HER2 Positivity Research Articles

Abstract PO4-15-06: Genomic landscape characterization after exposure to cyclin dependent kinase 4/6 inhibitors: a retrospective multi-institutional consortium analysis

Abstract Background: Limited data are available to determine the best therapeutic strategy for hormone-receptor positive (HR+) HER2 negative (HER2-) advanced breast cancer (ABC) after progression on cyclin dependent kinase 4/6 inhibitors (CDK4/6i). The aim of this study was to characterize the genomic and prognostic profile of patients (pts) that experienced disease progression after first-line therapy with a CDK4/6i. Methods: The study retrospectively analyzed a multi-institutional cohort of 75 patients (pts) with HR+/HER2- ABC after experiencing progression on first-line endocrine therapy (ET) with CDK4/6i and characterized by circulating tumor DNA (ctDNA) next-generation sequencing (Guardant 360). Oncogenic pathways (i.e., RTK, RAS, RAF, MEK, NRF2, ER, WNT, MYC, p53, cell cycle, notch, and PI3K) were defined based on previous research (Sanchez-Vega et al. Cell, 2018). Associations across single nucleotide variations (SNVs), copy number variations (CNVs), and pathway classification were tested by uni- and multivariable logistic regression with respect to a CDK4/6i naïve group comprising 247 patients with HR+/HER2- ABC (control). Prognosis was analyzed through Cox regression for overall survival (OS). Result: Our study cohort included 75 ABC pts who experienced progression after first line CDK4/6i plus ET: 43 pts (57.3%) were treated with ET while 31 (41.3%) with a non-ET- second line therapy. The most common histology was invasive ductal carcinoma (70.6%), 37.3% of pts were negative for progesterone expression and 26.7% had de novo metastatic disease. The PI3K (33.3%), p53 (28%) and ER (25.3%) pathways were the most mutated in the CDK4/6i-treated cohort. Comparing our population with a CDK4/6i naïve cohort (N=247), the multivariate analysis showed a higher prevalence in the study cohort of SNVs mutations in: i) ESR1 gene [Odds ratio (OR) 2.93; p=0.005]; ii) cell-cycle pathway (OR 4.24; p=0.033); iii) ER pathway (OR 2.04; p= 0.034). Moreover, in the study cohort a numerical but not significant increase of RB1 SNVs was also observed. Multivariable analyses of the 43 pts that received ET second line therapy showed a negative prognostic impact with TP53 SNVs in both progression-free survival (PFS) [Hazard ratio (HR) = 3.34; 95% CI: 1.15-9.66, p=0.026] and OS (HR = 3.85; 95% CI: 1.52-9.77, p=0.005). The prognostic role of p53 pathway mutations was also confirmed for both PFS (HR = 4.71, 95% CI: 1.64-13.50; p=0.004) and OS (HR = 3.25; 95% CI: 1.27-8.3; p=0.014). The potential interaction between the prognostic oncogenic pathways and the outcome was investigated according to the treatment strategy (ET vs non-ET). A consistent impact was observed across the above prognostic pathways both for PFS and OS. A numerical difference was observed in terms of PFS in pts with p53 pathway mutations that underwent non-ET second line. Conclusions: The genomic landscape of progressive disease after CDK4/6i exposure is significantly different from the genomic alterations detectable in treatment-naïve pts, which could potential impact future treatment strategies for patients with disease progression after adjuvant CDK4/6i exposure. Our data suggest that the choice of second-line treatment could potentially be guided by the identification of actionable mutation by ctDNA, although further prospective studies are needed to validate the clinical utility of this approach. Citation Format: Letizia Pontolillo, Carolina Reduzzi, Andrew Davis, Lorenzo Gerratana, Arielle Medford, Katherine Clifton, Whitney L. Hensing, Marko Velimirovic, Ami N. Shah, Jeannine Donahue, Laura Munoz Arcos, Charles S. Dai, Jennifer Keenan, Amir Behdad, William Gradishar, Emilio Bria, Cynthia Ma, Aditya Bardia, Massimo Cristofanilli. Genomic landscape characterization after exposure to cyclin dependent kinase 4/6 inhibitors: a retrospective multi-institutional consortium analysis [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 PO4-15-06.

Abstract PO5-18-11: Use of DiviTum®TKa as a biomarker assay for CDK4/6 inhibitor medication compliance and drug-drug interaction assessment in ER/PR positive metastatic breast cancer

Abstract Background: CDK4/6 inhibitor (CDK4/6i) with endocrine therapy (ET) is standard first line (1L) treatment for metastatic hormone positive (ER/PR+) HER2- negative breast cancer (mBC). Some patients have progression free survival (PFS) of 2 years or more whereas some patients have very short PFS on these medications. Thymidine kinase is a biomarker that reflects cell proliferation. DiviTum®TKa is an assay that was cleared by the FDA in July 2022 based on data that showed that thymidine kinase activity (TKa) value of < 250 DiviTum units (DuA) is associated with the decreased likelihood of disease progression within 30 days or 60 days post testing. The purpose of this study is to assess the use of TKa as a biomarker for identifying potential medical compliance issues and drug-drug interactions (DDI) in patients on CDK4/6i and to evaluate whether counseling and optimization of concurrent medications will lead to lower TKa levels in subsequent treatment cycles and possibly longer PFS. Trial design: This is a pilot study to assess whether TKa can serve as a biomarker to identify patients with a suboptimal reduction in tumor cell proliferation caused by a potential CDK4/6i compliance or DDI issue. We will also assess whether correction of the issue can improve suppression of TKa levels in ER/PR+ mBC patients on 1L CDK4/6i and ET. For screening, we are utilizing a novel automated real-time data driven cohort identification system designed by Dr. Guannan Gong at Yale. Patients will be treated and monitored as per standard of care. An aliquot of serum obtained during routine blood draws will be sent to a CLIA-certified Biovica lab for TKa testing. TKa results will be returned in real time. Patients with a detectable TKa baseline level (above 145 DuA), followed by a sustained TKa level (>145 DuA) at cycle 1 D15 and D28 will be assessed for medication compliance and DDI. TKa levels will be repeated at subsequent standard of care blood draws to assess if the intervention affected TKa levels. Patients will be followed for 2 years. Eligibility criteria: Participants must have ER+ mBC and starting 1L CDK4/6i + ET and be previously CDK4/6i -naïve. Specific aims: Primary objective: to estimate the rate of improvement in CDK4/6i response (change in TKa levels) after counseling for medication compliance and adjustment of potential deleterious DDIs. Secondary objectives: 1) estimate the rate of sub-optimal CDK 4/6i response in cycle 1 of treatment. 2) Compare clinical benefit rate (CBR) in patients with sub-optimal and optimal CDK4/6i response after both cycles 1 and cycle 3. 3) Compare PFS in patients with sub-optimal and optimal CDK 4/6i response after both cycles 1 and cycle 3. 4) Assess CDK4/6i response via TKa levels upon CDK4/6i dose reductions or changes in CDK4/6i regimens. 5) Compare CDK4/6i response profiles across the three CDK 4/6i among different patients and within the same patients if CDK4/6i is changed throughout treatment course. 6) Correlate TKa levels with tumor marker levels. 7) Assess plasma concentrations of CDK4/6i in patients with suboptimal TKa levels. Statistical methods: For binary endpoints measured at a given time point, we will estimate the two-sided 95% exact CI using Clopper-Pearson method. With a sample size of 120 patients, assuming 20% drop out rate, we predict that about 15% of patients will have suboptimal CDK4/6i response, estimating a 95% CI of 0.086-0.235 in the first cycle. Comparisons between paired outcomes will be completed using the paired t-test or Wilcoxon signed-rank test for continuous parameters of interest, or McNemar’s Chi-square test for categorical parameters of interest. Time to event endpoints will be estimated using Kaplan-Meier method. Present accrual and target accrual: This trial has just been activated. Target accrual is 120 patients. Contact information for people with a specific interest in the trial: Mariya.Rozenblit@yale.edu Citation Format: Mariya Rozenblit, Adriana Kahn, Guannan Gong, Amy Williams, Lajos Pusztai. Use of DiviTum®TKa as a biomarker assay for CDK4/6 inhibitor medication compliance and drug-drug interaction assessment in ER/PR positive metastatic 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 PO5-18-11.

Abstract PO2-01-07: Real-world efficacy of dual HER2-blockade in combination with anthracycline-containing and anthracycline-free neoadjuvant treatment in early breast cancer (BC)

Abstract BACKGROUND: Neoadjuvant therapy with antiHER-2 blockade is the standard of care for HER-2 positive early BC. The objective of this treatment is tumor downstaging to increase resectability and pathological complete response (pCR), a reliable surrogate endpoint for survival. Adding Trastuzumab (T) to chemotherapy resulted in an improvement in pCR, however, resistance to this agent is common and the incorporation of Pertuzumab (P) to the neoadjuvant scene demonstrated an increase in pCR in the Peony (39.3% vs 21.8%) and Neosphere trials (45.8% vs 29%). Across all studies, pCR is even higher in patients (pts) with negative hormonal receptor (HR) status (50%-63%) (3, 4). Tryphaena and Berenice found low rates of cardiotoxicity with T-P combination. Recently, TRAIN-2 data showed that anthracyclines and platinum have a similar pCR (67% vs 68%), but febrile neutropenia and cardiotoxicity is higher in the anthracycline group, concluding that omitting this therapy might be a preferred approach in the presence of dual HER2 blockade. Our study investigated the pCR benefit of dual HER2 blockade with anthracyclines and platinum in HER2 positive early BC. METHODS: We conducted a retrospective, unicenter, observational study of pts, treated with neoadjuvant T-P plus chemotherapy, in HER-2 positive early BC, between April 2015 and December 2022 at University Hospital A Coruña (Spain). The primary endpoint was total pCR in breast and axila (tpCR: ypT0/is ypN0). Secondary endpoints were: association between clinicopatological characteristics and pCR; and between cardiotoxicity and treatment pattern. Statistical analyses were conducted with Statistical Package for the Social Science (SPSS). RESULTS: During the study period, from April 2015 to May 2022, 154 pts were enrrolled. The median age was 51,3 years [range 26 – 799 years], all patients were female. Infiltrating ductal carcinoma was present in 92.2% pts, and 5.8% were inflammatory BC. At diagnosis, 11.7%, 61.7% and 26.6% had stages I, II and III, respectively, and 51.3% revealed axillary node involvement. Among observed cases, 94 (61%) were positive HR; 68 (45%) had histological grade 2 and 83 (53.9%) histological grade 3 tumors; and 151 pts (99.3%) presented a ki-67 level >20%. HER2 by immunohistochemistry (IHC) resulted in 3+ for 133 pts (86.9%) and in 2+ for 20 pts (13.1%), all of them with positive result by in situ hybridation (ISH). P-T were mostly combined with anthracyclines (64.9%). tpCR rate was 50.6%, and it was not significantly different according chemotherapy approach. tpCR was significantly higher among HR negative tumours (73.3%) compared with HR positive (36.2%) (p= 0.001), and in HER2 positive 3+ (55.6%) compared with HER2 positive 2+ (15%) tumours (p= 0.001). Achievement of tpCR was not significantly associated with tumor size, stage, histological grade and ki-67 level. Breast pCR was higher than tpCR (54.2%). 13 pts (8.4%) presented recurrence disease, in 76.9% of cases was a metastatic relapse. Cardiotoxicity was low during all stages of treatment and was not significantly associated with chemotherapy pattern. CONCLUSIONS: Neoadjuvant T-P plus chemotherapy with either anthracyclines or platinum therapy, demonstrated same efficacy and cardiac safety in our real-world study. pCR rates are lower in positive HR and HER2 positive 2+, needing more investigation with combination strategies including hormonotherapy, Our results are similar to data from randomized trials and other real-world efficacy studies, but we need more follow-up to identify late cardiotoxicity by anthracyclines and recurrences in positive HR tumors. Citation Format: Beatriz Alonso de Castro, Cristina Reboredo, Lourdes Calvo, Maria-Eva Perez-Lopez, Martin Igor Gomez Randulfe Rodriguez, Sofia silva diaz, Iria Parajo Vazquez, Silvia Antolin Novoa. Real-world efficacy of dual HER2-blockade in combination with anthracycline-containing and anthracycline-free neoadjuvant treatment in early breast cancer (BC) [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 PO2-01-07.

Abstract PO3-01-11: Clinical Significance of HER2-low Breast Cancer

Abstract Context: Breast cancers with a HER2 immunohistochemistry (IHC) result of 1+ or 2+ and a negative amplification test (FISH), previously treated as HER2 negative, are now termed HER2-low and are being targeted for treatment. We aim to explore the clinical significance of this group. Design: 394 breast cancer cases were included from our institution from 2010. Demographic and clinicopathological data on receptors status, recurrence/metastasis, treatment, and survival was collected. HER2 was re-evaluated according to the 2018 CAP ASCO guidelines and patients were treated according to standardized protocol. HER2 +2 with positive FISH and HER2 +3 were excluded. HER2-low was compared to HER2-0. Appropriate statistical analysis was performed. Results: 394 patients (76% IDC; 8% ILC; 16% others) were included, such that 91 (23%) were HER2-0 and 303 (77%) HER2-low. Median age was 58 years (range: 25-95). Median follow-up was 54 months (range: 0.5-259). Grade 3 tumors were significantly more frequent in HER2-0 than HER-2 low (52% vs. 33%; p=0.010). Grade 3 or ILC patients had higher risk of recurrence than Grade 1 (HR 2.55; p< 0.001) or IDC (HR 2.03; p=0.033). After adjusting for grade, HER2-low had a significantly worse RFS than HER2-0 (HR 1.58; p=0.043). In the ER negative subgroup, HER2-low had significantly worse RFS than HER2-0 (HR 2.02; p=0.023). No differences in overall survival were seen. Conclusions: Our data showed higher recurrence in HER2-low group compared to HER2-0. This suggests that breast cancer patients with HER2- low are a separate entity and might benefit from additional targeted therapy. Table 1 Hazard regression analysis of risk factors associated with recurrence Citation Format: Fadi Zaiem, Asem AbuJamea, Mira Kheil, Anna Numi, Omar Abbas, Sanaa Awada, Ragad Almsaddi, Saleh Al-Juburi, Lauren Larson, Deepti Jain, Maya AlSaghir, Hyejeong Jang, Seongho Kim, Sudeshna Bandyopadhyay, Sunil Jaiman, Rouba Ali-Fehmi. Clinical Significance of HER2-low 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 PO3-01-11.

Abstract PO1-06-05: Heterogeneity and prognostic characteristics of HER2-low breast cancer: A retrospective analysis of patients with HER2-negative metastatic breast cancer

Abstract Background: It remains uncertain as to whether low levels of HER2 positivity have any prognostic implications in breast cancer patients, whether HER2 levels can be inconsistent between primary tumors and metastatic lesions in individuals with advanced HER2-negative breast cancer, and how such inconsistencies may impact patient prognosis. Methods: A retrospective analysis of advanced breast cancer patients admitted to our hospital from from January 1st, 2010 to January 1st, 2019 was performed, with all patients that underwent at least one metastatic lesion biopsy being screened. The hormone receptor (HR) and HER2 profiles of both primary and metastatic lesions from these patients were confirmed, and HER2-positive patients (HER2 3+ immunohistochemistry [IHC] results or HER2 2+ IHC results with positive in situ hybridization [ISH] results) were excluded from further analyses. To examine the prevalence of HER2-low status across primary and metastatic cancers, the current study set out to detect inconsistencies between these two tumor compartments with respect to HER2-low status and to examine the prognostic implications of these findings in patients. Results: The median follow-up duration for this study at the cutoff date (December 31, 2021) was 49.3 (45.8-52.8) months. The current study examined 1,031 participants with HER2 and HR status data from both primary and metastatic tumors. The proportion of HER2-low expression was significantly higher in metastatic lesions than primary tumors (34.7% vs 25.7%), with a corresponding drop in the proportion of HER2-zero metastatic lesions (FIGURE 1). In a multivariate analysis, HER-2 upregulation was linked to HR status, which was established as an independent influencing factor, with such upregulation being most common in HR-positive individuals (P= 0.004). With respect to HER2 status of primary lesions, the medianl survival of patients in the HER2-zero was similar to HER2-low patients, regardless of HR status [44.8 months (95% CI 38.2-54.1) vs 41.5 months (95% CI 35.0-48.0)] (P = 0.954)(FIGURE 2A). However, when the HER2 status of metastatic lesions was examined, patients with HER2-low expression had a greater median OS than HER2-zero patients [47.6 months (95% CI 39.6-48.0) vs. 32.2 months (95% CI 24.6-40.0)] (P < 0.001)(FIGURE 2B). The median OS of patients that exhibited HER2 upregulation (zero→low) was longer than that of patients without such upregulation (zero-zero) (55.8 months (95% CI 45.0-66.6) vs. 32.4 months (95% CI 23.8-41.0)) (P < 0.001)(FIGURE 3A). Among HR-positive patients, HER2 upregulation was associated with significantly prolonged OS relative to patients without such upregulation [56.6 months (95% CI 44.6-68.6) vs. 41.7 months (95% CI 31.1-52.3)] (P=0.006)(FIGURE 3B), whereas survival outcomes were similar in these two groups in the HR-negative subgroup [44.8 months (95% CI 25.6-64.0) and 25.3 months (95% CI 20.4-30.3)] (P=0.103)(FIGURE 3C). However, independent of HR status, the median OS of patients who had HER2 downregulation (low→zero) was similar to those without downregulation (low→low)(FIGURE 3 D, E, F). Conclusion: These results support inconsistencies in HER2-low expression status between primary and metastatic lesions, with low HER2 levels in metastatic tumors being associated with improved survival outcomes. HR-positive patients are more likely to exhibit HER2 upregulation within metastatic lesions and experience corresponding prognostic benefits. Keywords: HER2-low, inconsistency, survival, prognosis, advanced breast cancer Citation Format: Huimin Lv, Min Yan, Mengwei Zhang, Limin Niu, Huiai Zeng, Huihui Sun, Shengnan Zhao, Jing Wang. Heterogeneity and prognostic characteristics of HER2-low breast cancer: A retrospective analysis of patients with HER2-negative metastatic 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 PO1-06-05.

Abstract PO2-05-13: HER2 status presented an unstable switching from primary to recurrent breast cancer

Abstract Background: Breast cancer patients with HER2-2+ expression had heterogeneous characteristic. Treatment decision is of great importance after progression. Objective: We explored patients with HER2-2+ in matched primary or recurrent/metastatic tumor samples from January 2010 to June 2022 in our institute were included to evaluate the evolution from or to HER2-2+ expression. Meanwhile, with an emerging of novel entity as HER2-low expression breast cancer, we included this category when analysis as well. Results: In the cohort of a total of 159 breast cancer patients with HER2-2+ expression in either primary tumor or locoregional/distant metastases samples, HER2-2+ breast cancer accounted for 44.0% in primary tumor and 88.8% in recurrent diseases. There were 18.5% and 15.2% patients with HER2 gene amplification on ISH assay among primary and recurrent/metastatic HER2-2+ breast cancers, respectively. The overall rate of HER2 IHC discordance was 67.1%. Among primary HER2-2+ cases, 74.6% maintained in HER2-2+ when disease relapsed. Discordance was mostly driven by cases switching from HER2-2+ to HER2-1+ (64.7%). In HER2-2+ recurrent/metastatic cases, discordance was mostly driven by cases switching from HER2-0 to HER2-2+ (47.1%). The proportion of HER2 discordant cases got a higher statistically trend among HR-positive patients in compared with HR-negative patients (44.1% vs. 21.7%, p = 0.062). There were 35.0% in primary HR-positive/HER2-negative patients and 11.8% in primary triple-negative patients switching from HER2-0 to HER2-low when disease progressed, respectively. Meanwhile, HER2 discordance rate had a significant difference across different metastatic sites (p = 0.026). All contralateral breast and skin metastasis presented with discordant HER2 results. While, all central nervous system metastasis maintained the same HER2-low expression. HER2-positive phenotype in primary breast cancer samples loss their positivity in 42.1% cases. There was a total of 6.6% cases gained HER2 positivity in recurrent breast cancer samples. Conclusion: HER2 expression from primary to relapse breast cancer samples were highly unstable. Biopsy of recurrent sites was necessary to find novel treatment. Citation Format: Anjie Zhu, Hui-Ping Li. HER2 status presented an unstable switching from primary to recurrent 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 PO2-05-13.

Abstract PO2-09-06: Interaction of racial disparities on outcomes and toxicities associated with treatment of HER2+Breast Cancer- a TrinetX Database study

Abstract Objective: Investigate the interaction of racial disparities on outcomes and toxicities associated with treatment of HER2+BrCa (Breast Cancer)- a TrinetX Database study Background: HER2+BrCa is an aggressive subtype accounting for about 1/3rd of all BrCa, for which Trastuzumab based therapy remains the mainstay of treatment. While we are starting to understand the breadth of racial disparities in BrCa , the knowledge about outcomes and toxicities in relation to treatment of HER2+ BrCa is still limited. Design/Methods: In this propensity score-matched cohort study we used the TriNetX Research Network, a multi-health care organization de-identified electronic health record (EHR) database, to compare the 1-, 3-, and 5-year mortality of HER2+BrCa non-Hispanic African American (NHAA) women to a corresponding non-Hispanic White cohort (NHW). Qualification into the two race based HER2+BrCa cohorts required the presence of a C50 ICD-10-CM diagnosis code and at least one proxy for HER2 positivity such as Trastuzumab administration (index event). Cohorts were matched for age, BMI, comorbidities (HTN, DM ), and lab values using 1:1 matching with a greedy nearest neighbor search. Toxicity outcomes of interest such as cardiomyopathy, neuropathy, diarrhea, rashes, leg swelling/edema, and fatigue as well as the frequency of emergency room visits were also compared between the cohorts. The associations of observed outcome frequencies in the two cohorts were tested for significance using the chi-square test. The odds ratios and p-values, corrected for multiple hypothesis testing using the Benjamini-Hochberg procedure, are reported as an effect size and significance estimation. Results: 15983 patients met the inclusion criteria for HER2+BrCa (13611-NHW and 2372-NHAA). The mean age at the index event was 55.6 ± 12.6 years for NHAA and 57.2 ± 13.3 years for NHW. After matching the two sub-cohorts, 2303 patients remained in each. NHAA women were found to have significantly increased odds of neuropathy and cardiomyopathy for 1, 3, and 5-year time intervals after the HER2+BrCa index date, as compared to the reference NHW women (abbreviated results given in Table 1). In addition, the odds of an emergency room visit (for any reason) was found to be increased by as much as 79% in NHAA women as compared to the NHW women. The odds of experiencing fatigue/malaise, diarrhea/nausea, and rash, were reduced for NHAA women across all time intervals investigated. Odds ratios for mortality and leg swelling did not meet the significance threshold (p-value < 0.05). Conclusion: This study, which examined racial disparities in outcomes and toxicities associated with HER2+BrCa, revealed significant findings. NHAA women with HER2+BrCa treated with Trastuzumab based therapy demonstrated increased odds of experiencing neuropathy and cardiomyopathy compared to their NHW counterparts. Additionally, NHAA women had a higher likelihood of emergency room visits for any reason. Conversely, NHAA women exhibited decreased odds of fatigue/malaise, diarrhea/nausea, and rash. These findings underscore the importance of considering the impact of race on HER2+BrCa outcomes and treatment toxicities and suggest the need for further research and targeted interventions to address disparities and thus enhance treatment outcomes in diverse populations. Table 1: Representative significant Odds ratios and corrected p-values for outcomes comparing the NHAA and NHW cohorts. Citation Format: Monali Vasekar, Justin Petucci, Avnish Katoch, Vasant Honavar. Interaction of racial disparities on outcomes and toxicities associated with treatment of HER2+Breast Cancer- a TrinetX Database 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 PO2-09-06.

Abstract PO3-05-04: Characteristics and clinical outcome of patients with HR positive HER2 low metastatic breast cancer treated with CDK 4/6 inhibitors

Abstract Introduction Breast cancer (BC) is a disease characterized by significant intra- and intertumoral heterogeneity. Hence, it is not surprising that new subtypes with distinct biological features are being discovered, even among previously well-defined BC groups. Recently, HER2-low BC emerged as a new entity with specific clinical behavior, response to treatment and prognosis. HER2-low is a subset of HER2-negative BC, with HER2 immunohistochemical (IHC) score of 1+ or 2+, without HER2 gene amplification measured by in situ hybridization (ISH). As new therapeutic options become available for HER2-low patients, the best treatment sequence is yet to be determined. Furthermore, it is important to distinguish whether there is a difference in the response to standard treatment lines, such as CDK 4/6 inhibitors in metastatic HR positive BC patients, depending on HER2-low status. Methods A retrospective study of 369 metastatic BC (mBC) cases who started CDK 4/6 inhibitor therapy from January 2018 through December 2022 at University Hospital Centre Zagreb was conducted, with prior Ethics Committee approval. All patients with HR positive HER2 negative mBC, determined by standard IHC and ISH, were included in the research. Patient demographics and clinical presentation, tumor characteristics and treatment information were collected. Progression-free survival (PFS) analysis was done with the final data cut-off date being June 1st, 2023. Type 1 right censoring was performed. The data was analyzed using the Kaplan-Meier method and Cox proportional-hazards regression for clinically relevant covariates (age, line of treatment, de novo metastatic disease, endocrine resistance, liver metastases, and detected PIK3CA mutation). Results Median follow-up was 23 months. Of the 283 patients included, 146 (51.59%) had HER2-low disease. A change in HER2 expression between primary tumor and metastasis was found in 16.96% (N=48) patients. Of them,10.25% (N=29) who were initially HER2-low, were found to be HER2-0 in metastatic disease. Meanwhile, 6.71% (N=19) of patients had a change in HER2 expression from 0 to low upon becoming metastatic. In the HER2-low group, 47.06% (N=45) patients had a PIK3CA mutation as opposed to 33.33% (N=30) in the HER2-0 group. Odds ratio for a PIK3CA mutation in HER2-low patients was 1.86 (95% confidence interval (CI): 1.01-3.43, p-value 0.046). Median PFS in the HER2-low group was 18 months (95% confidence interval (CI): 14-24) versus 23 (95% CI: 18-30) in the HER2-0 group. Using multivariable analysis an adjusted hazard ratio of 1.15 (95% CI:0.84-1.57; p-value 0.389) was calculated. Covariates associated with a statistically significant increased risk of disease progression were a higher line of therapy (HR 1.39, 95% CI 1.36-1.71, p-value 0.002) and the presence of liver metastases (HR 2.17, 95% CI 1.42-3.32, p-value 0.0004). A covariate associated with a statistically significant longer PFS was de novo metastatic disease (HR 0.63, 95% CI 0.41-0.97, p-value 0.034). Conclusion There was a trend toward worse PFS in HER2-low mBC that did not reach statistical significance. HER2-low patients were more likely to harbor PIK3CA mutations than HER2-0 patient group. Longer follow-up and a larger cohort are needed in order to make definitive conclusions. Citation Format: Katarina Čular, Kristina Kanceljak, Ana Magdalena Glas, Dora Gudelj, Marija Križić, Marina Popović, Natalija Dedić Plavetić, Maja Sirotković-Skerlev, Stjepko Pleština, Tajana Silovski. Characteristics and clinical outcome of patients with HR positive HER2 low metastatic breast cancer treated with CDK 4/6 inhibitors [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 PO3-05-04.

Abstract PO3-13-11: Quantitative Multiplex Immunofluorescence Assay for TROP2 and HER2 Expression in Breast Cancer: Towards Guiding Patient Selection for Antibody Drug Conjugate Therapies

Abstract Emerging antibody drug conjugate (ADC) therapies targeting human trophoblast cell-surface antigen (TROP2) and human epidermal growth factor receptor 2 (HER2) are transforming the treatment landscape for breast cancer. Sacituzumab govitecan (SG) and trastuzumab deruxtecan (T-DXd) have gained approval for an overlapping set of "HER2-low" metastatic breast cancers, including hormone receptor (HR)-positive HER2 non-amplified and "triple-negative" subtypes. Nevertheless, the optimal selection of patients and treatment sequencing for these ADC therapies remains a clinical challenge. Clinical trial objective response rates to SG are approximately 30%, compared to 30-90% for T-DXd depending on HER2 expression levels. While both drugs are thought to be targeted therapies, the value of measuring the target and the best methods to do so are still not established. We believe that quantitative measurement of TROP2 and HER2 antigen expression levels could establish thresholds for responders, enabling more effective patient selection for ADC therapies. Here, we present a TROP2, high-sensitivity HER2, and cytokeratin (CK) quantitative immunofluorescence (QIF) multiplex assay. Using a ten-cell line standard array and proteomic mass spectrometry, we can convert tumor compartment QIF intensity to protein concentration in fmol/mm2 for tissue specimens. Anti-HER2, anti-TROP2 antibodies, and fluorescence detection systems were titrated and combined to maximize signal-to-noise ratio on our cell line standard array and breast cancer tissue microarrays (TMA). The multiplex assay was designed for automated slide stainers (Leica BOND Rx) and fluorescence slide scanning (Rarecyte CyteFinder II HT). We perform our analyses in QuPath using an image processing plugin developed for automated QIF/IHC analysis (Qymia). Reproducible TROP2 and HER2 QIF scoring (R² > 0.95) was achieved across multiple staining batches using serial sections of breast cancer TMAs and cell standard arrays. This assay has a TROP2 linear range between 0.63 - 9.17 fmol/mm2 (about 1 million TROP2 receptors/cell) and HER2 linear range between 0.09 - 0.565 fmol/mm2 (about 60,000 HER2 receptors/cell). We then applied this multiplex assay to two serial retrospective primary breast cancer cohorts from Yale University to quantitatively measure TROP2 and HER2 expression (338 clinical cases). We find a weak negative correlation between TROP2 and HER2 expression in our breast cancer cohorts (Pearson r = -0.14, p = 0.0097, n = 338). TROP2 expression levels were above the limit of detection (LOD) in 90.2% of cases, with 4.1% exceeding the limit of linearity (LOL), and a mean TROP2 expression of 4.05 fmol/mm2. For HER2, 67.2% of cases were above the LOD, with 7.1% exceeding the LOL, and a mean HER2 expression of 0.186 fmol/mm2. Both TROP2 and HER2 were below the LOD in 3.0% of cases, which we define as “negative”. We found 29.9% expressed TROP2 and were HER2-negative, and 6.8% expressed HER2 and were TROP2-negative. Our future studies will aim to quantitatively define expression thresholds for T-DXd and SG response with the goal to produce a clinical grade assay for ADC patient selection and determine the value of the assay to help select which ADC to give first. HER2 and TROP2 protein expression summary in Yale breast cancer cohort Table 1: Summary of HER2 and TROP2 protein expression levels in serial retrospective primary breast cancer cohort of 338 cases using our high-sensitivity HER2 and TROP2 multiplex immunofluorescent assay Citation Format: Charles Robbins, Mengni He, Revekka Khaimova, Katherine Bates, Nay Nwe Nyein Chan, Daniel Liebler, Regan Fulton, David Rimm. Quantitative Multiplex Immunofluorescence Assay for TROP2 and HER2 Expression in Breast Cancer: Towards Guiding Patient Selection for Antibody Drug Conjugate Therapies [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 PO3-13-11.

Abstract PS05-06: Outcomes of Surveillance using Contrast Enhanced Mammography in Women with a Personal History of Breast Cancer

Abstract Background Women with a personal history of breast cancer (PHBC) have a high rate of subsequent breast malignancy. Annual mammography with selective ultrasound has been the standard method of surveillance after breast cancer for many years, aiming for early detection, treatment and improved survival. In surveillance populations, interval cancers, which can account for ~30% of subsequent breast cancers, are more likely to be larger, hormone receptor negative and lymph node positive than cancers detected by surveillance (Lee et al, Radiology 2021). Interval cancer rates of 3.6 per 1000 mammographic screens have been reported previously in women with PHBC (Houssami et al, JAMA 2011). For women with PHBC a more sensitive surveillance approach may be justified, noting mammography has lower program sensitivity in PHBC surveillance than in screening. Magnetic resonance imaging (MRI) is used selectively but with resource and access limitations. Contrast enhanced mammography (CEM) offers a more sensitive modality than conventional mammography with specificity comparable to MRI, but its utility for surveillance is uncertain. Methods Retrospective study of 1,190 women with PHBC who commenced annual CEM surveillance in an Australian hospital setting between June 2016 and December 2022 (Elder et al, Breast Cancer Res Treat 2023) combining outcomes of initial CEM and any subsequent surveillance imaging over that period, including incident surveillance-detected cancers and interval cancers (cancers diagnosed in the year following a negative surveillance episode), recalls for assessment, the contribution of contrast to recall, and pathology and treatment details for cancer diagnoses. Outcomes were reported using descriptive statistics and hazards modelling. Results There were 3,784 episodes for analysis: 1,190 first CEM surveillance episodes, and 2,594 subsequent surveillance episodes of which >90% were contrast based imaging. 79% of women had at least three annual rounds of surveillance imaging. 186 cases from the total 3784 surveillance episodes were recalled for assessment (recall rate 4.9%). 72 (39%) recalled cases identified malignant lesions (true positives (TP)), with 50 invasive cancers and 22 cases of DCIS. 114 (61%) recalled cases were false positives (FP). 51% of cases were only recalled due to contrast and 35% of these were TP. Invasive cancers were predominantly stage 1 (64%) or stage 2 (32%) and most were grade 2 (44%) or grade 3 (47%). The median invasive cancer size was 16mm (IQR 9-25mm). 62% of invasive cancers were hormone receptor positive HER2 negative, and 24% were triple negative. The median DCIS size was 19mm (IQR 10-26mm) with only a single low grade case. 40% of invasive cancers and 59% of DCIS were recalled due to contrast. Comparison of tumour features indicates similarities between contrast-directed recalls and other diagnoses; conclusive findings would require a larger sample. Five interval cancers were identified, of which three were asymptomatic and detected on surveillance imaging scheduled early for other reasons. Thus, the rate of symptomatic interval cancers was 0.8 per 1000 screens (program sensitivity 96.0%). Surveillance-detected cancer rates differed significantly by index cancer subtype (χ2=11.9, p=0.0026), with highest rates for women with triple negative index cancers. Incidence cancer rates were higher among the 6.9% of women with moderate or marked BPE at first CEM surveillance episode (χ2=8.8, p=0.032), but did not differ significantly by age group (χ2=5.2, p=0.39) nor breast density (χ2=4.7, p=0.19). Conclusions Routine use of CEM in annual surveillance of women with PHBC led to 1.85-fold increase in the detection of clinically significant malignant lesions, with lower interval cancer rates than previous published series of women with PHBC. CEM appears to increase the sensitivity of surveillance programs for women with PHBC, improving on imaging without contrast. Citation Format: Julia Matheson, Carolyn Nickson, Kenneth Elder, Allan Park, Allison Rose, Bruce Mann. Outcomes of Surveillance using Contrast Enhanced Mammography in Women with a Personal History of 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 PS05-06.

Abstract PO3-03-04: Metaplastic breast cancer: a single center retrospective study

Abstract Background: Metaplastic breast cancer (MBC) is a rare malignancy that accounts for up to 1% of all primary invasive breast carcinomas (BC). It is histologically heterogeneous, usually presents with a triple-negative phenotype and comprises low-grade and high-grade (HG) variants. HG variants have a higher risk of recurrence and a shorter disease-free and overall survival compared to other BC subtypes. Our research aimed to estimate the prevalence of HG-MBC among the Slovenian population and determine the characteristics of patients (pts) and tumours and the disease outcome. Patients and methods: Our retrospective study included pts diagnosed with HG-MBC at the Institute of Oncology Ljubljana from January 1983 until January 2021. Clinicopathologic characteristics such as tumour subtype, size and grade, nodal status, hormonal receptors (HR) and HER-2 status, lymphovascular invasion (LVI), tumour-infiltrating lymphocytes (TIL) and presence of germline BRCA mutation status were determined. The survival analyses were performed using the Kaplan-Meier method. The Cox proportional hazard model examined the association between risk factors and survival outcomes. Results: We evaluated 113 HG-MBC pts among a total of 27700 pts diagnosed with BC over 38 years (0.41%). The median age was 61.6 years (range 29.7 -93.9), majority of pts were postmenopausal (78.69%). The median follow-up was 15.5 years. The most common tumour subtype in our cohort was mixed MBC (53 cases, 46.9%), followed by MBC with mesenchymal differentiation (24 cases, 21.2%), squamous cell carcinoma (20 cases, 17.7%) and spindle cell carcinoma (16 cases, 14.2%). From the 113 evaluated pts, we obtained data about the stage in 105 pts, pathological tumour size in 100 pts, number of positive lymph nodes in 99 pts, HR status in 95 pts, HER2 status in 76 pts, grade in 97 pts, LVI in 85 pts, MIB-1 in 41 pts and TIL in 77 pts. At diagnosis, 17/105 pts (16.2%) had stage I disease, 59/105 pts (56.2%) stage II, 25/105 pts (23.8%) stage III and 4/105 pts (3,8%) stage IV. Most tumours were poorly differentiated (90/97, 92.2%) without LVI (60/85, 70.6%). Only 6/95 (6,3%) pts had positive HR, 7/76 (9.2%) pts had positive HER-2 status and 8/77(10.4%) pts intensive TIL. Overall, 13 pts were tested for BRCA germline mutation, among which only 1 (7,7%) had BRCA1 mutation. Modified radical mastectomy was the most frequent type of surgery (63.5%); 49.5% of the patients received radiotherapy. In total, 66/113 pts received CT: from 1983 to 2000, 16/36 (44.4%), and after 2000 50/77 (74.9%). In the first period, most pts received CMF (14/16; 87.5%) and anthracyclines and taxanes (27/50; 54%) in the second period. The disease progressed at 37 pts. At 19 pts, new malignancies were found. 55 pts died, 37 of them because of BC. Five- and 10-year disease-free survival (DFS) was 61.7% and 54.1%, while 5-and 10-year overall survival (OS) was 67.1 % and 56.7%, respectively. However, DFS and OS did not differ between the pre-2000 and post-2000 periods. The best outcome was found in pts with squamous cell carcinoma (5- and 10-year DFS 83.5% and 77.0% and 5-and 10- year OS 89.4 % and 83.0%). A subtype of MBC (squamous cell vs other) was the only predictive factor in multivariate analysis for both DFS (HR 0.21; 95% CI 0.05-0.92; p = 0.038 and OS (HR 0.27; 95%CI 0.09-0.78; p = 0.016), no association was seen between survival and tumour size, nodal status, stage, HR and HER2 status, grade, LVI and TILs. Visceral organs were the most common localization of distant metastases (21/37, 56.8%). Metastases in CNS occurred in 9/37 (24.3%) pts. Median OS after the first progression was only 0.9 years. Conclusions: The proportion of HG-MBC in our cohort of pts is 0.41%. Disease outcomes are poor; the 10-year OS of pts with early HG-MBC is only 56.6% and has not improved during the last decades. Squamous cell differentiation predicts a better outcome and is the only independent predictive factor of DFS and OS among HG-MBC pts. Citation Format: Maša Auprih, Gorana Gasljevic, Eva Setina, Anja Zizek, Simona Borstnar. Metaplastic breast cancer: a single center retrospective 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 PO3-03-04.

Abstract PO3-05-05: The effect of histological breast cancer subtype on progression free survival in patients with CDK4/6 inhibitors

Abstract Background: Multiple trials have proven that adding CDK4/6 inhibitors to endocrine treatment increases progression free (PFS) and overall survival (OS) of patients with metastatic estrogen receptor (ER)-positive HER2 negative breast cancer. However, only limited evidence is available of treatment efficacy of CDK4/6 inhibitors for invasive lobular carcinoma (ILC). This retrospective study aims to compare treatment duration of the three FDA/EMA approved CDK4/6 inhibitors in patients with no special type (NST) breast cancer versus patients with ILC. Methods: All patients with metastatic ER-positive HER2-negative breast cancer who were treated with a CDK4/6 inhibitor (1st, 2nd; 3rd line) in University Hospitals Leuven between December 2014 and February 2023, were included. A comparison of PFS and OS was made between patients with NST and ILC by use of the Kaplan Meier method. Other histological subtypes as well as mixed subtypes were excluded. Uni- and multivariable cox regression models were performed to quantify the association of histological subtype with PFS and OS. Results: A total of 418 patients were included of which 119 (28.5%) patients with ILC (median age at primary diagnosis 59 years, range 36 – 89 years) and 299 (71.5%) patients with NST (median age at primary diagnosis 55 years, range 23 – 90 years). Median follow-up was 26.8 months (range 1.1 – 88.1 months). Median PFS was 15.2 months (range 1.0 – 74.6 months) and 14.7 months (range 1.0 – 89.3 months) for patients with ILC and NST respectively. The OS rate after 60 months follow up was 39.2 % (CI 26.8 – 51.4) for ILC and 40.1% (CI 32.2 – 47.8) for NST. As shown in table 1, clear differences were observed in PFS rates after 12, 24 and 60 months between patients with NST that received CDK4/6 inhibitors in first line versus second or third line. These differences were less apparent for patients with ILC. For both NST and ILC, endocrine resistance at start of CDK4/6 inhibition impacted PFS rates negatively (table 2). In multivariable analyses, histological subtype was not predictive for CDK4/6 inhibition outcome (PFS: hazard ratio (HR) 0.996, CI 0.728 – 1.364, p-value 0.981; OS: HR 0.872, CI 0.602 – 1.263, p-value 0.468). Endocrine sensitivity vs. resistance at the time CDK4/6 inhibitor was started, was proven to be predictive for both PFS (HR 0.478, CI 0.337 – 0.678, p-value < 0.001) and OS (HR 0.528, CI 0.347 – 0.804, p-value 0.003). Conclusion: In our center, the histological subtype of breast cancer did not seem to impact PFS and OS significantly after treatment with CDK4/6 inhibition. Patients with NST seemed to have an increased benefit in PFS from treatment with CDK4/6 inhibition in first line as compared to later lines. While for patients with ILC, no difference between treatment lines were observed. Therefore, clinicians might be able to safely postpone CDK4/6 inhibitors to second- or third-line treatment in patients with metastatic ILC. Table 1: PFS rates by histological subtype and line of CDK4/6 treatment Table 2: PFS rates by histological subtype and endocrine sensitivity at start of CDK4/6 inhibition Citation Format: Cedric Bauters, Karen Van Baelen, Hans Wildiers, Giuseppe Floris, Sileny Han, Patrick Berteloot, Thaïs Baert, Ann Smeets, Ines Nevelsteen, Yannick Van Herck, Anne Deblander, Chantal Remmerie, Lieke Dullens, Maxime Van Houdt, Annouschka Laenen, Christine Desmedt, Patrick Neven. The effect of histological breast cancer subtype on progression free survival in patients with CDK4/6 inhibitors [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 PO3-05-05.

Abstract PO1-04-12: Palbociclib versus ribociclib in first-line treatment of patients with hormone-receptor positive HER2 negative advanced breast cancer – real world outcome data from the German registry platform OPAL

Abstract Introduction CDK4/6 inhibitors (CDKi) plus endocrine therapy (ET) are standard of care in first-line (1L) treatment of hormone receptor-positive (HR+) HER2-negative (HER2-) advanced breast cancer (ABC). In the pivotal trials the three CDK4/6i (palbociclib, ribociclib and abemaciclib) + ET showed similar progression-free survival (PFS) benefit over ET alone. However, other than ribociclib, palbociclib failed to demonstrate overall survival (OS) benefit. As patient (pts) characteristics differed between the trials, especially in the number of pts with treatment-free interval (TFI) of < 12 months after end of adjuvant ET, head-to-head comparisons of the CDKi are of clinical interest. Here we analyze the outcome of pts treated with palbociclib + ET or ribociclib + ET with real-world data from OPAL. Methods OPAL (NCT03417115) is a prospective observational, open, longitudinal multicenter cohort study (clinical registry) in Germany. Pts with ABC and early breast cancer can be recruited at start of their first systemic treatment. There are no treatment restrictions. Sites from all medical sectors can participate in OPAL (medical and gynecologic oncologists from outpatient centers and hospitals). Details on all (sequential) treatments, patient and tumor characteristics, biomarker testing, clinical and patient-reported outcomes are collected. Follow-Up is until death or up to 5 years. Between 01/2018 and 07/2021 1049 pts with HR+ HER2- ABC were recruited by 143 sites. Database cut was on 31/08/2022. 384 pts received palbociclib + ET and 231 pts received ribociclib + ET as 1L treatment. All endocrine combination partners including switch of ET during first line therapy was allowed, whereas switch of CDK4/6i (n=25) were excluded. PFS in registries can differ from PFS in clinical trials, since the RECIST criteria are usually not applied in routine care. PFS in registries represents the time to clinically relevant progression in routine care. PFS and OS were estimated using the Kaplan-Meier method. To adjust for confounding, inverse probability of treatment weighting (IPTW) by propensity score analysis was used to compare PFS and OS between 1L palbociclib+ET and ribociclib+ET. IPTW was performed for the following variables: age, menopausal status, ECOG, any comorbidity, Charlson comorbidity index, metastatic stage, type of metastasis, number of metastatic sites, estrogen-/progesterone status, IHC status, previous chemo-/endocrine therapy, kind of endocrine combination partner, disease-free interval, and treatment-free interval. Results From 2018 to 2021, the proportion of CDK4/6i increased from 68% to 86% in 1L of HR+HER2- ABC. Overall, palbociclib was used in 44% and ribociclib in 26% of all first-line treatments in OPAL. Median age of pts receiving palbociclib/ribociclib was 66/68 years and for 77/81% of pts at least one comorbidity was documented. 37/35% of pts already had metastasis at diagnosis (M1) and 25/26% of pts had a TFI < 12 months. After IPTW, the two treatment groups were comparable for all tested characteristics. 42/46% of patients had a progression (palbociclib/ribociclib group). IPTW-adjusted median PFS was 25.1 months (95% Confidence interval (CI) 20.1 – 30.1) for the palbociclib and 27.0 months (95%-CI 21.1 – 31.6) for the ribociclib group. Hazard ratio was 0.91 (0.71 – 1.17) for palbociclib versus ribociclib. 26/29% of patients had an OS event (palbociclib/ribociclib group). IPTW-adjusted median OS was 36.7 months (95%-CI 33.0 – NA) for the palbociclib and 36.6 months (95%-CI 33.1 – NA) for the ribociclib group. Hazard ratio was 0.95 (0.69 - 1.30) for palbociclib versus ribociclib. Conclusions This analysis of real word data in the OPAL registry platform showed similar PFS and OS for palbociclib + ET compared to ribociclib + ET, when adjusted for a wide range of potential confounding variables. Further analyses will investigate whether one drug showed favorable results in certain subgroups of pts. Citation Format: Marc Thill, Mark-Oliver Zahn, Anja Welt, Arnd Nusch, Matthias Zaiss, Kathrin Engelken, Gabriele Kaltenecker, Kai Ringwald, Katja Gratzke, Lisa Kruggel, Martina Jänicke, Holger Schulz, Christoph Losem, Volker Hagen, Roland Fricker, Elmar Stickeler, Nadia Harbeck, Achim Wöckel, Thomas Decker. Palbociclib versus ribociclib in first-line treatment of patients with hormone-receptor positive HER2 negative advanced breast cancer – real world outcome data from the German registry platform OPAL [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO1-04-12.

Abstract PO5-20-04: A Phase II Study of Ribociclib and Endocrine Treatment of Physician’s Choice for Locoregional Recurrent, Resected Hormone Receptor Positive HER2 Negative Breast Cancer (RaPhLRR Study)

Abstract Background Hormone receptor positive (HR+) breast cancer (BC) is the most common subtype of BC (70-80%). This subset tends to have good prognosis, therefore most patients with localized disease have excellent long-term survival, approaching 100% 5-year relative survival. However, 10% of patients experience loco-regional recurrence (LRR) within 5 year of final surgical management of the primary disease-well within the typical treatment window of adjuvant endocrine therapy. Few studies exists to guide the systemic treatment of patients who have suffered LRR of HR+ HER2 - BC. The randomized controlled CALOR trial demonstrated no benefit to systemic cytotoxic chemotherapy for this subgroup of patients and persistent high rate of subsequent recurrences (50% within 10 years on LRR event). There is no standard of care for managing this patient population. The combination of ribociclib and endocrine therapy (ET) (fulvestrant and aromatase inhibitors) is FDA approved for management of unresectable recurrences and metastatic HR+HER- BC (MONALEESA trials). CDK4/6 inhibitors have been investigated in early BC setting too, several trials showing positive results (monarchE, NATALEE). Data is needed to investigate their use in patients with LRR. Trial design This is a multicenter, single arm phase II study to evaluate efficacy and safety of ribociclib and ET in patients with LRR of HR+HER2- BC. Treatment includes ribociclib for 36 months, 600 mg daily for 21 days, 28-day cycle plus physician’s choice ET for 60 months (fulvestrant or AIs). Ribociclib dose was chosen based on approved dose in metastatic BC. Eligibility Criteria Patients ≥ 18 of age, with LRR of BC (ipsilateral breast, axilla, regional lymph nodes, chest wall), histologically confirmed estrogen receptor positive and/or progesterone receptor positive, HER 2 negative. Patients must have adequate local treatment for LRR (surgery and/or radiation) with negative microscopic margins, no evidence of distant metastatic disease. Prior treatment with neo-adjuvant and adjuvant chemotherapy and ET is allowed, no prior CDK 4/6 inhibitor in the last 12 months. Pre and post-menopausal women are allowed. Patient must enroll within 6 months of the last local therapy. Specific aims Primary objective: to estimate subsequent recurrence-free survival (RFS) at 3 years for ribociclib when administered with ET in patients with HR + HER2- BC with adequately resected local recurrence. Secondary objectives: to estimate distant metastasis-free survival and overall survival, to evaluate safety and tolerability, to identify predictors of LRR. Correlative analysis will explore prognostic and predictive biomarkers of treatment with ribociclib and ET and potential molecular mechanisms of resistance to treatment. Statistical Methods From previous published data (J Clin Oncol. 2018 Apr 10;36(11):1073-1079), we assume that patients receiving standard of-care management following recurrence would have a recurrence free survival (RFS) rate of 80% at 3 years and that treatment with ribociclib + ET will increase it by 7%. We wish to have at least 80% power at that significance level of 0.0487 to correctly detect that improvement in RFS rate at 3 years from 80 to 87%. Because only an improvement in RFS rate is of clinical interest, we have a directional hypothesis, and have used a 1-sided alpha. Using a one-sample survival study design, with assumed accrual duration of 3-years and additional follow-up time of 3 years, the minimum sample size requirement is N=180 patients. Target accrual The minimum sample size requirement is N=180 patients. A bigger sample size of N=200 patients will achieve a power of at least 84%. Current accrual is 6/200. This study will be open at up to 35 sites. Contact information The study is being administered through the HCRN, it can be identified as BRE20-468, NCT05467891, ocdanciu@uic.edu Citation Format: Oana Danciu, Nancy Chan, Kari Wisinski, Trish Millard, Kathleen Kemmer, Sneha Phadke, Zhengjia Chen, Ana Cuesta Fernandez, Melanie Clark, Alison Conlin, Coral Omene, Sima Ehsani, Stephanie Dublis, Vijayakrishna K. Gadi. A Phase II Study of Ribociclib and Endocrine Treatment of Physician’s Choice for Locoregional Recurrent, Resected Hormone Receptor Positive HER2 Negative Breast Cancer (RaPhLRR 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 PO5-20-04.

Abstract PO2-17-08: A RETROSPECTIVE ANALYZES OF 4,885 PATIENTS OF HORMONAL RECEPTOR POSITIVE, HER2 NEGATIVE BREAST CANCER TREATED IN A REFERENCE CENTER, A REAL-WORLD DATA

Abstract Background: Hormonal receptor positive Her2 negative also described as luminal breast cancer (LBC) is the most frequent tumor corresponding to about 60-65% of cases. There is great heterogeneity in these tumors and a great difference between treatments due to lack of access, mainly in developing countries. Clinical trials are important to understand the benefit of the treatments but only 5% of the breast cancer patients are enrolled in these trials and is because of that that Real World Data (RWD) is It's becoming more and more frequent. Objectives: To evaluate LBC and describe treatments and overall survival (OS) of patients treated in public hospital in São Paulo Brazil. Methods: This was a retrospective, single cohort study, that included female patients over 18 years of age, with a diagnosis of LBC. Clinical and pathological data was collected (date of diagnose, first treatment, type of treatment, stage, type of surgery, DFS and OS). This study was approved by our local ethics committee. Results: We’ve enrolled 5,510 patients in Perola Byington ’database from 2010 to 2021. After excluding patients without minimal complete records, a total of 4,885 patients were analyzed. Most patients were diagnosed in stage I (26,9%) and II (38,2%). There was 23,4% in stage III, 3,1% in stage IV and 5,7% in stage 0. In 2,6% the of the patient’s information was not complete. Mean age at diagnosis was 57.6 years. We identified 4,761 (86.4% of 5510) patients who underwent 4,848 surgical procedures. Of the total, 47.2% were mastectomies, 50.9% partial mastectomies and 1.9% were skin sparing mastectomy. Immediate reconstruction was done in 470 patients (69.8% underwent reconstruction with an expander, 22.3% with flap rotation and 7.9% reconstruction with implants). The mean and median time between diagnosis and the beginning of treatment was analyzed, in the sample it was observed that patients who were diagnosed in stages I, II and IV had the same mean of 2.6 months, but stage IV had the lowest median 1 ,9 months. 474 patients were treated in the first line setting during the follow up, 43 % received hormone therapy (HT) and 57% received chemotherapy (CT) as first line. The duration of the treatment in first line was 17,7 months for HT and 7,7 months for CT (p < 0,01). OS for patients diagnosed in stages I and II did not reach the median in the available period, for patients in stages III and IV, a median of 80.4 months and 41.2 months of overall survival was identified, respectively. Conclusions: These are the first results of this large cohort of luminal patients treated in the public reference center. Most patients are diagnosed in stage I or II and more than half undergo conservative surgery. Immediate reconstruction is not routinely performed. In the public setting CDK4/6 inhibitors are not available and that led to more chemotherapy use in first line (57%) and worse survival when compared to clinical trials. Discussions on the incorporation of drugs consolidated in the literature are important to improve the treatment of advanced cancer. Citation Format: Andre Mattar, Marcelo Antonini, Marina Diogenes, Andressa Amorim, Francisco Pimentel Cavalcante, Luiz Henrique Gebrim. A RETROSPECTIVE ANALYZES OF 4,885 PATIENTS OF HORMONAL RECEPTOR POSITIVE, HER2 NEGATIVE BREAST CANCER TREATED IN A REFERENCE CENTER, A REAL-WORLD DATA [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 PO2-17-08.

Abstract PO4-16-11: De-escalation of anthracyclines during adjuvant therapy based on Oncotype RS: A single institution experience in Mexico City

Abstract Introduction: In Mexico, hormone positive HER2 negative breast cancer is the most frequent subtype, accounting for 76.6% of cases. For patients undergoing local control management through surgery; adjuvant chemotherapy is usually followed depending on different risk factors. In order to avoid overtreatment, different genomic firms have been approved aiding in a more objective decision. One of these genomic firms is the Oncotype Recurrence score. The TAILORx and RxPONDER trials have provided guidance in determining which patients are candidates for chemotherapy depending on their menopausal status. However, it has not yet been determined whether patients requiring chemotherapy can receive an anthracycline-free regimen. In the Plan B clinical trial, a non-inferiority analysis was conducted on early-stage breast cancer patients who received anthracycline-based or non-anthracycline-based chemotherapy, with the non-anthracycline regimen being non-inferior, including patients with a RS > 25. We intend to reevaluate these findings in our Mexican population. Methods: We evaluated 217 patients with early stage hormone sensitive HER2 negative breast cancer who had an Oncotype Recurrence score (RS) result. This retrospective cohort study took place by analyzing electronic records from January 2011 to December 2017 with patients treated at the National Cancer Institute in Mexico City. We included patients 18 years of age or older, any sex with an Oncotype RS ≥ 16 in premenopausal patients or ≥ 26 in postmenopausal patients who received adjuvant chemotherapy with or without anthracyclines. Our primary endpoint was iDFS comparing TC vs AC-T. Overall survival was set as a secondary endpoint. Results: Of the 217 patients with an Oncotype recurrence score, only 46 patients received adjuvant chemotherapy of which 71.7% were premenopausal with a median age of 45 years. Stage II was the most common stage with 91.3% of the population, as well as ductal carcinoma with 82.6%. All patients had positive lymph nodes, 54.3% at least 1 lymph node. Most patients received AC-T adjuvant chemotherapy (60.9%), and only 39.1% received TC. Of the 46 patients analyzed, only 19.6% (9) had a recurrence upon follow-up (Table 1). Median time of follow up was 87.5 months. Difference in Disease free survival could not be established between patients receiving AC-T with 105 months (CI 95% 94.36-117.43 months) vs TC with 94.09 months (CI 95% 83.85-104.34 months, < p.918) (Figure 1). Overall survival did not have a statistical difference between both chemotherapy regimens, p< 0.649 (Figure 2A), when comparing Oncotype RS, overall survival was better in those with Oncotype OS < 26, p< 0.023 (Figure 2B). Discusion As described previously in the Plan B trial, TC was non inferior to the conventional adjuvant regimen of AC-T in Hormone positive HER2 negative early-stage breast cancer. Our results tend to show similar results when compared to the Plan B. An important aspect to our study was that 71.7% of our patients were premenopausal, where in the Plan B trial only 35% were premenopausal, considered a higher risk group of patients. Although a statical difference couldn´t be established due to our small sample size, in DFS or OS when comparing the chemotherapy regimen. Premenopausal patients with an Oncotype RS < 26 could receive an anthracycline free regimen, without impact in their overall survival. Larger prospective studies are necessary to assure this conclusion. Figure 1 DFS (TC vs AC-T) Figure 2 A and B Overall Survival Table 1 (Baseline characteristics) Citation Format: Carlos Arturo González Núñez, Paula Cabrera-Galeana, Juan Enrique Bargalló Rocha, Rafael Vazquez-Romo, Sergio Aguilar-Villanueva, Alexandra Garcilazo, Areli Velazquez-Martinez, Andrea Maliachi, Ruben Rodriguez, Esmeralda Romero-Bañuelos. De-escalation of anthracyclines during adjuvant therapy based on Oncotype RS: A single institution experience in Mexico City [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 PO4-16-11.

Immunohistochemical Characterization of Breast Carcinoma: Clinical Correlations, Molecular Subtypes, and Therapeutic Implications

Background: Breast carcinoma exhibits heterogeneity in terms of morphology, molecular, treatment response, and clinical outcomes. The objective of the study was to classify the various malignant breast cancer cases based on their immunohistochemical characteristics and understand their association and behavior, which may be useful for predicting treatment and prognosis. Methods: In this study, 12808 malignant breast cancer cases were studied based on hormone receptor IHC biomarkers, age, gender, histological type, grade and molecular classifiers. Results: The mean age of patients was 53.63+13.08 years, around 45.43% were grade 3 tumors and the invasive duct carcinoma of non-specified type (NST) was the most common type seen (93.83%). ER positivity was 83.89% in grade 1, 69.9% in grade 2, and 36.86% in grade 3 tumors, and the overall PR and Her-2 positivity was 47.06% and 18.67%, respectively. A relatively higher percentage of Triple Negative cases was seen (36.58%), followed by 25.43% Luminal A cases. There was a significant association between molecular subtypes with respect to age, gender, Scarff Bloom Richardson (SBR) grade, and histological type (P<0.0001). Overall, grade 3 tumor cases were most common, the majority of which were Triple Negative. Maximum cases of triple negative tumors were seen among women, being mostly concentrated in younger age group i.e. <40 years. Conclusion: Immunohistochemistry for hormone receptor positivity remains the mainstay of diagnosis and molecular sub-classification. The hormone response of tumors is important prognostically, in predicting the treatment outcomes. Going further, molecular analysis and gene expression studies can further augment the histopathological diagnosis to assist strategies of targeted therapy and precision medicine resulting in better patient outcomes.

Neoadjuvant chemotherapy for triple-negative and Her2 +ve breast cancer: striving for the standard of care.

Neoadjuvant chemotherapy (NAC) for triple-negative (TN) and Her2-positive (HER2) breast cancers is supported by international guidelines as it can decrease extent of surgery, provide prognostic information, and allow response-driven adjuvant therapies. Our goal was to describe practice patterns for patients with TN and HER2-positive breast cancer and identify the factors associated with the receipt of NAC versus surgery as initial treatment. A retrospective population-based cohort study of adult women diagnosed with stage I-III TN or HER2-positive breast cancer (2012-2020) in Ontario was completed using linked administrative datasets. The primary outcome was NAC as first treatment. The association between NAC and patient, tumor, and practice-related factors was examined using multivariable logistic regression models. Of 14,653 patients included, 23.9% (n = 3500) underwent NAC as first treatment. Patients who underwent NAC were more likely to be younger and have larger tumors, node-positive disease, and stage 3 disease. Of patients who underwent surgery first, 8.8% were seen by a medical oncologist prior to surgery. On multivariable analysis, increasing tumor size (T2 vs T1/T0: 2.75 (2.31-3.28)) and node-positive (N1 vs N0: OR 3.54 (2.92-4.30)) disease were both associated increased odds of receiving NAC. A considerable proportion of patients with TN and HER2-positive breast cancer do not receive NAC as first treatment. Of those, most were not assessed by both a surgeon and medical oncologist prior to initiating therapy. This points toward potential gaps in multidisciplinary assessment and disparities in receipt of guideline-concordant care.

SLC35A2 expression is associated with HER2 expression in breast cancer

The role of SLC35A2 in breast cancer remains poorly understood, with limited available information on its significance. This study aimed to investigate the expression of SLC35A2 and clinicopathological variables in breast cancer patients. Immunohistochemical analysis of SLC35A2 protein was conductedon 40 adjacent non-neoplastic tissues and 320 breast cancer tissues. The study also assesed the association between SLC35A2 expression and breast cancer clinicopathological features of breast cancer, as well as its impact on overall survival. In comparison to adjacent non-neoplastic tissues, a significantly higher expression of SLC35A2 was observed in breast cancer tissues (P = 0.020), and this expression was found to be independently correlated with HER2 positivity (P = 0.001). Survival analysis indicated that patients with low SLC35A2 expression had a more favorable prognosis in HER2-positive subtype breast cancer (P = 0.017). These results suggest that SLC35A2 is overexpressed in breast cancer tissues compared to adjacent non-neoplastic tissues and may serve as a potential prognostic marker for HER2-positive subtype breast cancer. Furthermore, breast cancer patients with the HER2 positive subtype who exhibited decreased levels of SLC35A2 expression demonstrated improved long-term prognostic outcomes.

Estrogen Receptor, Progesterone Receptor, and Human Epidermal Growth Factor Receptor 2 Expression Rates in Invasive Breast Carcinoma: A Study of 21 Institutions.

Laboratories performing predictive marker testing for breast carcinoma are encouraged to compare patient results to published benchmarks. To collect expression rates for estrogen receptor (ER), progesterone receptor (PgR), and human epidermal growth factor receptor 2 (HER2) in invasive breast carcinoma from multiple laboratories. Participants submitted data from up to 50 primary cases during the study period. Participants reported ER, PgR, and HER2 results in addition to demographic and histologic information. Participants also provided annual institution-level expression rates. A total of 21 institutions submitted data for 687 cases. Aggregate positivity rates for ER and PgR were 85.6% and 75.1%, respectively. Receptor positivity rates were higher in well-differentiated (grade 1) tumors (ER, 97.4%; PgR, 88.0%) compared with moderately differentiated (grade 2) tumors (ER, 92.4%; PgR, 84.0%) and poorly differentiated (grade 3) tumors (ER, 61.8%; PgR, 48.0%). Expression rates were higher in postmenopausal women (ER, 87.2%) than premenopausal women (ER, 79.6%) and higher in lobular carcinomas (ER, 98.7%; PgR, 85.3%) than ductal carcinomas (ER, 84.1%; PgR, 74.5%). The aggregate HER2 positivity (score 3+) rate was 9.0%. The aggregate HER2 equivocal (score 2+) rate was 14.5%. Of 81 equivocal (score 2+) cases, 70 (86.4%) were nonamplified. The data from this study provide multi-institutional benchmark data to assist laboratories performing periodic comparisons as part of a quality management program. Overall expression rates were generally similar to those of other published reports, with the exception of the ER-negative and HER2-positive rates, both of which were somewhat lower.