Background:The Tyrer-Cuzick (TC) or IBIS risk calculator is a widely used tool to estimate the probability of developing breast cancer. The latest version incorporates various factors to assess the risk of breast cancer, including family history, personal history, breast density, and past medical history. The TC is commonly used to guide patients toward further diagnostic imaging, genetic testing, chemoprevention, or risk-reducing surgery. However, it is unclear whether the TC is associated with non-BRCA1/2 pathogenic variants (PVs) in breast cancer susceptibility genes. Methods:A population of 964 patients with TC was evaluated for 12 PVs and variants of unknown significance (VUS) using lab-agnostic genetic testing. Patients were enrolled from 2019 to 2022. Historical TC were used for the subgroup of patients who developed breast cancer after enrollment. TC scores were compared between the three patient cohorts that had BRCA gene mutations, non-BRCA PVs, and negative for PVs, using the Kruskal-Wallis test followed by pairwise comparison using DSCF adjustment for multiple comparisons. Data collection for patient cohorts occurred simultaneously and was only separated in analysis. Logistic regression was carried out to predict BRCA versus negative in a model with TC scores, as well as non-BRCA versus negative. Area under the receiver operating characteristic (ROC) curve (AUC) was calculated to assess model fit. Results:This study found an average TC of 7.71%. A family history of cancer was noted in 78.30% of patients, and a personal history of cancer other than breast occurred in 20.74% of patients. The presence of PVs and VUS was evaluated, and 12.03% of patients were found to have a PV, with an average TC of 8.98%. The most common PVs were CHEK2, BRCA2, BRCA1, and BARD1. Out of those with PVs, 52% had non-BRCA1/2 PVs with an average TC of 5.47%. A total of 102 patients (10.58%) had a VUS, with an average TC of 8.29%. In further statistical analysis, TC were distributed significantly differently among the three groups, with differences observed between the BRCA group and negative group, as well as between BRCA and non-BRCA1/2 PVs group. A higher TC was also associated with BRCA1/BRCA2 variants compared to non-BRCA1/2 PVs. Conclusion:TC scores provide valuable information regarding the lifetime risk of an individual of developing breast cancer. However, the study found they were not associated with prediction of non-BRCA1/2 PVs. When choosing a genetic testing panel for breast cancer genes, TC is not as a reliable predictor on individual patient's family history, NCCN guidelines, or ASBrS guidelines. Our study supports the need to develop a genetic risk calculator that incorporates the predictive value for these non-BRCA1/2 PVs in otherwise low or average TC women.

Clinical T3 (cT3) breast cancer (BC) presents a challenge for achieving cosmetically acceptable breast conservation, and neoadjuvant chemotherapy (NAC) is commonly used for cytoreduction in these high-risk cancers. MammaPrint® risk-of-recurrence and BluePrint® molecular subtyping genomic signatures have demonstrated high accuracy in predicting chemotherapy benefits. Here, we examined the utility of MammaPrint/BluePrint for predicting pathological Complete Response (pCR) rates to NAC among 404 patients diagnosed with cT3 early-stage BC. The association of genomic subtype and clinical features with the likelihood of pCR was evaluated by multivariate logistic regression. Differences in pCR rates between genomic risk categories were evaluated by a two-sided proportional z-test and stratified by nodal status. MammaPrint/BluePrint subtyping was associated with significantly higher odds ratios (ORs) for pCR in MammaPrint High-Risk/BluePrint Basal-Type (OR = 3.06, 95% CI: 1.15-8.19, p = 0.025) and HER2-Type (OR = 6.27, 95% CI: 2.19-19.38, p = 0.001) compared to BluePrint Luminal-Type. Of the 209 patients with hormone receptor-positive, HER2-negative disease, 6.7% achieved pCR, and MammaPrint High-Risk was associated with a significantly higher pCR rate (9.3%) compared to MammaPrint Low-Risk cancers (0%), regardless of nodal involvement (p = 0.036). These data show that for patients with MammaPrint Low-Risk, cT3 tumors are less likely to have clinically impactful cytoreduction from NAC, regardless of nodal involvement.

Background: Clinical T3 (cT3) breast cancer is a vexing problem due to the challenge of cosmetically acceptable breast conservation leading NCCN and ASCO to recommend neoadjuvant chemotherapy (NCT). However, MammaPrint® risk of recurrence and BluePrint® molecular subtyping genomic signatures have demonstrated high accuracy in predicting chemotherapy response. Thus, genomic profiling can potentially enable Choosing Wisely® informed treatment choices and reduced toxicity for patients unlikely to benefit from NCT, despite larger size at presentation. In this study, we examined the utility of MammaPrint and BluePrint for identifying cT3 tumors that respond to NCT. Methods: A pooled analysis from NBRST (NCT01479101), FLEX (NCT03053193) and MINT (NCT01501487) trials was conducted on all cT3 patients who received NCT, had MammaPrint and BluePrint results, and post-surgical pathological Complete Response (pCR) data. MammaPrint risk was characterized as Low or High Risk. BluePrint subtype classified tumors as Luminal-Type, HER2-Type, or Basal-Type. Luminal-Type tumors were further classified as Luminal A (Low Risk) or Luminal B (High Risk). Tumor pCR rates were analyzed as an outcome measure. The association of genomic subtype and clinical features with likelihood of pCR was evaluated by multivariate logistic regression. Differences in pCR rates between genomic risk categories were evaluated by two-sided proportional z-test and stratified by nodal status. Results: A total of 404 patients (MINT, n=67; NBRST, n=214; FLEX, n=123) with cT3 breast cancer underwent NCT followed by resection and 87 (21.5%) achieved pCR. The mean (SD) age was 52 (±12) years; 186 (51.7%) were premenopausal; 287 (71%) were node positive. Logistic regression revealed that MammaPrint/BluePrint subtyping showed significantly higher odds ratios for pCR in High Risk Basal-Type (OR= 3.06, 95% CI: 1.15-8.19, p=0.025) and HER2-Type (OR=6.27, 95% CI: 2.19-19.38, p=0.001) compared to the reference category (Luminal-Type), indicating strong positive associations. Only clinical subtype hormone receptor-positive (HR+), human epidermal growth factor-positive (HER2+) exhibited a higher likelihood of pCR (OR = 2.91, 95% CI: 0.97-8.23, p=0.048). Menopausal status, nodal status, and grade were not significantly associated with likelihood of pCR. Of the 209 (51.7%) patients with HR+, HER2- disease, 6.7% (14) achieved pCR. Among patients with HR+HER2-, cT3 MammaPrint/BluePrint Low Risk, Luminal A tumors (n=58), no (0%) pCR was achieved regardless of nodal involvement (n=37 node positive Low Risk). In contrast, MammaPrint High Risk (n=151) had significantly higher rates of pCR compared to Low Risk (p=0.036). By molecular subtype, pCR was achieved for 7 (5.8%) of the 120 Luminal B, and 7 (23.3%) of the 30 Basal Type, cT3 tumors. Conclusion: These data suggest that patients with MammaPrint Low Risk, cT3 tumors are unlikely to respond to NCT. These data are in alignment with long-term follow-up, level 1A evidence from MINDACT showing that patients with MammaPrint Low Risk HR+HER2- tumors may safely omit chemotherapy, regardless of nodal involvement. Intuitively, testing newer agents or neoadjuvant endocrine therapy for downstaging or proceeding to definitive surgery should be considered for genomically low-risk, cT3 cancers. Citation Format: Rakhshanda Rahman, Laura Lee, Alfredo Santillan, Mehran Habibi, Peter Blumencranz, James Pellicane, Peter Beitsch, Pat Whitworth, Harshini Ramaswamy, Nicole Stivers, Andrea Menicucci, William Audeh, Joyce O'Shaughnessy. Neoadjuvant Chemotherapy for T3 tumors in the Era of Precision Medicine - Biology is Still King [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2024; 2024 Dec 10-13; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2025;31(12 Suppl):Abstract nr P1-11-24.

Abstract Background: Neoadjuvant chemotherapy (NCT) yields low pathologic complete response (pCR, ypT0/is ypN0) rates in hormone receptor positive (HR+), HER2- early-stage breast cancer (ESBC). Genomic signatures may predict chemosensitivity and treatment benefit better than receptor status based clinical subtyping. The 70-gene expression signature, MammaPrint (MP), classifies patients with ESBC as having a High or Low Risk of distant recurrence. In the NBRST and ISPY2 trials, further stratification of MammaPrint High Risk into High 1 (H1) or High 2 (H2) showed significantly higher pCR rates to NCT or targeted agents in MP H2 cancers compared to MP H1 tumors. We evaluated MammaPrint H1 and H2 status as a biomarker for neoadjuvant chemosensitivity in patients with HR+HER2- ESBC enrolled in the real-world evidence FLEX study. Methods: FLEX (NCT03053193) is an ongoing prospective, observational trial that has currently enrolled 12,328 patients with ESBC who were tested with MammaPrint as standard of care, with or without molecular subtyping signature, BluePrint (BP), and consented to clinically annotated full genome data collection (data locked Feb. 2023). Patients with HR+HER2-, MP High Risk tumors who received NCT (majority received AC-T) and had pCR data available were included in this analysis (n = 214). Patients were stratified into MP H1 (index 0.000 to -0.569) and H2 (index -0.570 to -1.000) groups. BP classified MP High Risk tumors into Luminal B-, HER2-, or Basal-Type. Differences in clinical characteristics and pCR rates between H1 and H2 tumors was assessed by Chi-Squared test and two-sided proportional z-test, respectively. The association between MP H1 and H2, BP subtype, and pCR was assessed using logistic regression and was adjusted for age, race, grade, T stage, N stage, and NCT regimen. Results: MammaPrint classified 142 (66%) cancers as H1 and 72 (34%) as H2 tumors. Age, menopausal status, race, tumor stage, and lymph node status were comparable between both groups. Although most H2 tumors (78%) were Grade 3, only 59% of all Grade 3 tumors were H2. Nearly all (98%) H1 tumors were Luminal B whereas for H2 tumors, 51% were Luminal B and 49% were Basal by BP classification. pCR rate was significantly higher in H2 tumors (29.2%) compared to H1 tumors (6.3%, p < 0.01) (Table). Basal-Type, H2 tumors (n=35) exhibited the highest pCR rate of 37.1%. Among BP Luminal B tumors, those with MP H2 tumors had a significantly higher pCR rate (21.6%) vs. MP H1 tumors (5.8%, p = 0.003). Multivariate analysis revealed MP H2 (OR=4.91, p=0.003) and BP Basal-Type (OR=3.54, p=0.03) were significantly associated with likelihood of pCR, whereas clinical variables were not associated with pCR. Conclusion: These data demonstrate MammaPrint and BluePrint utility to predict the likelihood of achieving pCR after NCT in HR+HER2- ESBC. Although both MP High Risk groups exhibit chemosensitivity, High 2 tumors have higher chemosensitivity than High 1 tumors. MP High 2 status can be utilized to identify ER+ patients who are the most likely to experience pathologic downstaging and pCR after NCT. Also, patients with High 2 tumors treated with PD-L1 or PARP inhibitors in the ISPY2 trial exhibited significantly higher pCR rates than those observed for High 2 tumors treated with NCT alone. These data suggest that for patients with MP High 2 tumors, neoadjuvant use of chemotherapy is appropriate and these patients may further benefit from the addition of targeted agents to standard NCT. Table: Distribution of pCR rates among MammaPrint H1 and H2 and BluePrint molecular subgroups Data presented as # of patients with pCR/(total # patients in subgroup) and as percentage Citation Format: Joyce O'Shaughnessy, Lajos Pusztai, Cathy Graham, Pat Whitworth, Peter Beitsch, Cynthia Osborne, Rakhshanda Rahman, Andrea Menicucci, William Audeh, FLEX Investigators' Group. MammaPrint index predicts neoadjuvant chemosensitivity in patients with HR+HER2- early-stage breast cancer in the real-world evidence FLEX study [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 PO5-15-04.

506 Background: The 70-gene signature, MammaPrint (MP), classifies patients (pts) with early-stage breast cancer (EBC) as having an UltraLow, Low, High 1 (H1), or High 2 (H2) risk of distant recurrence. I-SPY 2 showed that pts with MP H2, HR+HER2- tumors have significantly higher response rates to neoadjuvant chemotherapy + immunotherapy relative to pts with MP H1 tumors. Expression-based immune deconvolution provides more detailed information about immune cell function beyond conventional methods enumerating tumor infiltrating lymphocytes. To elucidate the underlying biology that mediates immune therapy response, we performed in silico analysis of full transcriptome data to characterize immune cell frequencies and antigen presentation in HR+HER2-, MP High Risk EBC from pts enrolled in FLEX. Methods: The prospective, observational FLEX Study (NCT03053193) includes stage I-III pts with EBC who received MP testing and consented to full transcriptome and clinical data collection. Women with HR+HER2-, and MP High Risk invasive ductal EBC were included (n = 2916). Tumors were stratified into MP H1 or MP H2. The R-package Limma was used to preprocess gene expression data. The gene signature-based method xCell was used to determine immune cell abundances for each group based on enrichment score. Expression of genes involved in “antigen processing and presentation KEGG pathway”, and immune regulation, were evaluated between groups. Differences in immune cell frequency and gene expression were determined by a t-test with an adjusted p-value < 0.05. Results: MP classified 79% (n=2292) of HR+HER2- EBC as H1 and 21% (n=624) as H2. Pts with H2 EBC were more likely to be ≤ 50 years (32%) compared to pts with H1 tumors (23%). Although low ER staining (1-10%) tumors were more frequent in H2 vs H1 (15% vs 1%), a majority of H2 tumors (75%) had ER staining > 10%. Nearly 30% of H2 tumors were Grade 1 or 2, whereas 22% of H1 tumors were Grade 3. H2 tumors had significantly higher frequency of antigen presenting cells (APCs) including activated dendritic cells and macrophages, CD4+ memory T cells, CD8+ T cells, memory B cells and plasma cells relative to H1 tumors. The genes expressing PD-1 and PDL-1 and genes involved in antigen processing, including B2Mand TAP1/2, and presentation, i.e., major histocompatibility (MHC) class I ( HLA-A, -B, -F) and class II molecules ( HLA-DM, -DQ), were significantly upregulated in H2 vs H1. Conclusions: H2 tumors exhibited a heighted immune active state compared to H1 tumors among HR+HER2- EBC pts. The presence of APCs and increased antigen presentation, which are critical in eliciting T- and B-cell activation may explain the improved response rates to immunotherapy observed in H2 tumors. Selecting pts based on grade or ER% alone may exclude pts likely to benefit from immune therapy. These data support ongoing trials evaluating the response and benefit of adding immunotherapy to standard of care treatment regimens in MP H2 tumors. Clinical trial information: NCT03053193 .

511 Background: The MammaPrint (MP) risk of distant recurrence signature identifies hormone receptor-positive (HR+), HER2-negative early-stage breast cancer (EBC) patients (pts) with increased or decreased chemosensitivity and chemotherapy (CT) benefit. The MINDACT trial demonstrated excellent outcomes for MP Low Risk tumors without CT, and previous studies show MP High Risk tumors exhibit higher sensitivity and benefit with CT. There remains an unmet clinical need for identifying biomarkers to inform specific regimen planning for pts who qualify for CT. Here, the association of MP index and 3-year (yr) Recurrence-Free Interval (RFI) was evaluated in pts with HR+HER2-, genomically High Risk Luminal B-Type EBC treated with taxane and cyclophosphamide (TC) vs anthracycline + TC (AC-T). Methods: The prospective, observational FLEX Study (NCT03053193) includes stage I-III breast cancer pts who received MP testing, with or without BluePrint (BP) molecular subtyping, and consented to full transcriptome and clinical data collection. Pts with HR+HER2- MP High Risk and BP Luminal B-Type tumors who received chemotherapy with 3-yr follow-up data (N = 614) were included. High Risk tumors were further classified into High 1 (H1; 0.000 to -0.569) or High 2 (H2; -0.570 to -1.000). Differences in 3-year RFI, defined as time from diagnosis to a local-regional recurrence, distant recurrence, or breast cancer specific death per STEEP 2.0 criteria, between H1 and H2 tumors were evaluated by Kaplan-Meier analysis and log-rank test, stratified by CT regimen. Results: Patients had similar age, menopausal status, race, and lymph node status between H2 vs H1 tumors. H2 tumors were more likely Grade 3, compared to H1 tumors. 86% of tumors were classified as H1 Luminal B-Type (N = 530) and 14% were classified as H2 Luminal B-Type (N = 84). AC-T treated tumors had non-significant differences in 3-yr RFI between H1 Luminal B-Type (95.3% [95% CI, 91.8-98.8]; N = 184) and H2 Luminal B-Type (97.7% [95% CI, 93.4-100.0]; N = 44). In contrast, pts with H2 Luminal B-Type (N = 40) tumors treated with TC demonstrated a significantly worse RFI of 86.4% (95% CI, 74.2-100.0) compared with 97.1% (95% CI, 95.1-99.2) in pts with H1 Luminal B-Type (N = 346) tumors, with an absolute difference of 10.7% (p = 0.0076). Conclusions: These data show that among pts with Luminal B-Type tumors, MP H2 have significantly worse 3-yr RFI than pts with MP H1 tumors when treated with TC. This further supports ongoing research demonstrating the significant benefits of anthracycline-based CT for treating H2 Luminal B-Type tumors. Conversely, MP H1 tumors do not appear to benefit from the addition of anthracycline to CT regimen. These FLEX data add to the growing evidence identifying MammaPrint as a comprehensive genomic signature regarding both prognosis as well as selection of systemic therapy for HR+HER2- EBC pts. Clinical trial information: NCT03053193 .

Current guidelines recommend single variant testing in relatives of patients with known pathogenic or likely pathogenic germline variants in cancer predisposition genes. This approach may preclude the use of risk-reducing strategies in family members who have pathogenic or likely pathogenic germline variants in other cancer predisposition genes. Cascade testing using multigene panels was performed in 3696 relatives of 7433 probands. Unexpected pathogenic or likely pathogenic germline variants were identified in 230 (6.2%) relatives, including 144 who were negative for the familial pathogenic or likely pathogenic variant but positive for a pathogenic or likely pathogenic variant in a different gene than the proband and 74 who tested positive for the familial pathogenic or likely pathogenic variant and had an additional pathogenic or likely pathogenic variant in a different gene than the proband. Of the relatives with unexpected pathogenic or likely pathogenic germline variants, 36.3% would have qualified for different or additional cancer screening recommendations. Limiting cascade testing to only the familial pathogenic or likely pathogenic variant would have resulted in missed, actionable findings for a subset of relatives.

Background: Genetic resources are underutilized when it comes to being incorporated into a breast cancer patient’s treatment, but that isn’t the only piece being overlooked. The Ki-67 proliferation index expressed (Ki-67%) is an established marker of tumor proliferation and aggressive behavior. We hypothesized that Ki-67% could have increased clinical utility when correlated with genomic testing results. Methods: Data was obtained from the Informed Genetics Annotated Patient Registry (iGAP), an IRB-approved, multi-center longitudinal registry designed to capture biomarker test results and their impact on treatment practices and outcomes. Tumor grades and Ki-67% were taken from patient pathology reports. The average Ki-67% was then calculated and compared for each tumor grade, MammaPrint genomic recurrence risk category (ultra low risk, low risk, and high risk), and Blueprint molecular subtype (Luminal type A, Luminal type B, Basal, and HER 2 type). ANOVA statistical analysis was performed for significance values. Results: Of 3102 patients enrolled in the iGAP Registry, 733 were diagnosed with breast cancer and had available tumor grade and Ki-67% data. Among these patients, 357 had genomic recurrence risk (MammaPrint) and 220 genomic molecular subtyping (BluePrint) reports. As expected, tumor grades were significantly positively correlated with Ki-67% (p< 0.0001 between all 3 tumor grade groups). Average Ki-67% in each genomic recurrence risk revealed a significant difference between Low Risk (14%, range 1-70%) and High Risk (36%, range 1-95%, p< 0.0001). Among the genomic molecular subtypes, there were significant differences in Ki-67% between Basal (avg 69%, 17-95%) and Luminal type A (avg 13%, 1-70%, p< 0.0001)) and all other subtypes, while Luminal type B (avg 24%, 1-80%) and HER 2 (avg 38%, 29-45%) were not significantly different from each other (p=0.2817), but still significantly different to all other subtypes. Conclusion: From these results, we can deduce that molecular subtype correlates with, but is clinically distinct from, Ki-67 proliferation index. These results also indicate that molecular subtype correlates with higher tumor grades, possibly due to increased cell proliferation. Achieving truly personalized clinical decision making requires utilizing multiple modalities and biomarkers, integrating the results into management. Citation Format: Chloe Wernecke, Krista Ortega, Kelly Bontempo, Brenna Bentley, Christina Hoyer-Kimura, Peter Beitsch, Rakesh Patel, Barry Rosen, Gia Compagnoni, Ian Grady, Eric Brown, Lindsay Gold, Pat Whitworth, Linda Ann Smith, Richard Reitherman, Mariusz Wirga, Steven Cai, Toan Nguyen, Valerie Traina, Dennis Holmes, Paul Baron, Brittany Krautheim, Anne Peled, Walt Taylor. Genomic testing and Ki-67 Percentage: Two puzzle pieces being undervalued in breast cancer treatment [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 P3-05-44.

Background: With the rise of genomic testing, more clinicians are using panels to understand the genetic profile of breast cancer to help aid in clinical management. However, little is known about the relationship between the results of genomic tests and the likelihood of identifying an underlying germline variant, and how this should integrate into clinical decision making. Methods: Data was obtained from the Informed Genetics Annotated Patient Registry (iGAP), an IRB-approved, multi-centered longitudinal registry designed to capture biomarker test results and their impact on treatment practices and outcomes. Two genomic tumor profiling tests were studied - MammaPrint recurrence risk and Blueprint molecular subtypes, including Luminal type A, Luminal type B, Basal, and HER 2 type. Of the 3400 patients currently enrolled in the registry, 528 have been diagnosed with breast cancer and underwent tumor profiling by both MammaPrint and BluePrint as well as germline genetic testing, including analyses of 24 cancer susceptibility genes (ATM, BARD1, BRCA1, BRCA2, BRIP1, CDH1, CHEK2, NBN, PALB2, PTEN, STK11, TP53, APC, BMPR1A, CDK4, EPCAM, MLH1, MSH2, MSH6, MUTYH, PMS2, RAD51C, RAD51D, SMAD4). Differences in positive germline variant rates were tested for with two-sided, Chi-Square tests using the prop.test function in R. Results: 231 (44.17%) were classified as High-Risk for recurrence on MammaPrint, with a 0.13 PVs detected per patient tested (positive germline variant (PV) Rate), 269 (51.34%) were identified as having a Low-Risk, with a 0.0849 PV rate, and 23 (4.4%) Ultra-Low-Risk, with a 0.0455 PV rate. There is not a significant difference between the High-Risk and Low-Risk for recurrence (p=0.09). 45 (8.54%) Basal molecular subtype identified by BluePrint panel, with a 0.1778 PV rate, 292 (55.41%) classified as Luminal A type, with a 0.0819 PV rate, 171 (32.45%) Luminal B with 0.1078 PV rate, and 13 (2.47%) HER2 Type with 0.07 PV rate. There was a significant difference between Basal and Luminal A PV rates (p=0.042), but no other statistically significant differences were found. Conclusions: Patients with a Basal molecular subtype have a significantly higher likelihood of having a germline pathogenic variant compared to Luminal A subtype. There was a trend that did not reach statistical significance for MammaPrint High Risk to have a higher likelihood of germline pathogenic result compared to MammaPrint Low Risk. This data adds another parameter for germline testing in those breast cancer patients who fall outside of current NCCN testing criteria. Citation Format: Peter Beitsch, Chloe Wernecke, Rakesh Patel, Barry Rosen, Eric Brown, Gia Compagnoni, Ian Grady, Lindsay Gold, Pat Whitworth, Linda Ann Smith, Mariusz Wirga, Richard Reitherman, Steven Cai, Toan Nguyen, Valerie Traina, Dennis Holmes, Paul Baron, Brittany Krautheim, Anne Peled, Walt Taylor, Kelly Bontempo, Brenna Bentley, Krista Ortega, Pouyan Ahmadi. Germline Testing Results in Patients with Genomic Tumor Profiling [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 P3-05-43.

521 Background: Hormone receptor positive (HR+), HER2- early stage breast cancer (ESBC) is a heterogeneous disease that has shown lower response to neoadjuvant chemotherapy (NCT) compared with other clinicopathologic subtypes. Genomic profiling may help inform neoadjuvant treatment decisions for ESBC by predicting likelihood of pathological complete response (pCR) or chemosensitivity. The 70-gene MammaPrint (MP) test classifies ESBC patients as having a Low or High Risk of distant metastasis. In the ISPY2 trial, further stratification of MP High Risk into High 1 (H1) or High 2 (H2) improved prediction of chemosensitivity, with significantly higher pCR rates in H2 vs. H1 tumors, particularly in response to immune therapy. Here we evaluate the utility of H1/H2 risk as a biomarker for chemosensitivity and 5 year distant-metastasis free survival (DMFS) in NCT treated patients from the Neoadjuvant Breast Registry Symphony Trial (NBRST). Methods: NBRST (NCT01479101) is an observational prospective study that included 1069 patients with ESBC who received neoadjuvant therapy. Patients with HR+HER2-, MP High Risk tumors who received NCT were included in this analysis (n = 327). Patients were further stratified into H1 (score ≤ 0, > -0.57) or H2 (score ≤ -0.57) groups. Differences in pCR between MP High Risk subcategories were assessed by two-sided proportional z-test. Differences in DMFS was evaluated by Kaplan Meier analysis and log-rank test. Results: MP classified 198 (61%) patients with H1 tumors and 129 (39%) patients with H2 tumors. Age, tumor stage, and lymph node status were comparable between both groups. However, there was a higher proportion of Grade 3 tumors in the H2 group. A significantly higher percentage of pCR was achieved in H2 tumors (30/129; 23%) vs. H1 tumors (12/198; 6.1%) (p < 0.001). Median follow-up was 5.3 years. The 5-year DMFS (% [95% CI]) was significantly worse for patients with H2 tumors (64.8 [55.9 – 75.1]), with most events occurring early ( < 3 years), compared with H1 tumors (77.1 [70.4 – 84.3]; p = 0.012). Patients with H1 tumors that achieved pCR had improved 5-year DMFS (81.8 [61.9 – 100]) compared to H1 tumors that did not achieve pCR (76.8 (69.9 – 84.4; p = 0.009). Patients with H2 tumors that had a pCR demonstrated significantly better 5-year DMFS (80.7 [65.3 – 99.8]) than patients with residual disease (60.2 [50.1 – 72.4]; p = 0.009). Conclusions: These data suggest MammaPrint predicts pCR in HR+HER2- BC patients, with H2 risk tumors exhibiting higher chemosensitivity than H1 tumors. Patients with either H1 or H2 tumors that achieved pCR had similar outcomes, which were significantly improved compared to those with residual disease. Notably, the worst outcomes were observed among patients with H2 risk and residual disease; it should be investigated whether addition of immune therapy to standard NCT would enhance the pCR rates in this patient population. Clinical trial information: NCT01479101 .

10515 Withdrawal Notice: Abstract 10151 by Beitsch et al, entitled "Rates of pathogenic variants in common cancer genes among different racial/ethnic groups," was withdrawn by the authors from presentation and publication. As they were preparing for presentation at the meeting, the authors discovered additional data that potentially altered the abstract's conclusions. The abstract was withdrawn on May 13, 2022.

This cohort study evaluates the clinical utility of universal germline genetic testing for patients with breast cancer.

With the rise of somatic testing, more physicians are using panels to understand the genetic profile of breast cancer to help aid in clinical management. Agendia, a molecular diagnostics company focused on breast cancer, has developed two tests to support clinical decisions. MammaPrint analyzes 70 genes associated with breast cancer recurrence and reports whether an individual has a low (1.3%) or high (11.7%) risk for recurrence. BluePrint analyzes 80 genes to identify the breast cancer's molecular subtype: Luminal A (low-risk), Luminal B (high-risk), HER2 (respond well to HER2-targeted therapies), and Basal-Type (aggressive subtype).

Background: As more patients with early-stage breast cancer receive neoadjuvant endocrine therapy (NET), there is a need for reliable biomarkers that can identify patients with HR+ HER2-tumors who are likely to benefit from NET. NBRST (NCT01479101) compared the prognostic value of the 70-gene risk classification and 80-gene molecular subtyping signatures with conventional pathological classification methods in response to neo-adjuvant therapy. We evaluated the association of these signatures with clinical response and 5-year outcome of patients treated with NET. Methods: 1091 patients with early-stage breast cancer scheduled to receive neoadjuvant therapy were prospec-tively enrolled into NBRST, and a sub-analysis of 67 patients treated with NET was performed. Patients received standard of care genomic testing using the 70-gene and 80-gene signatures and were treated with NET, per physician's discretion. The primary endpoint was pathologic partial response (pPR) and secondary endpoints were distant metastasis-free survival (DMFS) and overall survival (OS). Clinical benefit was defined as having a pPR or stable disease (SD) with NET.Results: Overall, 94.4% of patients with genomically (g) Luminal A-Type (50.0% pPR and 44.4% SD) and 95.0% with Luminal B-Type tumors (55.0% pPR and 40.0% SD) exhibited clinical benefit. At 5 years, patients with gLuminal B tumors had significantly worse DMFS (75.6%, 95% CI 50.8-89.1) than patients with gLuminal A (91.1%; 95% CI 74.8-97.1; p = 0.047), with a similar trend for OS, albeit not significant (81.0%, 95% CI 56.9-92.4 and 91.1%, 95% CI 74.8-97.1, respectively; p = 0.13).Conclusions: Genomic assays offer a broader understanding of the underlying tumor biology, which adds preci-sion to pathology as a preoperative risk classifier. Patients with 70-gene signature Low Risk, gLuminal A tumors treated with endocrine therapy alone have excellent 5-year outcomes. Most patients with genomically-defined Luminal A-and B-Type tumors respond well to NET, suggesting these patients may be safely treated with NET, while those with gLuminal B tumors will also require post-operative chemotherapy or CDK4/6 inhibitors to improve long-term outcomes. Overall, these findings demonstrate that genomic classification, defined by the combined 70-and 80-gene signatures, is associated with tumor response and prognostic of long-term outcomes.