women with breast cancer ≤30 years while monitoring their clinicopathological characteristics and outcomes. In this cohort, a significant proportion (39.7%) carried germline pathogenic variants (PVs) distributed in 8 genes. The majority, namely 36.7%, involved BRCA1, TP53, and BRCA2. PVs in BRCA1 were the most prevalent (28.1%), followed by TP53 (4.5%) and BRCA2 (4.1%) PVs. The contribution of PVs in CHEK2, ATM, PALB2, PTEN, and RAD51C was limited to 3%. In the patient group ≤26 years, TP53 PVs were significantly higher compared to the group 26-30 years (p = 0.0023). A total of 74.8% of TP53 carriers did not report a family history of cancer. Carriers of PVs receiving neoadjuvant chemotherapy showed an improved event-free survival (p < 0.0001) compared to non-carriers. Overall, many women with early-onset breast cancer carry clinically actionable variants, mainly in the BRCA1/2 and TP53 genes. The inclusion of timely testing of TP53 in these patients provides essential information for appropriate clinical management. This is important for countries where reimbursement involves the cost of genetic analysis of BRCA1/2 only.

Abstract PO4-14-11: Findings of clinically significant variants (Tier IA) with OmniSeq INSIGHT ® in a breast cancer cohort of 987 patients

Abstract Background: There were an estimated 2.3 million new breast cancer cases worldwide in 2020, with breast cancer now the most diagnosed type of cancer representing 25% of cancer cases and 17% of cancer deaths (1). The GLOBOCAN Cancer Tomorrow prediction tool estimates that incidence will increase by &amp;gt; 45% by 2040 (2). Optimal treatment for breast cancer is increasingly dependent upon knowing a patient’s somatic and germline genomic alteration status. To highlight the importance of these genomic alterations, we provide an overview of the genomic findings in 987 consecutive breast cancer patients tested in the course of routine clinical care. Methods: Comprehensive Genomic and Immune Profiling (CGIP) was performed on 987 qualified breast cancer samples at a CAP/CLIA and NYS CLEP certified reference laboratory with the OmniSeq INSIGHT ® test (3). OmniSeq INSIGHT ® is a next generation sequencing-based laboratory developed test for the detection of genomic variants, signatures, HLA Class I genotypes, and immune gene expression in formalin-fixed paraffin-embedded (FFPE) tumor tissue. DNA is sequenced to detect small variants in the full exonic coding region of 523 genes, copy number alterations in 59 genes (gains and losses), as well as analysis of microsatellite instability (MSI) and tumor mutational burden (TMB). RNA is sequenced to detect fusions and splice variants in 55 genes, in addition to mRNA expression in 64 immune genes. The resultant information, along with PD-L1 protein expression by immunohistochemistry (IHC), is intended for use by qualified health care professionals in accordance with professional guidelines in oncology for management of patients with solid neoplasms. Tier IA variants include variants with strong clinical significance as per AMP–ASCO–CAP recommendations (4). Results: There were 384 Tier IA variants detected in 370 of 987 breast cancer patients (~37.5%) with 251 in PIK3CA (65.3%), 60 in ERBB2 (15.6%), 46 in BRCA2 (11.9%), 19 in BRCA1 (4.9%), 4 in NTRK3 (1.0%), 1 in NTRK1 (0.26%) and 1 in PALB2 (0.26%) including copy number variations (CNV), gene fusion and single nucleotide variants (SNV). At the individual gene level for Tier IA variants, PIK3CA had 251 SNVs detected, ERBB2 had 55 CNVs, 1 gene fusion and 4 SNVs detected, BRCA2 had 39 SNVs and 8 CNVs detected, BRCA1 had 19 SNVs, NTRK3 had 4 gene fusions, NTRK1 had 1 gene fusion and PALB2 had 1 SNV detected. At the variant class level, there were 63 CNVs, 6 gene fusions and 315 SNVs observed. Conclusions: CGIP for breast cancer patients identified one or more clinically significant Tier IA genomic alterations that directs targeted therapy in ~ 37.5% of patients in a cohort of real world patients tested during the standard course of clinical care. This highlights the need for comprehensive genomic testing in breast cancer patients to drive therapeutic decision making.

Abstract PO4-10-10: NAVYA-AI enabled intervention to increase real-world guideline compliant care: Improving NGS testing in breast cancer

Abstract BACKGROUND: Navya-AI is a validated online cancer informatics solution that combines artificial intelligence based analysis of the guidelines and evidence, along with asynchronous expert review. Navya-AI releases preliminary system-generated opinions for patients whose treatment plans fit high confidence based on NCCN Guidelines and prior expert reviews. Prior research (SABCS 2014-2018 and ASCO 2021 showed: 1) 97% concordance of Navya-AI predictions with an academic medical center in India and in the US 2) 80% of patients implement treatment concordant with Navya-AI recommendations on the ground 3) Navya’s NCCN and evidence-based treatment plans reduce the patient waiting times for an expert opinion by an average by 3.5 days. Next generation sequencing (NGS) is an expensive but necessary method for identifying patients for risk reduction and therapy selection in breast cancer (BC). NGS testing can be over-used or under-used, and compliance with NCCN guidelines on patient selection is especially important in resource-constrained settings and Low Middle Income Countries (LMIC) such as India. The aim of this study is to find the physician compliance to NCCN guidelines on NGS testing in India, and how Navya-AI can identify the opportunity for improved care, and improve compliance with guidelines for optimal care. METHODS: From January 2022 to May 2023, Breast Cancer patients receiving Navya-AI treatment plan (based on guidelines and live expert-review) were analyzed. Patients who could afford NGS testing and targeted therapies, and who met the Enhanced tier of NCCN resource stratified guidelines for their care centers were identified. Their records were screened by Navya-AI to assess if they met NCCN criteria for NGS testing for risk reduction or for treatment selection (young age, positive family history, triple negative breast cancer etc.). Treating physicians were then analyzed if they had ordered NGS appropriately, or had missed an opportunity for NGS (undertreatment), or had over-ordered NGS (overtreatment).RESULTS: 521 BC patients who could afford NGS tests received a Navya-AI plan during this period. Of these, 85% were Indian patients (415/521) and were analyzed. Patients were diverse with respect to age,cancer stage, family history of cancer and histology: Age &amp;lt; 35: 6.7%, 35-50: 33%, 51-65: 43.76%, &amp;gt;65: 16.51%; early stage: 21.5%, locally advanced stage: 29.56%,metastatic stage: 47.79% and benign disease: 1%; positive family history of cancer: 37.35%, triple negative BC: 21.9%. Of 415 indian breast cancer patients who could afford testing, NGS testing was indicated in 69.64% (289/415) as per NCCN guidelines. The treating physician was compliant with NCCN guidelines in only 47.95% (199/415) of the cases: 19.2% (80/415) of the time, NGS was indicated and the treating physician ordered the same; 28.67% (119/415) of the time, NGS was not indicated, and the treating physician did not order NGS. The remaining 52% were not compliant with NCCN. Under-treatment was present in 50.36% (209/415) of cases, and was the vast majority of fallouts. Over-treatment was only present in 1.69% (7/415). In all 50.63% (209/415) cases, where NGS was not ordered by the treating oncologist, but was indicated, and affordable to the patient, Navya requested the patient to discuss the risks/benefits of NGS testing with their treating oncologist. CONCLUSION: NGS testing in BC patients has significant impact on risk-reduction, genetic counseling, choice of surgery, and treatment options for adjuvant therapy. Missed opportunities for NGS testing in more than 50% of the patients who can afford the testing and resultant therapies, points to a signficant area where compliance with guidelines and expert opinions can impact outcomes. A 'Technological Earthshot" that significantly increases adoption of guideline-based care is the first and an easy step towards 'Cancer Moonshots'. Citation Format: RA Badwe, Premal Thaker, Farzana Begum, Mayukh Acherjee, Gitika Srivastava, Naresh Ramarajan, Shona Nag, Sudeep Gupta, Seema Gulia, Jaya Ghosh, Bhawna Sirohi. NAVYA-AI enabled intervention to increase real-world guideline compliant care: Improving NGS testing in 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 PO4-10-10.

Germline pathogenic variants associated with triple-negative breast cancer in US Hispanic and Guatemalan women using hospital and community-based recruitment strategies

PurposeRecruit and sequence breast cancer subjects in Guatemalan and US Hispanic populations. Identify optimum strategies to recruit Latin American and Hispanic women into genetic studies of breast cancer.MethodsWe used targeted gene sequencing to identify pathogenic variants in 19 familial breast cancer susceptibility genes in DNA from unselected Hispanic breast cancer cases in the US and Guatemala.Recruitment across the US was achieved through community-based strategies. In addition, we obtained patients receiving cancer treatment at major hospitals in Texas and Guatemala.ResultsWe recruited 287 Hispanic US women, 38 (13%) from community-based and 249 (87%) from hospital-based strategies. In addition, we ascertained 801 Guatemalan women using hospital-based recruitment. In our experience, a hospital-based approach was more efficient than community-based recruitment. In this study, we sequenced 103 US and 137 Guatemalan women and found 11 and 10 pathogenic variants, respectively. The most frequently mutated genes were BRCA1, BRCA2, CHEK2, and ATM. In addition, an analysis of 287 US Hispanic patients with pathology reports showed a significantly higher percentage of triple-negative disease in patients with pathogenic variants (41% vs. 15%). Finally, an analysis of mammography usage in 801 Guatemalan patients found reduced screening in women with a lower socioeconomic status (p < 0.001).ConclusionGuatemalan and US Hispanic women have rates of hereditary breast cancer pathogenic variants similar to other populations and are more likely to have early age at diagnosis, a family history, and a more aggressive disease. Patient recruitment was higher using hospital-based versus community enrollment. This data supports genetic testing in breast cancer patients to reduce breast cancer mortality in Hispanic women.

Abstract 977: Germline BRCA1/2 mutations detected by circulating tumor DNA testing in breast cancer patients: A retrospective mutiinstitutional analysis

Abstract Background: The use of circulating tumor (ct) DNA testing allows to detect resistant and actionable somatic alterations and it could be associated with the incidental identification of germline mutations. An univocal variant allele frequency (VAF) threshold to distinguish germinal form somatic mutations has not been assessed yet. We aimed to correlate BRCA1/2 ctdNA detected mutations with germline mutational status to determine potential VAF cutoff. Materials and methods:We retrospectively analyzed the incidence of both somatic (s) and germinal (g) BRCA1/2 alterations in a multiinstitutional retrospective breast cancer (BC) cohort to assess the VAF threshold for the likelihood of germline mutations’ detection by ctDNA next-generation sequencing (Guardant 360) testing. Clinical variables were analyzed using descriptive analyses and receiving operating characteristic (ROC) curves were generated to determine the VAF cutoff. Results: Two hundred and fourteen patients (pts) with sBRCA1/2 mutations (including variant of uncertain significant and synonymous) detected by ctDNA testing, referred to the enrolling centers between January 2015 to May 2023 were included in the analysis. The median age at diagnosis was 50 years old (Interquartile range (IQR)43,5-61.5), 43% had a family history of cancer. Hormone receptor positive/HER2 negative was the most represented subtype (68%) followed by the HER2 positive (16%) and triple negative (16%) ones. At ctDNA baseline, 95.8% of pts had a metastatic disease; the main sites of metastases were bone (67.4%) and visceral (59.3%). Ninetyfour (43.9%) and 137 (64%) pts had a sBRCA1 and sBRCA2 alterations respectively, while 17 (7.9%) had a co-mutation in BRCA1 and BRCA2. The mean VAF value for sBRCA1 alterations was 10.1% (standard deviation (SD) 19.5%, range [0.04%-84.3%]) while for sBRCA2 alterations was 10.8% (SD 18.9%, range [0.21%-80.3%]). The germinal testing, performed per standard of care, was available for 100 pts (46.7%). Among these, 42 (42%) had at least a pathogenic variant detected. A gBRCA1 mutation was present in 11 (11%) pts while 25 (25%) had a gBRCA2 mutation. Comparing the somatic and germinal testing, 9/100 pts had a concordance for BRCA1 detection, the 2 discordant cases had both a low allele frequency sBRCA2 alterations; the concordance for BRCA2 detection was instead 100%. An optimal cutoff of 38.4% (AUC 0.98) for BRCA1 and 19.5% (AUC 0.96) for BRCA2 was assessed by ROC analysis as the likelihood of a germline meaning of a somatic mutation detected by ctDNA analysis. Conclusion: The identification of BRCA1/2 alterations in ctDNA could guide the use of germline testing. The VAF cutoff identified for the likelihood of a germinal mutation is lower than expected, suggesting that a wider population should be screened for germinal mutation with relevant impact on the therapeutic choices and family screening. Citation Format: Letizia Pontolillo, Carolina Reduzzi, Andrew A. Davis, Arielle J. Medford, Annika Putur, Lorenzo Gerratana, Katherine Clifton, Whitney L. Hensing, Marko Velimirovic, Surbhi Warrior, Mara S. Serafini, Eleonora Nicolò, Laura Munoz-Arcos, Jeannine Donahue, Charles S. Dai, Jennifer C. Keenan, Amir Behdad, William J. Gradishar, Diana Giannarelli, Emilio Bria, Cynthia X. Ma, Aditya Bardia, Massimo Cristofanilli. Germline BRCA1/2 mutations detected by circulating tumor DNA testing in breast cancer patients: A retrospective mutiinstitutional analysis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 977.

BRCA testing in patients with breast cancer with Medicaid vs. commercial insurance.

148 Background: Systemic therapies targeting breast cancers associated with germline BRCA1/2 mutations (gBRCAm) have been available since 2018, approved first for locally advanced or metastatic HER-2 negative disease and more recently for use in the adjuvant setting. Prior studies have found substantial underuse of BRCA testing in breast cancer patients and disparities by socioeconomic factors. We compared rates of BRCA testing in non-elderly breast cancer patients with Medicaid vs. commercial insurance. Methods: We used the Clarivate Real-World Data Product (Clarivate RWD), a database of open claims from clearinghouses. The database links medical and pharmacy claims from ≥98% of commercial and government health insurance plans and covers 300 million lives. We identified adults ages 18-64 with commercial insurance or Medicaid with claims for breast cancer diagnosis and treatment in 2016-2021. The primary outcome was receipt of a BRCA test within 6 months after the first breast cancer (index) claim. We compared the proportion who received a BRCA test in Medicaid vs. commercial insurance. In multivariable logistic regression we estimated the impact of insurance type on receipt of a BRCA test, controlling for demographic and health characteristics. We also examined trends over time. Results: We identified 147,050 patients with commercial insurance and 41,259 with Medicaid who met inclusion criteria. The cohort was 99% female, 65% were age 50-64, 35% lived in the South, 11% had diagnosis codes for metastatic disease, and 61% had an Elixhauser comorbidity score of 0. Compared to those with commercial insurance, patients with Medicaid were younger, less likely to live in the South, more likely to have metastatic disease and have comorbid conditions. Medicaid beneficiaries were more likely to receive a BRCA test within 6 months of index claim than commercially insured patients (16.8% vs. 11.7%), with an adjusted odds ratio of 1.41 (95% CI 1.36-1.46). Receipt of a BRCA test was also more likely in patients who were male; younger; lived in the Northeast, Midwest or West; had metastatic disease or greater comorbidity. In analysis stratified by presumed stage, the advantage of Medicaid coverage was statistically significant only in patients with metastatic disease. While the proportion of all patients who received a BRCA test increased substantially in both groups beginning in 2019, it grew at a much greater rate among those with Medicaid, exceeding 20% in those patients by late 2021. Conclusions: In this analysis of health insurance claims, breast cancer patients with Medicaid were more likely to receive a BRCA test than their peers with commercial insurance, and this difference was driven by testing rates in those with presumed metastatic disease. Expanding testing in both groups could facilitate access to effective therapies for both metastatic and non-metastatic breast cancers associated with gBRCAm, thereby improving health outcomes.

Mainstreamed genetic testing of breast cancer patients: experience from a single surgeon's practice in a large US Academic Center.

This study evaluated the impact of mainstreamed genetic testing (MGT) on the timing and uptake of testing in an academic breast surgeon's practice. Before September 2019 (pre-MGT phase), a breast surgery practice at Massachusetts General Hospital followed a traditional model of a pre-test consultation with a genetic counselor (GC) following a referral. After September 2019 (post-MGT phase), the same practice offered patients genetic testing in a single clinical encounter with a breast surgeon. We evaluated the waiting time between referral and GC visit in the pre-MGT phase and compared the uptake and positivity rates between both phases. In the pre-MGT phase (204 patients), the median waiting time for GC visit was seven days for patients with a newly diagnosed cancer, 211 days for patients with a personal history of cancer, and 224 days for non-cancer patients who had a family history. A total of 105 (51.5%) patients completed a GC appointment. In the post-MGT phase (202 patients), a significantly higher proportion of patients (88.1%, p < 0.001) consented to genetic testing, while the proportion of patients who tested positive was lower (pathogenic variant: 11.9% vs. 20.0%; variant of uncertain significance: 19.9% vs. 28.0%; p = 0.047). Implementing MGT can reduce the number of clinical visits, significantly shorten patients' wait time to test initiation, and increase the completion of genetic testing. Successful integration of this model relied on the genetic expertise of the breast surgeon involved and the support of the GC team.

Clinical implications of universal germline testing in breast cancer patients in an Arab population: The Jordanian Exploratory Cancer Genetics (Jo-ECAG) study.

e22535 Background: Germline genetic testing (GGT) for breast cancer (BC) has implications for surgical decision-making, treatment selection, clinical follow-up and cascade testing. As uptake of GGT increases globally, it is important to examine its impact on clinician decision-making, particularly in different ethnic groups. Methods: The Jo-ECAG Study consisted of unselected, newly diagnosed cancer patients (pts) from a single center in Jordan. Pts were classified as meeting (in criteria, IC) or not meeting (out of criteria, OOC) National Comprehensive Cancer Network (NCCN) v.1.2020 GGT criteria. Pts underwent a 84 gene test with clinician-reported outcomes collected &gt;2 months post GGT. Analysis was limited to pts with BC. Pts with one PGV in a gene associated with autosomal recessive inheritance (“carriers”) were excluded from overall PGV count. Blank responses were considered uninformative. Descriptive statistics and Fisher’s exact test were employed. Results: 1648 (21 male) Arabic pts with BC, 36% metastatic, with a mean age at diagnosis of 50.5 were tested; 67% were IC. 212 PGVs were identified in 202 (12%) pts, with a significantly higher rate in IC vs. OOC pts (14% vs. 8%, p=0.0002). PGVs were most common in BRCA1/2 (4%), APC I1307K (4%), and other BC-associated genes such as ATM, CHEK2, PALB2 and TP53 (collectively, 3%). 2% of pts were carriers and 57% had uncertain results. Among pts with PGVs and informative responses (Table), 18% had changes to treatment (11% OOC) and 82% to surveillance/follow up (16% OOC) based on GGT results. Genetic counseling and/or GGT was recommended for relatives of &gt;90% of PGV and carrier pts. No changes to treatment or follow-up were made for pts with negative or uncertain results. Conclusions: 1 in 8 Jordanian BC pts had a PGV identified, with a similar breakdown of PGVs observed in other ethnic cohorts, aside from a higher percentage of APC I1307K. Both treatment and surveillance/follow-up decisions were impacted by GGT results. Appropriately treatment or management was not escalated for pts with negative or uncertain results. [Table: see text]

Abstract 1938: Germline mutations in breast cancer genes are associated with early age of diagnosis and triple negative disease in Guatemalan and US Hispanic women

Abstract Abstract Background: Mutations in hereditary breast cancer genes play an essential role in cancer risk. Little is known of the type and frequency of mutations in Hispanic populations in the United States and Central American countries, including Guatemala. Methods: We used exome sequencing to identify mutations in blood DNA from unselected Hispanic breast cancer cases from community recruitment and from two hospitals each in Texas and Guatemala. Data from a structured questionnaire was used to compare mutation carriers of medium and high penetrance genes. Variants were annotated with ClinVar and VarSome. Results: We recruited 262 Hispanic US women, 37 (14%) from community-based recruitment and 225 (86%) from hospitals in Texas. In addition, we ascertained 633 patients from two hospitals in Guatemala City. A total of 91 out of 895 subjects (10%) had a variant classified as pathogenic in a gene with known high or medium penetrance for inherited breast cancer. The most frequently mutated genes were the high penetrance BRCA1 (44/895, 4.9%) followed by BRCA2 (23/895, 2.6%), PALB2 (5/895, 0.6%), CHEK2 (5/895 0.6%), ATM (6/895, 0.7%) and TP53 (6/895, 0.7%). Pathogenic variants were also detected in the moderate penetrance genes BARD1 and MSH6, and rare pathogenic variants detected in the low penetrance genes AXIN2, FH, MLH1, MSH2, MUTYH, NF1, and SDHB. The high ratio of BRCA1/BRCA2 mutations is due to the presence of two potential founder mutations, BRCA1 c.212+1G&amp;gt;A splice mutation (18 cases) and BRCA1 c.799delT (9 cases) in Guatemala. Compared to all others, cases with pathogenic mutations had a significantly earlier age at diagnosis (45 vs. 52 years, P&amp;lt;0.001) and were more likely to have a diagnosis before menopause. A higher percentage of mutation carriers had a relative with any cancer (51% vs. 37%, P=0.038) or breast cancer (33% vs. 15%, P&amp;lt;0.001). Patients with pathogenic mutations had a significantly higher percentage of triple-negative disease (60% vs. 13%, P=0.00046). Finally, mammography usage was less frequent in women with a lower socioeconomic status, indicating that this group is less likely to be screened for breast cancer (P&amp;lt;0.001). Conclusions: Guatemalan women have rates of hereditary breast cancer mutations like other populations, and these women are more likely to have early age at diagnosis, triple-negative disease, and family history. Patient recruitment was higher using hospital-based versus community enrollment. This data supports genetic testing in breast cancer patients and those at high risk as part of a strategy to reduce breast cancer mortality in Hispanic women. Citation Format: Jesica Godinez Paredes, Isabel Rodriguez, Megan Ren, Anali Orozco, Jeremy Ortiz, Anaseidy Albanez, Catherine Jones, Zeina Nahleh, Lilian Barreda, Lisa Garland, Dongjing Wu, Jiahui Wang, Victor Argueta, Roberto Orozco, Eduardo Gharzouzi, Michael Dean. Germline mutations in breast cancer genes are associated with early age of diagnosis and triple negative disease in Guatemalan and US Hispanic women [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1938.

Abstract P6-02-12: Underutilization and disparities in germline genetic testing for breast cancer patients diagnosed in Chile

Abstract Introduction 10% of Breast Cancer (BC) cases are thought to carry a germline pathogenic variant (PV) in a susceptibility gene. Most clinicians utilize the National Comprehensive Cancer Network (NCCN) guidelines criteria to both identify these patients and, in those who test positive, to provide adequate follow-up and/or surgery recommendations. In Chile, BC Guidelines, established in 2004, defined treatment strategies for invasive BC (iBC) which significantly reduced mortality. However, these guidelines do not define strategies for germline genetic testing nor contemplate coverage for those who needs them. Thus, we face many obstacles to genetic testing implementation such as out-of-pocket cost and lack of genetic counsellors. The aim of the study is to determine how many BC Chilean patients are at risk according to international guidelines, how many are being tested and what are their clinical characteristics. Methods Retrospective analysis of a prospective database of iBC patients treated in a public hospital (PH) and in an Academic Private Centre (AC) in Santiago, Chile from January 2012 to March 2022. All patients who had enough information (age, family history (FH), BC subtype) for NCCN Version 2.2022 categorization were included. Patients whose only indication for germline testing was the potential use of PARP-inhibitors were excluded. Clinical characteristics were extracted from clinical charts. Results 4,365 iBC patients met criteria. 51.1% were treated in PH and 49.9% in a AC. 2,260 patients (51.8%) fulfilled NCCN criteria for germline testing, distributed unevenly between PH (46.0%) vs. AC (56.9%, p=0.0001). Compared to PH, patients in AC were diagnosed at younger age (54 vs 56 years, p=0.0001) and were more likely to report FH (69.4% vs. 53.7%, p=0.0001). No difference between BC subtypes was reported. Considering only those fulfilling criteria, germline genetic testing was performed in 326 patients (14.4%) with a significant difference according to UH vs AC (18.7% vs. 9.1%, p= 0.0001). 58% of these tests were performed in the last 3 years. Multivariate logistic regression showed that being diagnosed before 46 (HR=5.3, p=0.0001); FH (HR=2.2, p=0.0001); localized vs. metastatic disease (HR=3.7, p=0.001); triple negative (TN) BC (HR=1.8, p=0.0001) and being treated in AC (HR=1.9, p=0.0001) were independently associated with germline genetic testing being performed in patients fulfilling NCCN criteria. 82 PV were documented, being the most frequent BRCA1/2 (18.1%) followed by PALB2 (1.8%) and ATM (1.2%). Being diagnosed with TNBC (HR=3.8, p=0.0001) and having a first-degree relative with cancer (HR=4.4, p=0.0001) were the only factors associated with carrying a pathogenic BRCA1/2 mutation. Conclusion In Chile, less than 20% of iBC patients who meet NCCN criteria for germline testing are being tested. In this sample of our Public Health System, where over 80% of the Chilean population is treated, fewer than 1 in 10 individuals fulfilling criteria have undergone testing. New evidence suggests that probably a wider span than suggested by NCCN of patients should be counselled and tested, deepening even further the underutilization of germline testing in Chile. Lack of knowledge and training in oncology providers and out-of-pocket costs might influence these results. National guidelines are urgently needed. Citation Format: FRANCISCO ACEVED, Benjamin Walbaum, Lidia Medina, Tomas Merino, Paula Reyes, Militza Petric, Francisco Dominguez, Paulina Gonzalez, CÉSAR SÁNCHEZ. Underutilization and disparities in germline genetic testing for breast cancer patients diagnosed in Chile [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P6-02-12.

Abstract P5-05-08: Dual ctDNA and tissue sequencing improves detection of actionable variants in breast cancer patients

Abstract Background: Next-generation sequencing of circulating tumor DNA (ctDNA) and solid-tissue can identify clinically actionable genomic variants that may be used for both treatment selection and disease surveillance. Due to differences in tumor biology and assay design, ctDNA and solid biopsies may identify unique variants. Here, we investigate a real-world dataset of breast cancer patients to determine whether clinically actionable variant detection is enhanced by dual ctDNA and solid tissue testing. Methods: We used the deidentified Tempus Lens database to retrospectively analyze stage IV breast cancer patients with known hormonal subtype. Each patient had dual testing defined as Tempus xF (ctDNA) and Tempus xT (tumor tissue)—which resulted in clinical reports for both tests. Patients were further stratified according to the timing of ctDNA biopsy relative to tissue biopsy. Concurrent dual testing was defined as samples collected ≤30 days apart and longitudinal dual testing was defined as liquid &amp;gt;30 days after solid. Variants were included in analyses if they met the limit of detection criteria of both assays. Clinical actionability was defined by indication-matched OncoKB Level 1-3. Fisher exact test was used to calculate significance. Results: Of the 1,341 breast cancer patients with dual ctDNA and tissue sequencing, at least one actionable variant was identified in 61% (n=823) of patients. In the subset of concurrent tested patients (n=782), 60% (n=473) had one or more actionable findings: 54% (n=257/473) of patients with actionable variants had perfectly concordant variants, 29% (n=136/473) had at least one unique variant detected only by solid tumor testing, and 20% (n=93/473) had at least one unique variant detected only by ctDNA testing. Similarly, in the longitudinal set (n=559), 63% (n=350) had one or more actionable findings: 34% (n=118/350) were concordant, 43% (n=150/350) were unique to solid, and 27% (n=96/350) were unique to ctDNA. When stratifying concurrent patients by OncoKB levels of evidence, 72% (n=98/136) of patients with variants unique in solid had at least one level 1-2 variant, while 39% (n=53/136) contained unique level 3 variants. Level 1-2 variants in PIK3CA were the most frequent variants seen uniquely in solid tumors, occurring in 54% (n=73/136) of patients. In contrast, in patients with unique ctDNA variants, 37% (n=34/93) of patients had at least one level 1-2 variants and 72% (n=67/93) had level 3 variants. Level 3 variants in ESR1 were the most frequent variants seen uniquely in ctDNA, occurring in 57% (n=53/93) of patients. The proportion of concurrent patients with actionable variants found exclusively in ctDNA significantly differed by subtype (p=0.04): Luminal A (22%) and Luminal B (23%) contained the most patients with unique ctDNA variants. This ability to detect additional variants in ctDNA remained true even if profiling occurred over time. Indeed, in patients with ESR1 variants tested with ctDNA &amp;gt; 1 year after tissue, 78% (n=43/55) had ESR1 variants only detected in blood. Conclusions: We show that dual testing in breast cancer patients improves the identification of clinically actionable variants which may be missed by either ctDNA or solid tissue biopsy alone. Adoption of dual testing should be considered as standard practice to provide a comprehensive view of actionable molecular alterations. Citation Format: Matthew Mackay, Kabir Manghnani, Adam Hockenberry, Joshua Drews, James Chen, Rotem Ben-Shachar, Justin Guinney. Dual ctDNA and tissue sequencing improves detection of actionable variants in breast cancer patients [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P5-05-08.

HEREDITARY CANCER MUTATIONS PREVALENCE AMONG BREAST CANCER PATIENTS ACCORDING TO NGS PANEL TESTING RESULTS, ITS IMPORTANCE IN CHOOSING THE EXTENT OF SURGICAL TREATMENT

Summary. Genetic testing for hereditary cancer gene mutations is important for breast cancer patients in many aspects (including the degree of risk determining the extent of surgical treatment) and helps the patient to choose the best option, both from the point of view of risk reducing, and from the point of view of the best aesthetic result and minimizing the consequences of treatment. Aim: to determine the spectrum of gene mutations in breast cancer patients who had at least one of the risk factors for heredity of the disease. Object and methods: the study included 160 breast cancer patients who had at least one of the risk factors for heredity of the disease according to the criteria defined in the NCCN version 2.2019 guideline. All patients underwent next-generation DNA sequencing (NGS) genetic testing for a panel of 30 hereditary cancer genes. Statistical analysis of the obtained results was carried out in the EXCEL. Results: among 160 patients, 90 mutations were detected in 72 patients (45.0%). Among them, 59 patients (81.9%) had one mutation, 13 patients (18.1%) had more than one mutation. 51 pathogenic or likely pathogenic mutations were detected in 45 patients. 39 VUS (variant of uncertain significance) mutations were detected in 31 patients. The rate of hereditary breast cancer among the studied patients was 27.5%. The most frequent gene mutations were: BRCA1 (47.1%), CHEK2 (17.6%), BRCA2 (17.6%), ATM (5.9%), PALB2 (3.9%), BRIP1 (2, 0%), others (5.9%). Among them, the most frequent mutation was 5382ins C of the BRCA1 gene. For 64.3% of patients, the results of genetic testing had the highest importance when choosing the extent of surgical intervention, and for only 5.1% of patients they were completely unimportant. Conclusion: genetic testing is important for patients in many aspects, from the choice of the scope of surgical treatment to the features of followup, preventive measures to reduce the risk of new events (multiple primary neoplasms), the feasibility of testing children, etc. It is relevant to continue studying the role of genetic testing for breast cancer patients in various aspects, in particular, in choosing the scope of surgical treatment.

The Role of Race and Insurance Status in Access to Genetic Counseling and Testing Among High-Risk Breast Cancer Patients.

PurposeThe role of germline genetic testing in breast cancer patients is crucial, especially in the setting of the recent trials showing the benefit of PARP inhibitors. The goal of this study was to identify racial disparities in genetic counseling and testing in patients with high-risk breast cancer.MethodsPatients with 2 unique breast cancer diagnoses were examined to understand demographics, insurance coverage, characteristics of breast cancer, and whether they were recommended for and received genetic counseling and testing.ResultsA total of 69 patients with a dual diagnosis of breast cancer between the years 2000 and 2017 were identified (42% identified as White compared to 58% that identified as non-White). White patients were more likely to be recommended for genetic counseling (OR = 2.85; 95% CI, 1.07-7.93, P < .05), be referred for genetic counseling (OR = 3.17; 95% CI, 1.19-8.86, P < .05), receive counseling (OR = 3.82; 95% CI, 1.42-10.83, P < .01), and undergo genetic testing (OR = 2.88; 95% CI, 0.97-9.09, P = .056) compared to non-White patients. Patients with private insurance were significantly more likely to be recommended for genetic counseling (OR 5.63, P < .005), referred (OR 6.11, P < .005), receive counseling (OR 4.21, P < .05), and undergo testing (OR 4.10, P < .05). When controlled for insurance, there was no significant racial differences in the rates of GC recommendation, referral, counseling, or testing.ConclusionThe findings of this study suggest that disparities in genetic counseling and testing are largely driven by differences in health insurance.

RNA‐Seq and Recurrence Risk Testing for Breast Cancer: Implications for Patient Education

Rapid advances in RNA­seq technology and bioinformatic analysis of gene expression has normalized the use of precision diagnostics and recurrence risk testing for breast cancer patients. While these diagnostic approaches have numerous benefits, patients often lack the scientific literacy to evaluate data models ‐ and their uncertainties ‐ for enhancing their health decision‐making. To increase access to scientific knowledge for stakeholders, we designed an educational module that evaluates the validity of RNA‐seq gene expression as a tool for subtyping and determining the prognostic signature of a human breast tumor. Using a crowdsourced approach in the context of an undergraduate course, we recreated the workflow of prominent precision oncology companies ‐ we prepared a whole transcriptome library from a single breast cancer patient, and used multiplex sequencing on twelve uniquely barcoded Illumina preparations. Datasets obtained from the sequencing were subjected to quality control analysis using the Green Line of DNA Subway (FAST QC, FAST X, Kallisto, Sleuth algorithms). Log­ transformed gene expression ratios were used to determine the molecular subtype of the tumor. To calculate the recurrence risk, the Oncotype DX model was used, including 16 cancer genes and 5 reference genes. Results from the proof‐of‐concept experiment indicated significant overexpression of ER and PR genes (p&lt;0.01) and concomitant underexpression of HER2 and Ki67 genes (p&lt;0.01), consistent with a Luminal A tumor subtype. The Oncotype DX score was &gt;25, suggesting high risk for 10 year distant recurrence (95% CI). Further exploration of the model indicated that normalization to aberrantly expressed reference genes can greatly skew the recurrence risk calculation, highlighting limits to the predictive power of this tool. Taken together, our findings illustrate the validity of RNA‐seq‐based tumor subtyping through an educational module, and underscores the importance of equitable access to genomics education as a form of patient self‐empowerment and decision‐making. We discuss the future implications of this work for education and policy.

Revisiting the Implications of Positive Germline Testing Results Using Multi-gene Panels in Breast Cancer Patients.

The use of multi-gene panels for germline testing in breast cancer enables the estimation of cancer risk and guides risk-reducing management options. The aim of this study was to present data that demonstrate the different levels of actionability for multi-gene panels used in genetic testing of breast cancer patients and their family members. We performed an analysis in our clinical database to identify breast cancer patients undergoing genetic testing. We reviewed positive results in respect of risk estimation and management, cascade family testing, secondary findings and information for treatment decision-making. A total of 415 positive test reports were identified with 57.1%, 18.1%, 10.8% and 13.5% of individuals having pathogenic/likely pathogenic variants in high, moderate, low and with insufficient evidence for breast cancer risk genes, respectively. Six point seven percent of individuals were double heterozygotes. Germline findings in 92% of individuals are linked to evidence-based treatment information and risk estimates for predisposition to breast and/or other cancer types. The use of germline findings for treatment decision making expands the indication of genetic testing to include individuals that could benefit from targeted treatments.

6q deletion is frequent but unrelated to patient prognosis in breast cancer

BackgroundDeletions involving the long arm of chromosome 6 have been reported to occur in breast cancer, but little is known about the clinical relevance of this alteration.MethodsWe made use of a pre-existing tissue microarray with 2197 breast cancers and employed a 6q15/centromere 6 dual-labeling probe for fluorescence in situ (FISH) analysisResultsHeterozygous 6q15 deletions were found in 202 (18%) of 1099 interpretable cancers, including 19% of 804 cancers of no special type (NST), 3% of 29 lobular cancers, 7% of 41 cribriform cancers, and 28% of 18 cancers with papillary features. Homozygous deletions were not detected. In the largest subset of NST tumors, 6q15 deletions were significantly linked to advanced tumor stage and high grade (p < 0.0001 each). 6q deletions were also associated with estrogen receptor negativity (p = 0.0182), high Ki67 proliferation index (p < 0.0001), amplifications of HER2 (p = 0.0159), CCND1 (p = 0.0069), and cMYC (p = 0.0411), as well as deletions of PTEN (p = 0.0003), 8p21 (p < 0.0001), and 9p21 (p = 0.0179). However, 6q15 deletion was unrelated to patient survival in all cancers, in NST cancers, or in subsets of cancers defined by the presence or absence of lymph-node metastases.ConclusionOur data demonstrate that 6q deletion is a frequent event in breast cancer that is statistically linked to unfavorable tumor phenotype and features of genomic instability. The absence of any prognostic impact argues against a clinical applicability of 6q15 deletion testing in breast cancer patients.

Germline variants in hereditary breast cancer genes are associated with early age at diagnosis and family history in Guatemalan breast cancer

PurposeMutations in hereditary breast cancer genes play an important role in the risk for cancer.MethodsCancer susceptibility genes were sequenced in 664 unselected breast cancer cases from Guatemala. Variants were annotated with ClinVar and VarSome.ResultsA total of 73 out of 664 subjects (11%) had a pathogenic variant in a high or moderate penetrance gene. The most frequently mutated genes were BRCA1 (37/664, 5.6%) followed by BRCA2 (15/664, 2.3%), PALB2 (5/664, 0.8%), and TP53 (5/664, 0.8%). Pathogenic variants were also detected in the moderate penetrance genes ATM, BARD1, CHEK2, and MSH6. The high ratio of BRCA1/BRCA2 mutations is due to two potential founder mutations: BRCA1 c.212 + 1G > A splice mutation (15 cases) and BRCA1 c.799delT (9 cases). Cases with pathogenic mutations had a significantly earlier age at diagnosis (45 vs 51 years, P < 0.001), are more likely to have had diagnosis before menopause, and a higher percentage had a relative with any cancer (51% vs 37%, P = 0.038) or breast cancer (33% vs 15%, P < 0.001).ConclusionsHereditary breast cancer mutations were observed among Guatemalan women, and these women are more likely to have early age at diagnosis and family history of cancer. These data suggest the use of genetic testing in breast cancer patients and those at high risk as part of a strategy to reduce breast cancer mortality in Guatemala.

Racial disparities in genetic testing of breast cancer patients.

10591 Background: TNBC is disproportionately prevalent in African American (AA) populations and in women with BRCA-1 germline mutations. BRCA mutation carriers are candidates for targeted therapy with PARP-inhibitors, and testing results may influence risk-reducing surgery choice. Methods: We evaluated genetic testing patterns and outcomes for TNBC patients treated in the prospectively maintained databases of academic cancer programs in two metropolitan cities in the Northeast (New York City, NYC) and Midwest (Detroit, Det), 1998-2018. Median follow up was 3.73 years. Testing patterns were also analyzed by time, comparing pts diagnosed before versus after the mid-2013 Supreme Court ruling that expanded testing availability by banning gene patenting. Results: Of 810 pts, 600 were from NYC and 200 from Det; 202 were AA and 488 WA. Pts undergoing genetic testing were younger (median age 50 vs 62; p &lt; 0.0001). Compared to WA, AA pts were less likely to undergo genetic testing overall (23.8% vs 42.0%; p &lt; 0.0001) and within site (NYC: 25.6% vs 42.8%, p = 0.008; Det: 22.3% vs 38.6%, p = 0.025). No significant differences were seen in frequency of pathogenic BRCA mutations (AA-14.6%; WA-29.3%) or VUSs (AA-6.3%; WA- 4.9%); p = 0.20. Genetic testing disparities were reduced among pts diagnosed after mid-2013 (AA-31.4% vs WA-44.0%; p = 0.01) compared to pre-mid-2013 (AA-18.3% vs WA-40.7%; p &lt; 0.0001). No differences were seen in local or distant recurrence free survival between patients with BRCA, BRCA variants of uncertain significance, non-BRCA mutations, and patients without genetic mutations (local recurrence p = 0.827; distant recurrence p = 0.574). This outcome equivalence was consistent when stratified by WA vs AA identity. Conclusions: Genetic testing has increased for TNBC pts following the mid-2013 Supreme Court ban on gene patenting, but race-associated disparities persist. Pts undergoing genetic testing are more likely to undergo risk-reducing mastectomy, but testing results do not affect survival outcomes, regardless of race. Addressing genetic testing disparities will become increasingly important as mutation-associated targeted therapies are identified through advances in precision medicine.