Breast Cancer Assay Research Articles

Validation of a breast cancer assay for radiotherapy omission: an individual participant data meta-analysis.

There are currently no molecular tests to identify individual breast cancers where radiotherapy (RT) offers no benefit. Profile for the Omission of Local Adjuvant Radiotherapy (POLAR) is a 16-gene molecular signature developed to identify low risk cancers where RT will not further reduce recurrence rates. An individual participant data meta-analysis was performed in 623 cases of node-negative ER+/HER2-negative early breast cancer enrolled in three RT randomized trials for whom primary tumor material was available for analysis. A Cox proportional hazards model on time to locoregional recurrence (LRR) was used to test the interaction between POLAR score and RT. 429 (69%) patients' tumors had a high POLAR score and 194 (31%) had a low score. Patients with high POLAR score had, in the absence of RT, a 10-year cumulative incidence of LRR: 20% (15%-26%) vs 5% (2%-11%) for those with a low score. Patients with a high POLAR score had a large benefit from RT (hazard ratio [HR] for RT vs no RT: 0.37 [0.23-0.60], p < .001). In contrast, there was no evidence of benefit from RT for patients with a low POLAR score (HR: 0.92 [0.42-2.02], p = .832). The test for interaction between RT and POLAR was statistically significant (p = .022). POLAR is not only prognostic for locoregional recurrence but also predictive of benefit from radiotherapy in selected patients. Patients ≥ 50 years with ER+/HER2-negative disease and a low POLAR score could consider omitting adjuvant RT. Further validation in contemporary clinical cohorts is required.

CA15-3 Assay Contribution in the Management of Breast Cancer: Study of 177 Cases

Introduction: Breast cancer is the leading cause of cancer mortality in women worldwide. CA15-3 is the most widely used serum marker in this cancer. The aim of this study is to investigate the CA15-3 assay in breast cancer and its correlation with classical prognostic factors for the disease, as well as with the post-therapeutic evolution of patients. Materials and Methods: This is a retrospective study, carried out at the Clinical Biochemistry Laboratory of the Tangier university hospital center, involving 177 patients treated at the Tangier Oncology Center, having benefited from a CA15-3 assay according to the ELFA (Enzyme Linked Fluorescent Assay) immunoassay technique, with a threshold value of 30U/ml, as part of their therapeutic management, for a period of 10 months. Results: A statically significant correlation was found between the marker's level and TNM classification, the expression of hormonal receptors for estrogen (ER) and for progesterone (RP). The high value of CA15-3 is correlated with the number and location of metastatic sites, and also with an unfavourable outcome. Furthermore, monitoring and post-therapeutic evaluation of patients during the metastatic phase, using biomarker kinetics, shows that an increase in biomarker levels relative to the initial value correlates with radiological progression of metastasis and therefore with the advancement of disease. Conclusion: This study supports the interest of CA15-3 assay in the post-treatment follow-up and in the prognostic evaluation of breast cancer patients.

The population-level effects of omitting chemotherapy guided by a 21-gene expression assay in node-positive breast cancer: a simulation modeling study

BackgroundA recent trial showed that postmenopausal women diagnosed with hormone receptor-positive, human epidermal growth factor receptor-2 (HER2)-negative, lymph node-positive (1–3 nodes) breast cancer with a 21-gene recurrence score of ≤ 25 could safely omit chemotherapy. However, there are limited data on population-level long-term outcomes associated with omitting chemotherapy among diverse women seen in real-world practice.MethodsWe adapted an established, validated simulation model to generate the joint distributions of population-level characteristics of women diagnosed with early-stage breast cancer in the U.S. Input parameters were derived from cancer registry, meta-analyses, and clinical trial data. The effects of omitting chemotherapy on 10-year distant recurrence-free survival, life-years, and quality adjusted life-years (QALYs) were modeled for premenopausal and postmenopausal women. QALYs were discounted at 3%. Results were evaluated for subgroups stratified by race and ethnicity. Sensitivity analyses included testing results across a range of inputs. The model was validated using the published RxPONDER trial data.ResultsIn premenopausal women, the 10-year distant recurrence-free survival rates were 85.3% with chemo-endocrine and 80.1% with endocrine therapy. The estimated life-years and QALYs gained with chemotherapy in premenopausal women were 2.1 and 0.6, respectively. There was no chemotherapy benefit in postmenopausal women. There was no variation in the absolute benefit of chemotherapy across racial or ethnic subgroups. However, there were differences in distant recurrence-free survival rates, life-years, and QALYs across groups. Sensitivity analysis showed similar results. The model closely replicated the RxPONDER trial.ConclusionsModeled population-level outcomes show a small chemotherapy benefit in premenopausal women, but no benefit among postmenopausal women. Simulation modeling provides a useful tool to extend trial data and evaluate population-level outcomes.

HER2DX Genomic Assay in HER2-Positive Early Breast Cancer Treated with Trastuzumab and Pertuzumab: A Correlative Analysis from the PHERGain Phase II Trial.

The purpose of this study was to assess the predictive capability of HER2DX assay following (neo)adjuvant trastuzumab-pertuzumab (HP)-based therapy in HER2-positive (HER2+) early breast cancer. HER2DX was analyzed in baseline pretreatment tumors from the PHERGain trial. Patients with stage I-IIIA HER2+ early breast cancer were randomized to group A [docetaxel, carboplatin, and HP (TCHP)] and group B (HP ± endocrine therapy). PET response was evaluated after two cycles. Group A received TCHP for six cycles regardless of PET response. Group B continued with HP ± endocrine therapy for six cycles (PET responders) or with TCHP for six cycles (PET nonresponders). The primary objective of this retrospective study was to associate the HER2DX pathologic complete response (pCR) score with pCR. The secondary objective was the association of the HER2DX risk score with 3-year invasive disease-free survival (iDFS). HER2DX was performed on 292 (82.0%) tumors. The overall pCR rate was 38.0%, with pCR rates of 56.4% in group A and 33.8% in group B. In multivariable analysis including treatment and clinicopathologic factors, the HER2DX pCR score (continuous variable) significantly correlated with pCR [OR, 1.29; 95% confidence interval (CI), 1.10-1.54; P < 0.001]. HER2DX-defined pCR-high, -med, and -low groups exhibited pCR rates of 50.4%, 35.8%, and 23.2%, respectively (pCR-high vs. pCR-low OR, 3.27; 95% CI, 1.54-7.09; P < 0.001). In patients with residual disease, the HER2DX high-risk group demonstrated numerically worse 3-year iDFS than the low-risk group (89.8% vs. 100%; HR, 2.70; 95% CI, 0.60-12.18; P = 0.197). HER2DX predicts pCR in the context of neoadjuvant HP-based therapy, regardless of chemotherapy addition, and might identify patients at higher risk of recurrence among patients with residual disease.

Methotrexate-Loaded Surface-Modified Solid Lipid Nanoparticles Targeting Cancer Expressing COX-2 Enzyme.

Cancer is a major public health problem worldwide, and it is the second leading cause of death of humans in the world. The present study has been directed toward the preparation of methotrexate-loaded surface-modified solid lipid nanoparticles (SLNs) for potential use as a chemotherapeutic formulation for cancer therapy. A lipid (C14-AAP) derived from myristic acid (C14H30O2) and acetaminophen (AAP) was employed as a targeting ligand for human breast and lung cancer cells that overexpress the cyclooxygenases-2 (COX-2) enzyme. The SLNs consisting of stearic acid and C14-AAP were characterized by several methods, including dynamic light scattering (DLS), differential scanning calorimetry (DSC), powder X-ray diffraction (PXRD), ultraviolet-visible (UV-vis) spectroscopy, high-resolution transmission electron microscopy (HRTEM), and field emission scanning electron microscopy (FESEM) techniques. An in vitro cell cytotoxicity study was done by carrying out an MTT assay and flow cytometry study in the human breast cancer (MCF7) and human lung cancer cell line (A549). The expression level of COX-2 enzyme in MCF7 and A549 cell lines was examined by reverse transcription polymerase chain reaction (RT-PCR). A high level of COX-2 expression was observed in both cell lines. In vitro cell cytotoxicity study in MC7 and A549 cell lines showed the surface-modified, methotrexate-loaded SLN is more effective in cell killing and induction of apoptotic death in both the cell lines than free methotrexate in MTT, flow cytometry, clonogenic assay, and Western blot studies. The surface-modified SLN was radiolabeled with 99mTc with %RCP greater than 95%. In vivo biodistribution study of the 99mTc-labeled SLN in melanoma tumor-bearing C57BL6 mice showed moderate tumor uptake of the radiotracer at 3 h post injection. The SPECT/CT image aligns with the biodistribution results. This study shows that AAP-modified SLNs could be a potential chemotherapeutic formulation for cancer therapy.

Deliberate inclusion of multiple co-correlated gene target sets during discovery for improved biomarker translation to a clinical assay in early-stage breast cancer.

e12560 Background: Co-correlation between gene targets provides a more robust, and often nonlinear, understanding of human biology, resulting in more accurate and reliable diagnostics. When translating from discovery to a clinical assay, detectability of promising targets often hinders diagnostic development. Translating a single set of co-correlated targets becomes more challenging, as the success of the program is dependent on the interrelationship between all targets and the ability of the entire set to translate clinically. Given target translation uncertainty, we hypothesized that the deliberate inclusion of multiple independent sets of co-correlated targets during discovery could bridge the gap between promising biology and a clinically viable assay. We set out to discover and clinically validate multiple sets of co-correlated targets required for noninvasive breast cancer detection. Methods: Nonlinear statistical methods were repeatedly applied to microarray gene expression profiles from peripheral blood (PBMCs) obtained from 140 patients with and without breast cancer. Four independent cohorts were used for subsequent studies to assess efficacy and reproducibility of discovered targets. In total, five independent sets of highly efficacious co-correlated targets, totaling 26 unique genes, were discovered and analytically validated across the five patient cohorts (n=357). A sixth independent cohort of 197 plasma samples (breast cancer n=116, controls n=81) was obtained and used to clinically translate and validate the 26 targets using real-time qPCR (qPCR). Results: qPCR revealed strong and reproducible clinical signal from 8/26 previously discovered targets (Table). To evaluate the efficacy of the targets, an 8-gene signature was trained on the PBMC discovery cohort, achieving &gt;99% sensitivity, 83% specificity, indicating a promising classifier could be trained from the 8 qPCR targets. During CLIA validation of the assay, in normalized qPCR data from 87 patients, the 8-gene assay achieved a statistically significant &gt;99% sensitivity, 89% specificity in stage I breast cancer. Conclusions: Given the performance observed from the 8-gene qPCR assay, we conclude that the deliberate inclusion of multiple sets of co-correlated targets, including those considered mathematically redundant during discovery, contributed to the success of a clinically viable assay for the detection of early-stage breast cancer in plasma. [Table: see text]

Quantitative HER2 mRNA assay in breast cancer with HER2 immunohistochemistry 0

Objective: To investigate HER2 mRNA expression in breast cancer with HER2 immunohistochemistry (IHC) 0 and to analyze the feasibility of distinguishing between the tumor with HER2 μltra-low expression and the one without expression of HER2 (no staining by IHC) by HER2 mRNA level preliminarily. Methods: HER2 mRNA was analyzed by reverse transcription digital PCR in 41 cases of formalin-fixed paraffin-embedded surgical tissue samples of invasive breast cancer obtained between January 2020 and March 2023 at Peking Union Medical College Hospital. The cohort included 21 HER2 IHC 1+ and 20 IHC 0 (12 ultra-low and 8 non-expression of HER2). HER2 mRNA expression level was quantitatively evaluated by the FAM (HER2)/VIC (reference gene) ratio. Results: The expression of HER2 mRNA for the cases with 1+, ultra-low, and non-expression of HER2 by IHC was 0.30 to 1.78 (average 0.90, median 0.82), 0.55 to 1.51 (average 0.93, median 0.90) and 0.22 to 0.78 (average 0.41, median 0.36), respectively. For the mean and median HER2 mRNA levels, there was no significant difference between HER2 IHC 1+ and HER2 ultra-low expression diseases (P=0.757). A remarkable difference in HER2 gene expression was found between the tumors with 1+ and non-expression of HER2 by IHC (P=0.002). And, HER2 ultra-low cases contained statistically higher levels of HER2 mRNA compared with non-expression of HER2 subgroup by IHC (P=0.001). Conclusions: Based on HER2 mRNA, HER2 non-expression and HER2 weak expression (including HER2 IHC 1+ and ultra-low) belong to two different types of the tumor and the disease with HER2 IHC 1+ and HER2 ultra-low expression may be the same. It is necessary to further test the performance of HER2 mRNA detection for stratifying the HER2 weak expression subgroup and to determine the threshold.

Abstract PO5-13-09: Clinical usage of a CLIA accredited protein/phosphoprotein assay for breast cancer: Primary usage cases and significant findings in the HER2- setting

Abstract Background: A CLIA-accredited assay that measures the expression and/or activation levels of 32 clinically actionable protein and phosphoprotein analytes in clinical tissue biopsy samples was launched in January 2021. The current intended use population for the assay is for patients with late/advanced stage breast cancer wherein molecular profiling is being utilized for clinical decision making. Assessment of physician ordering practices, clinical use dynamics as well as protein/phosphoprotein actionability frequencies were determined for clinically actionable biomarkers. Methods: A total of 219 cases have been processed to date, with mean turn-around time of 16.4 days. The assay utilizes laser capture microdissection to enrich tumor epithelium from FFPE core needle biopsy and resection material coupled to reverse phase protein array. Results for each of the 32 analytes are generated by comparing each patient to a reference population and reported both as a relative quartile and as a continuous percentile compared to the reference population (0-100%). For the purposes of this analysis, significant expression/activation cutpoints were set at the 40th percentile threshold. Results: To date, clinicians have requested the test most frequently to identify potential therapeutic targets in patients with HER2-negative disease (84% of all tested patients, 36% were triple-negative). Despite the majority of cases being HER2-negative, we found that phosphorylated (p) HER2 (Y1248) was found to be activated in 17% of all HER2-negative cases and 19% of triple negative breast cancer cases (TNBC). pHER2 was concurrently activated with pHER3 (Y1289) in 15% (12/80) of TNBC cases and 13% (24/187) of all HER2-negative cases. pHER2 presented concurrently with pEGFR (Y1068 or T654) in 14% (11/80) of TNBC cases and 14% (26/187) of all HER2- cases. Expression of TROP2 was observed in 16% of HER2-negative patients including 11% of ER+/HER2- and 23% of TNBC cancers. MHCII expression, a recently described candidate predictive biomarker of anti-PDL1/PD1 response in TNBC, was found to be expressed in 29% of TNBC patients. Activation frequencies of other clinically relevant drug targets in HER2-negative disease such AKT and mTOR pathway activation was also assessed. We found that pAKT (S473 and/or T308) was activated in 7% of ER+/HER2- cases and 14% of TNBC. Concurrent with AKT activation, at least one additional member of the AKT-mTOR pathway (mTORC1 (S2448), 4E-BP1 (S65), p70S6K (T389), or S6RP (S235/S236) was co-activated in 50% and 45% of ER+/HER2- and TNBC cancers respectively. Conclusion: This initial assessment of a CLIA LDT protein/phosphoprotein assay utilized to date found that physicians most often order the test for advanced stage HER2-negative breast cancer. Activation/expression of clinically important protein drug targets with potential actionability in HER2-negative disease was observed in a significant number of cases and demonstrates the power of the assay to elucidate actionable targets for potential therapeutic intervention. Citation Format: Claudius Mueller, Brian Corgiat, Emanuel Petricoin, Kayla Sparks, Joyce O'Shaughnessy, Chelsea Gawryletz, Matthew Schwartz, Justin Davis. Clinical usage of a CLIA accredited protein/phosphoprotein assay for breast cancer: Primary usage cases and significant findings in the HER2- setting [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 PO5-13-09.

Abstract PO2-15-07: HER2DX genomic assay in triple-negative breast cancer (TNBC) patients treated with 12-weeks of neoadjuvant chemotherapy: a correlative analysis from WSG-ADAPT-TN phase II trial

Abstract HER2DX genomic assay in triple-negative breast cancer (TNBC) patients treated with 12-weeks of neoadjuvant chemotherapy: a correlative analysis from WSG-ADAPT-TN phase II trial Background: Biomarkers for de-escalation and escalation of systemic therapy in early-stage TNBC are needed. HER2DX is a standardized prognostic (risk-score) and predictive (pathological complete response [pCR]-score) assay based on clinical and gene expression-based data. Here we aimed to test the value of HER2DX assay in early TNBC. Methods: Standardized HER2DX was evaluated centrally using RNA from baseline FFPE tumor biopsies from the WSG-ADAPT-TN study (NCT01815242), a multicenter phase II trial that randomized 336 patients with stage I–III early TNBC to 12-weeks of nab-paclitaxel 125 mg/m2 plus gemcitabine 1000 mg/m2 d1,8 every 3 weeks (arm A) versus nab-paclitaxel 125 mg/m2 plus carboplatin AUC2 day 1,8 every 3 weeks (arm B). The primary aim was to test the ability of HER2DX pCR and risk-score models to predict pCR (ypT0/isN0) and survival endpoints, respectively, such as invasive disease-free survival (iDFS), distant disease-free survival (DDFS) and overall survival (OS). Secondary objectives were to assess the association of the i) HER2DX immune signature score and ii) percentage (%) of stromal tumor infiltrating lymphocytes (sTILs) with efficacy endpoints. Uni- and multi-variable logistic regression and Cox models tested the association of each variable with each endpoint. Results: HER2DX was evaluated in 126 (37.5%) baseline pre-treatment tumors. Mean age was 52.1 (range 26-76). cT1 represented 40.5% of cases and 72.2% were cN0. Overall, pCR rate was 34.1% (95%CI 26.1 – 43.2) and median follow-up was 5.0 years. Median sTILs at baseline was 31.6% (range 0-90) and moderately correlated with the IGG signature (coefficient=0.57). The % of HER2DX high-, medium- and low-pCR groups was 41.3%, 47.6% and 11.1%, respectively. HER2DX pCR score (as a continuous variable) was significantly associated with pCR in univariate (odds ratio [OR per 10-unit increase]=1.31, 1.06-1.64, p=0.016) and after adjusting by treatment arm (OR=1.31, 1.06-1.65, p=0.015). Overall, the pCR rates in HER2DX pCR-high, -medium and -low groups were 46.2%, 26.7% and 21.4%, respectively (high vs medium/low OR=2.48, 1.17-5.34, p=0.018). In arm B (n=51), the pCR rates in HER2DX pCR-high, -medium and -low groups were 47.8%, 25.0% and 0.0% respectively (high vs medium/low OR=3.36, 1.02-12.0, p=0.051). In terms of the risk-score, the % of HER2DX low-risk and high-risk groups was 60.3% and 39.7%, respectively. HER2DX risk score as a continuous variable was significantly associated with iDFS, DDFS and OS (p&amp;lt; 0.001 in all univariate analysis), and after adjusting by variables such as arm and pCR status (all p&amp;lt; 0.05). sTILs were not associated with any survival endpoint (all p &amp;gt;0.35). The HER2DX immune signature was significantly associated with iDFS (p=0.012), DDFS (p=0.022) and OS (p=0.012). Conclusion: The HER2DX genomic test in TNBC provides valuable insights into the response and survival following neoadjuvant taxane-based chemotherapy in the absence of immunotherapy. The development of a tailored genomic assay for TNBC is currently in progress. Citation Format: Oleg Gluz, Fara Brasó-Maristany, Ulrike Nitz, Laia Paré, Matthias Christgen, Guillermo Villacampa, Benedetta Conte, Sherko Kuemmel, Ronald Kates, Cornelia Kolberg-Liedtke, Eva-Maria Grischke, Helmut Forstbauer, Michael Braun, Mathias Warm, John Hackmann, Christoph Uleer, Bahriye Aktas, Claudia Schumacher, Ana Vivancos, Rachel Wuerstlein, Joel S. Parker, Monika Graeser, Charles M. Perou, Christine zu Eulenburg, Patricia Villagrasa, Hans-Heinrich Kreipe, Aleix Prat, Nadia Harbeck. HER2DX genomic assay in triple-negative breast cancer (TNBC) patients treated with 12-weeks of neoadjuvant chemotherapy: a correlative analysis from WSG-ADAPT-TN phase II trial [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 PO2-15-07.

Abstract PO2-02-03: Clinical and pathological factors associated with Oncotype DX® 21-Gene recurrence score in patients diagnosed with early stage breast cancer in a low-middle income country

Abstract INTRODUCTION: Oncotype DX® recurrence score (ODX RS) is a 21-gene assay warranted to determine the the prognosis in patients with hormone receptor positive, HER-2 negative early stage breast cancer. In this context, the test is also predictive of benefit of adjuvant chemotherapy.1,2,3 OBJECTIVES: We aimed to correlate the clinical and pathological factors associated with Oncotype DX® 21-Gene in patients diagnosed with early stage Breast Cancer. Additionally, description of adjuvant treatment patterns and survival outcomes were described according to the Oncotype DX® 21-Gene result. METHODS: Data from medical records from a single center in Brazil were collected retrospectively from women over 18 years diagnosed with early breast cancer between 2012 and 2022. Included patients were diagnosed with stage T1-T2 breast cancer, hormone receptor positive, HER-2 negative, with up to three positive lymph nodes. All included patients had an Oncotype DX® test performed after definitive breast surgery. The ODX RS has been categorized into two levels according to menopausal status. Correlation between breast cancer recurrence and clinicopathological characteristics was done. The software SPSS was used for statistical analyzes with the significance of 0.05. RESULTS: From 197 patients, 20 have had breast cancer recurrence (10.15%) whom 10 were premenopausal and 10 were postmenopausal. The median ODX RS in these 20 patients was 15 (ranged from 9 to 31). The most common site of recurrence was breast and regional recurrence in 18 patients (90%). Adjuvant chemotherapy was omitted in 16 patients (80%) who have had breast cancer recurrence. Among premenopausal patients whose ODX RS was &amp;gt;20, 33 patients (91.66%) received adjuvant chemotherapy. Among postmenopausal patients whose ODX RS was &amp;gt;25, 19 (86.36%) received adjuvant chemotherapy. The probability of recurrence free survival was worse in premenopausal patients &amp;gt; 44-years-old compared to those with &amp;lt; =44 years-old (p = 0.036) and also worse in histological grade 3 tumors compared to grade 1 (p=0.0048). Tumor size &amp;gt;14 millimeters (mm) was correlated to worse recurrence free survival in premenopausal patients (p=0.017). Low estrogen and progesterone receptor was associated with a higher ODX RS (p=0.0035 and p&amp;lt; 0.0001, respectively) in premenopausal patients, but not associated with recurrence free survival. Clinicopathological characteristics and recurrence free survival correlation in postmenopausal patients were not significant. CONCLUSION: This retrospective analysis suggests that factors other than the Oncotype DX® score, such as age and grade contributed to worse survival outcomes among our patients population. Of note, age older than 44 years-old, histological grade 3 and tumor size &amp;gt;14 mm were associated with a higher probability of recurrence in premenopausal patients, despite the Oncotype DX® score. REFERENCES: 1. Paik S, Shak S, Tang G, Kim C, Baker J, Cronin M, et al. A multigene assay to predict recurrence of tamoxifen-treated, node-negative breast cancer. N Engl J Med [Internet]. 2004;351(27):2817–26. Available from: http://dx.doi.org/10.1056/NEJMoa041588. 2. Sparano JA, Gray RJ, Makower DF, Pritchard KI, Albain KS, Hayes DF, et al. Adjuvant chemotherapy guided by a 21-gene expression assay in breast cancer. N Engl J Med [Internet]. 2018;379(2):111–21. Available from: http://dx.doi.org/10.1056/NEJMoa1804710. 3. Kalinsky K, Barlow WE, Gralow JR, Meric-Bernstam F, Albain KS, Hayes DF, et al. 21-gene assay to inform chemotherapy benefit in node-positive breast cancer. N Engl J Med [Internet]. 2021;385(25):2336–47. Available from: http://dx.doi.org/10.1056/NEJMoa2108873. Table 1 – Clinical and pathological characteristics of 197 hormone receptor positive, HER-2 negative early breast cancer patients who did the Oncotype DX® 21-Gene Recurrence Score assay. Data from medical records collected retrospectively of women diagnosed with early breast cancer between 2012 and 2022 from a single center in Brazil. Figure 1 – Probability of recurrence free survival in premenopausal patients according to age &amp;lt;=44 (blue line) or &amp;gt; 44-years-old (pink line). Data from medical records collected retrospectively of women with hormone receptor positive, HER-2 negative early breast cancer who did the Oncotype DX® 21-gene assay diagnosed between 2012 and 2022 from a single center in Brazil. Figure 2 – Probability of recurrence free survival in premenopausal patients according to histological grade. Tumor with histological grade 1 (blue line) or histological grade 3 (pink line). Data from medical records collected retrospectively of women with hormone receptor positive, HER-2 negative early breast cancer who did the Oncotype DX® 21-gene assay diagnosed between 2012 and 2022 from a single center in Brazil. Citation Format: Carolina Cavalcanti Gonçalves Ferreira, Julio Araujo, Shermann Brandão Rodrigues Moreira, Antônio Buzaid, Débora Gagliato. Clinical and pathological factors associated with Oncotype DX® 21-Gene recurrence score in patients diagnosed with early stage breast cancer in a low-middle income country [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 PO2-02-03.

Abstract PO3-01-13: A study of the impact of the implementation of the Oncotype Dx 21-gene breast-cancer assay during the SARS-CoV-2 pandemic for 1-3 node positive early breast cancer: The Clatterbridge Cancer Centre Experience

Abstract Background: The 21-gene breast cancer (BC) assay (Oncotype Dx) is used to predict chemotherapy benefit in ER+, HER-2- lymph node (LN) negative BC. The RxPONDER trial demonstrated that post-menopausal patients with ER+, HER2- BC with 1-3 LN and a recurrence score (RS) of &amp;lt; 25 did not benefit from adjuvant chemotherapy. In response to the SARS-CoV-2 pandemic Oncotype Dx was implemented for ER+, HER2- 1-3 LN+ BC patients in Merseyside, UK (population 2.6 million) This study sought to understand the impact of this measure on clinical practice. Methods: All patients whose tumours were assessed with Oncotype Dx assay between Mar 20 - Nov 22 were identified through the Exact Sciences portal. Menopausal status, tumour characteristics, RS and chemotherapy regimen were recorded. The impact on cancer care was estimated using the number of infusions and clinic visits specified by our institution chemotherapy protocol for node positive disease. The financial impact was calculated using the test list price, estimated costs of adjuvant chemotherapy in the UK (Annals of Oncology, Volume 32, suppl 2 S46). The number of patients predicted to receive chemotherapy pre-oncotype DX was calculated using data from the UK PONDx trial data. Results: A total of 242 patients were tested over the 32 month period. Table 1 summarises the clinico-pathological characteristics including by RS score. The median age was 58.5 and 77.3% (n=187) were post-menopausal. The median tumour size was 25mm and median LNs with macrometastasis was 1. 198 (81.9%) patients had an RS &amp;lt; 25. Overall 73 patients (30%) received chemotherapy of which 34 had an RS &amp;lt; 25. Pre-menopausal patients were more likely to receive chemotherapy with RS &amp;lt; 25 than post-menopausal patients, 47.9% (23/48) vs 7.3% (11/150) respectively. In the absence of Oncotype Dx testing 169 patients would have received adjuvant chemotherapy. Therefore, 96 patients avoided chemotherapy. This equates to 1,620 chemotherapy infusions and 324 clinic attendances. The estimated cost saving was ~£50K. Conclusions: This real-world study demonstrates that the use of Oncotype DX assay for ER+,HER2- 1-3 LN+ early BC spared a significant number of patients chemotherapy during the SARS-CoV-2 pandemic, so avoiding the risk of adverse effects. This also resulted in benefits to the healthcare system with a reduction in scheduled cancer care and achieved financial savings. This, therefore, demonstrates the benefit of using the Oncotype Dx assay. Table 1: Clinico-pathological information Citation Format: Alexandra Johnson, Sonia Bathla, Leena Chagla, Joanne Cliff, Allison Hall, Anita Hargreaves, Clare Hart, Zafar Malik, Chandeena Roshanlall, Raj Sripadam, Carlo Palmieri, Helen Innes. A study of the impact of the implementation of the Oncotype Dx 21-gene breast-cancer assay during the SARS-CoV-2 pandemic for 1-3 node positive early breast cancer: The Clatterbridge Cancer Centre Experience [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 PO3-01-13.

DPP3 promotes breast cancer tumorigenesis by stabilizing FASN and promoting lipid synthesis.

DPP3, a dipeptidyl peptidase, participates in a variety of pathophysiological processes. DPP3 is upregulated in cancer and might serve as a key factor in the tumorigenesis and progression of various malignancies. However, its specific role and molecular mechanism are still unknown. In this study, the expression of DPP3 in breast cancer tissues is analyzed using TCGA database. Kaplan-Meier survival analysis is performed to estimate the effect of DPP3 on the survival outcomes. To explore the biological function and mechanisms of DPP3 in breast cancer, biochemical and cell biology assays are conducted in vitro. DPP3 expresses at a higher level in breast cancer tissues than that in adjacent tissues in both TCGA database and clinical samples. Patients with high expression of DPP3 have poor survival outcomes. The proliferation and migration abilities of tumor cells with stable DPP3 knockout in breast cancer cell lines are significantly inhibited, and apoptosis is increased in vitro. GSEA analysis shows that DPP3 can affect lipid metabolism and fatty acid synthesis in tumors. Subsequent experiments show that DPP3 could stabilize FASN expression and thus promote fatty acid synthesis in tumor cells. The results of the metabolomic analysis also confirm that DPP3 can affect the content of free fatty acids. This study demonstrates that DPP3 plays a role in the reprogramming of fatty acid metabolism in tumors and is associated with poor prognosis in breast cancer patients. These findings will provide a new therapeutic target for the treatment of breast cancer.

Identification of miR-125a and miR-106b signature as a potential diagnostic biomarker in breast cancer tissues

MicroRNAs (miRNAs) have essential roles in the etiology of breast cancer and are regarded as possible markers in this malignancy. In order to find new markers for breast cancer, the current study has measured expression level of four miRNAs, namely miR-125a, miR-106b, miR-96 and miR-92a-3p in the paired breast samples. Expression levels of miR-125a and miR-106b were higher in tumoral tissues compared with control tissues (Expression ratios (95% CI) = 4.01 (1.96–8.19) and 3.9 (1.95–7.81); P values = 0.0005 and 0.0003, respectively). miR-106b and miR-125a differentiated between malignant and non-malignant tissues with AUC values of 0.7 and 0.67, respectively. We detected association between expression of miR-106b and clinical stage (P = 0.03), in a way that its expression was the lowest in the advanced stages. Finally, significant relationships were found between miR-96 and miR-125a in both tumoral and non-tumoral specimens (ρ = 0.76 and 0.69, respectively). This nonparametric measure of rank correlation also showed relationship between miR-106b and miR-96 in both sets of samples (ρ = 0.63 and 0.61, respectively). Cumulatively, the assessed miRNAs, particularly miR-125a and miR-106b are putative targets for further expression and functional assays in breast cancer.

Abstract 2420: Evaluating circulating tumor DNA (ctDNA) as a prognostic biomarker utilizing a tissue-free epigenomic assay in early-stage triple negative breast cancer (TNBC)

Abstract Background: ctDNA has shown promise as a prognostic biomarker in early-stage solid tumors. Current breast cancer clinical guidelines do not recommend routine screening for metastatic disease outside of clinical features suggestive of disease recurrence. The detection of ctDNA may be a useful biomarker for the management of early-stage cancer patients to identify patients who are at high risk of recurrence. Methods: Patients with stage II or III TNBC undergoing neoadjuvant docetaxel and carboplatin chemotherapy on a clinical trial (NCT02124902) followed by surgery were included in this study. Blood samples were prospectively collected prior to, during, and after completion of neoadjuvant chemotherapy, post-surgery, and throughout pre-specified surveillance time points (every 6 months for 5 years). Plasma samples were analyzed using Guardant Reveal powered by Infinity, a tissue-free, multiomic assay that interrogates differentially methylated regions of DNA using an applied bioinformatics filter optimized to detect breast cancer DNA from non-cancerous cell-free DNA and estimate quantitative tumor fraction. Samples were sequenced and resulted blinded to the patients’ clinical data. Results: A total of 120 patients with evaluable plasma samples were included in this study. At baseline prior to chemotherapy, ctDNA was detected in 75% (54/72) of patients. Baseline ctDNA detection was higher in node-positive cancers (100%; 29/29) versus node-negative cancers (58%; 25/43; p&amp;lt;0.0001). ctDNA quantity was higher in node-positive cancers (p&amp;lt;0.0001), and in stage III versus stage II disease (p=0.0179). During surveillance follow-up, the sensitivity for detecting any distant metastatic recurrence was 71% (5/7). Among patients with samples drawn within one year of recurrence, the sensitivity for detecting distant recurrence was 83% (5/6) with a sample-level specificity of 98% (186/190) and a patient-level specificity of 94% (63/67). ctDNA detection prior to recurrence had a median lead time of 5.0 months (range, 4.6-5.6). Notably, the detection of ctDNA during follow-up was associated with worse recurrence-free (HR 23.3, 95% CI 2.70-201, p&amp;lt;0.0001) and distant-recurrence free survival (HR 29.3, 95% CI 1.86-461, p&amp;lt;0.0001). Conclusions: ctDNA is detected with a tissue-free MRD assay with high sensitivity and specificity for distant recurrence in early-stage TNBC. Furthermore, the presence of ctDNA during follow-up is a prognostic indicator. Additional prospective studies are needed to assess the clinical utility of ctDNA monitoring in early-stage TNBC. Citation Format: Foluso O. Ademuyiwa, Cynthia X. Ma, Katherine Weilbaecher, Rama Suresh, Lindsay Peterson, Ron Bose, Nusayba Bagegni, Caron E. Rigden, Ashley Frith, Katherine Clifton, Andrew Davis, Derek Dustin, Mingyang Cai. Evaluating circulating tumor DNA (ctDNA) as a prognostic biomarker utilizing a tissue-free epigenomic assay in early-stage triple negative breast cancer (TNBC) [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 2420.

Abstract 1030: Concordance between the DESTINY-Breast04 clinical trial assay (4B5[CDx]) and other HER2 IHC assays for HER2-low breast cancer in real-world practice: First phase of a large-scale, multicenter global ring study

Abstract Background: DESTINY-Breast04 (DB-04) showed that trastuzumab deruxtecan improves survival vs chemotherapy in patients with human epidermal growth factor receptor 2 (HER2)-low (immunohistochemistry [IHC] 1+ or IHC 2+ with in situ hybridization negative) metastatic breast cancer (BC). The VENTANA 4B5(CDx) IHC assay, now approved in the United States (US) as a companion diagnostic, was used as the clinical trial assay (CTA) in DB-04. Real-world differentiation of HER2-low vs HER2 IHC 0 BC with non-CTAs is difficult. This is the first phase of a study assessing agreement between CTA and non-CTA scores. Methods: 50 clinical BC samples with HER2 IHC scores of 0, 1+, 2+, and 3+ were sent to laboratories in Europe, Canada, and the US for HER2 IHC testing per ASCO/CAP 2018 guidelines. After routine protocol scoring, pathologists were trained and rescored the samples 2 weeks later. Post training scores were compared with reference CTA scores determined by a central laboratory and a panel of experts. The primary endpoint was positive percentage agreement (PPA) and negative percentage agreement (NPA) between CTA and non-CTA scores, assessed after training, considering HER2-low as positive and HER2 IHC 0 as negative. Results: A total of 3449 post training non-CTA scores were available for analysis. PPA for HER2-low vs HER2 IHC 0 was 87.5% and NPA was 61.9%, with Cohen κ of 0.51 (Table). HER2-low vs HER2 IHC 0 agreement between CTA and non-CTA varied across subgroups. PPA &amp;gt;95% was shown with 4B5 Laboratory Developed Tests (LDTs) and HercepTest (Omnis), NPA of 80% with Leica, and overall agreement &amp;gt;80% with HercepTest (Link48), 4B5 LDTs, and German, French, and Italian laboratories. Conclusions: The degree of concordance between the CTA and non-CTAs varied among assay types and laboratory locations. A low NPA for some non-CTAs suggests the need for further assay optimization for HER2 IHC 0 evaluation. Post training non-CTA results HER2-low vs HER2 IHC 0 BC Post training scores PPA (95% CI), % NPA (95% CI), % Overall percentage agreement (95% CI), % Cohen κ (95% CI) Overall non-CTA test results (N = 3449) 87.5 (86.0-89.0) 61.9 (58.9-64.9) 78.7 (77.1-80.1) 0.51 (0.48-0.54) Non-CTA subgroups HercepTest (Omnis) (n = 467) 95.5 (92.3-97.7) 36.9 (28.9-45.4) 75.2 (70.8-79.4) 0.37 (0.28-0.46) HercepTest (Link48) (n = 790) 88.5 (85.2-91.2) 64.3 (57.8-70.4) 80.3 (77.2-83.2) 0.55 (0.48-0.61) Leica (n = 96) 59.3 (45.0-72.4) 80.0 (61.4-92.3) 66.7 (55.5-76.6) 0.35 (0.17-0.53) Non-4B5 LDTs (n = 1609) 83.8 (81.2-86.1) 67.8 (63.5-72.0) 78.2 (75.9-80.3) 0.52 (0.47-0.57) 4B5 LDTs (n = 487) 96.0 (93.0-98.0) 58.8 (50.4-66.8) 83.0 (79.1-86.4) 0.59 (0.51-0.68) Country subgroups Germany (n = 340) 93.1 (88.5-96.3) 64.4 (54.2-73.6) 83.1 (78.3-87.2) 0.61 (0.51-0.70) France (n = 342) 95.4 (91.5-97.9) 64.4 (54.4-73.6) 84.7 (80.1-88.6) 0.64 (0.55-0.73) Italy (n = 395) 89.9 (85.2-93.5) 72.5 (63.6-80.3) 83.9 (79.6-87.6) 0.64 (0.55-0.72) Spain (n = 567) 83.0 (78.4-86.9) 64.2 (56.6-71.3) 76.3 (72.3-80.0) 0.48 (0.40-0.56) US/Canada (n = 1029) 86.6 (83.6-89.2) 61.8 (56.1-67.3) 78.2 (75.4-80.8) 0.50 (0.44-0.56) Europe, other (n = 776) 85.0 (81.3-88.2) 52.8 (46.2-59.3) 73.8 (70.3-77.1) 0.40 (0.32-0.47) Citation Format: Hans-Ulrich Schildhaus, Sunil Badve, Corrado D’Arrigo, Gelareh Farshid, Annette Lebeau, Vicente Peg, Fréderique Penault-Llorca, Josef Rueschoff, Wentao Yang, Neil Atkey, Jessica Baumann, Elisabeth Beyerlein, Amy Hanlon Newell, Alexander Penner, Akira Moh, Guiseppe Viale. Concordance between the DESTINY-Breast04 clinical trial assay (4B5[CDx]) and other HER2 IHC assays for HER2-low breast cancer in real-world practice: First phase of a large-scale, multicenter global ring study [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 1030.

Abstract 4704: Biochemical and cell-based assay platforms for development of RAF inhibitors against human cancers

Abstract The RAF protein kinases are key intermediates in cellular signal transduction, functioning as direct effectors of the RAS GTPases and as the initiating kinases in the ERK cascade. In human cancer, RAF activity is frequently dysregulated due to mutations in the RAF family members (ARAF, BRAF, and CRAF) or to alterations in upstream RAF regulators, including RAS and receptor tyrosine kinases. The first and second generations of RAF inhibitors have yielded dramatic responses in malignant melanomas containing BRAF mutations; however, their overall usefulness has been limited by both intrinsic and acquired drug resistance. In addition, cancers with hyperactive RAS exhibit intrinsic resistance to these drugs. In particular, issues related to the dimerization of the RAF kinases can impact the efficacy of these compounds and are a primary cause of drug resistance. We have established biochemical HotSpotTM kinase assay, NanoBRETTM and NanoBITTM cell assay platforms for High Through Screening of kinase inhibitors. Here, we demonstrate that the 3rd generation of pan-RAF inhibitors LY3009120, LXH254, and Belvarafenib inhibit ARAF, BRAF, CRAF, BRAF(V600E), and CRAF(R391W) kinase activity in biochemical HotSpotTM assay. Our NanoBRETTM target engagement and NanoBITTM cellular assay data show that LY3009120, LXH254, and Belvarafenib bind to KRAS(G12C) primed BRAF and CRAF, and block BRAF and CRAF dimerization. Furthermore, our results show these inhibitors can block the downstream ERK phosphorylation in cellular HTRF assay and induce caspase-3/7 activation in Western blot assay in the triple negative breast cancer MDA-MB-231 cells. Taken together, our results indicate the biochemical HotSpotTM kinase activity assay, and NanoBRETTM target engagement and NanoBITTM cellular assays can serve as great platforms to facilitate RAF drug discovery against human cancers. Citation Format: Jianghong Wu, Yong Wan, Shuguang Liang, Peter Gallagher, Li Liang, Christian Loch, Haiching Ma. Biochemical and cell-based assay platforms for development of RAF inhibitors against human cancers [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 4704.

Prevalence of BRCA1, BRCA2, and PALB2 genomic alterations among 924 Taiwanese breast cancer assays with tumor-only targeted sequencing: extended data analysis from the VGH-TAYLOR study

BackgroundThe homologous recombination (HR) repair pathway for DNA damage, particularly the BRCA1 and BRCA2 genes, has become a target for cancer therapy, with poly ADP-ribose polymerase (PARP) inhibitors showing significant outcomes in treating germline BRCA1/2 (gBRCA1/2) mutated breast cancer. Recent studies suggest that some patients with somatic BRCA1/2 (sBRCA1/2) mutation or mutations in HR-related genes other than BRCA1/2 may benefit from PARP inhibitors as well, particularly those with PALB2 mutations. The current analysis aims to evaluate the prevalence of genetic alterations specific to BRCA1, BRCA2, and PALB2 in a large cohort of Taiwanese breast cancer patients through tumor-targeted sequencing.MethodsA total of 924 consecutive assays from 879 Taiwanese breast cancer patients underwent tumor-targeted sequencing (Thermo Fisher Oncomine Comprehensive Assay v3). We evaluated BRCA1, BRCA2, and PALB2 mutational profiles, with variants annotated and curated by the ClinVAR, the Oncomine™ Knowledgebase Reporter, and the OncoKB™. We also conducted reflex germline testing using either whole exome sequencing (WES) or whole genome sequencing (WGS), which is ongoing.ResultsAmong the 879 patients analyzed (924 assays), 130 had positive mutations in BRCA1 (3.1%), BRCA2 (8.6%), and PALB2 (5.2%), with a total of 14.8% having genetic alterations. Co-occurrence was noted between BRCA1/BRCA2, BRCA1/PALB2, and BRCA2/PALB2 mutations. In BRCA1-mutated samples, only p.K654fs was observed in three patients, while other variants were observed no more than twice. For BRCA2, p.N372H was the most common (26 patients), followed by p.S2186fs, p.V2466A, and p.X159_splice (5 times each). For PALB2, p.I887fs was the most common mutation (30 patients). This study identified 176 amino acid changes; 60.2% (106) were not documented in either ClinVAR or the Oncomine™ Knowledgebase Reporter. Using the OncoKB™ for annotation, 171 (97.2%) were found to have clinical implications. For the result of reflex germline testing, three variants (BRCA1 c.1969_1970del, BRCA1 c.3629_3630del, BRCA2 c.8755-1G > C) were annotated as Pathogenic/Likely pathogenic (P/LP) variants by ClinVar and as likely loss-of-function or likely oncogenic by OncoKB; while one variant (PALB2 c.448C > T) was not found in ClinVar but was annotated as likely loss-of-function or likely oncogenic by OncoKB.ConclusionOur study depicted the mutational patterns of BRCA1, BRCA2, and PALB2 in Taiwanese breast cancer patients through tumor-only sequencing. This highlights the growing importance of BRCA1/2 and PALB2 alterations in breast cancer susceptibility risk and the treatment of index patients. We also emphasized the need to meticulously annotate variants in cancer-driver genes as well as actionable mutations across multiple databases.

A new methodology to predict the oncotype scores based on clinico-pathological data with similar tumor profiles.

The Oncotype DX (ODX) test is a commercially available molecular test for breast cancer assay that provides prognostic and predictive breast cancer recurrence information for hormone positive, HER2-negative patients. The aim of this study is to propose a novel methodology to assist physicians in their decision-making. A retrospective study between 2012 and 2020 with 333 cases that underwent an ODX assay from three hospitals in the Bourgogne Franche-Comté region (France) was conducted. Clinical and pathological reports were used to collect the data. A methodology based on distributional random forest was developed to predict the ODX score classes (ODX [Formula: see text] and ODX [Formula: see text]) using 9 clinico-pathological characteristics. This methodology can be used particularly to identify the patients of the training cohort that share similarities with the new patient and to predict an estimate of the distribution of the ODX score. The mean age of participants is 56.9 years old. We have correctly classified [Formula: see text] of patients in low risk and [Formula: see text] of patients in high risk. The overall accuracy is [Formula: see text]. The proportion of low risk correct predicted value (PPV) is [Formula: see text]. The percentage of high risk correct predicted value (NPV) is approximately [Formula: see text]. The F1-score and the Area Under Curve (AUC) are of 0.87 and 0.759, respectively. The proposed methodology makes it possible to predict the distribution of the ODX score for a patient. This prediction is reinforced by the determination of a family of known patients with follow-up of identical scores. The use of this methodology with the pathologist's expertise on the different histological and immunohistochemical characteristics has a clinical impact to help oncologist in decision-making regarding breast cancer therapy.

Analysis of the association of HER-2 low carcinomas and PAM50 assay in hormone receptor positive early-stage breast cancer.

HER2-low has emerged as a new predictive biomarker in metastatic breast cancer. However, its prognostic value in early-stage carcinomas needs to be revisited. We aimed to evaluate the association of HER2-low carcinomas with PAM50 risk groups combined with clinicopathological variables in early breast cancer. We conducted a retrospective analysis of 332 patients with early-stage breast cancer that underwent PAM50 signature analysis between 2015 and 2021at Hospital Universitario 12 de Octubre (Madrid, Spain). Clinical and pathological variables were collected from medical records. After adjusting for potential confounders, we estimated Odds Ratio (OR) and 95% confidence interval for high-risk PAM50 subgroup, comparing HER2-low versus HER2-zero carcinomas by multivariable logistic regression. P values below 0.05 were deemed statistically significant. 192 (57%) patients were classified as HER2-low carcinomas. Median follow-up was 34 months. Adjusted OR for high-risk PAM50 when comparing HER2-low versus HER2-zero carcinomas was 1.31 (95% CI: 0.75-2.30, p=0.33). The multivariable model detected significant associations for Ki-67% (≥20% vs. <20%: OR=4.03, 95% CI: 2.15-7.56, p<0.001), T staging category (T2/T3 vs. T1: OR=3.44, 95% CI: 1.96-6.04, p<0.001), progesterone receptor (PR≥20% vs. <20%: OR=0.44, 95% CI: 0.23-0.83, p=0.01), nodal staging category (N+ vs. N0: OR=3.8, 95% CI: 1.89-7.62, p<0.001) and histological grade (grade 2 vs. 1: OR=2.41, 95% CI: 1.01-5.73, p=0.04; grade 3 vs 1: OR=5.40, 95%CI: 1.98-14.60, p=0.001). In this early-stage breast cancer cohort, HER2-low was not associated with a high-risk PAM50 compared to HER2-zero carcinomas. Ki-67≥20%, T2/T3, histological grade 2/3, N+ and PR<20% were significantly associated to a high-risk PAM50.

Relationship between homologous recombination deficiency and clinical features of breast cancer based on genomic scar score.

Homologous recombination deficiency (HRD) phenotype will sensitize tumors to poly (ADP-ribose) polymerases inhibitors and platinum. However, previous studies did not focus on the prevalence of HRD among Chinese breast cancer (BC) patients. One hundred and forty-seven BC patients were included in this study. Their HRD status was assessed by Genomic Scar Score (GSS), which was determined according to the length, site, and type of copy number. HRD was defined as positive when a harmful BRCA1/2 mutation was detected or GSS ≥50. Our data revealed that 9.5% of the 147 patients tested positive for BRCA1/2 mutation, while approximately 34.7% were HRD-positive. For triple negative BC (TNBC), HRD positivity rate (60.5%) was higher than Luminal A (5.3%), Luminal B (HER2-) (28.8%), and Luminal B (HER2+) (31.6%) subgroups. HRD-positive tumors were more likely to be ER/PR-negative and exhibited higher Ki-67 expression. 50.0% of the HRD-positive patients achieved pathologic complete remission (pCR) after neoadjuvant therapy. HRD-positive patients tended to have a higher risk for cancer recurrence or metastasis compared to HRD-negative patients (29.4% vs. 13.5%). We investigated the HRD status among Chinese BC patients using an HRD detection tool developed based on the Chinese population. The clinical characteristics, pathological profile, family history pattern, neoadjuvant efficacy, and disease progression events of HRD-positive and negative patients were described and compared. Thus, our data provided an evidence-based basis for applying the original HRD assay in Chinese BC.