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Background: Hormone-receptor (HR)+/HER2- breast cancer (BC) is a biologically heterogeneous disease. Homologous recombination deficiency (HRD) and BRCA mutations have been previously reported to be associated with worse outcomes in HR+/HER2- metastatic BC patients receiving CDK4/6 inhibitors and endocrine therapy. Here, we assess the relation between HRD and RB-loss signatures, intrinsic subtyping, the PAM50-based chemo-endocrine score, and response to chemotherapy-based therapy and endocrine treatment in HR+/HER2- early BC. Methods: GIADA is a multicentric neoadjuvant phase II trial that treated premenopausal patients with Luminal B (LumB)-like BC (HR-positive, HER2-negative, with Ki67>20% and/or histologic Grade 3) with a combination of chemotherapy, immunotherapy and endocrine treatment. Expression of 758 genes on baseline tumor samples from all 43 patients was quantified by nCounter platform. The LETLOB phase II trial randomized postmenopausal women with clinical stage II-IIIA HR+/HER2- BC to neoadjuvant letrozole + lapatinib or letrozole + placebo for 6 months (Guarneri, JCO 2014). Gene-expression data (Affymetrix platform) from pre-treatment frozen core-biopsies was available from 66 out of 92 pts enrolled. Intrinsic subtype was assigned using a research-based PAM50 subtype predictor. A published HRD signature (Peng, Nat Commun 2014) and a signature of RB loss (RBsig), previously reported to potentially predict resistance to CDK4/6 inhibitors in HR+/HER2- BC (Malorni, Oncotarget 2016) were computed. The PAM50 based chemo-endocrine score (CES) was calculated using published definition (Prat, CCR 2017). Higher values of CES indicate increased endocrine sensitivity, while lower values indicate chemosensitivity. Association between genomic signatures was assessed through Pearson’s correlation coefficient. Association of genomic signatures with pCR was assessed through logistic regression and association with PEPI scores was assessed through Kruskal-Wallis test. Results: HRD signature levels were significantly higher in non-luminal (Basal-like and HER2-enriched) tumors as compared to Luminal (A or B) tumors (p>0.001 in the GIADA trial, p=0.021 in the LETLOB trial). Moreover, higher levels of HRD signature were associated with higher levels of RB-loss signature (Pearson correlation 0.355, p=0.020 in the GIADA trial; Pearson correlation 0.942, p< 0.001 in the LETLOB trial), higher levels of Basal-like signature (Pearson correlation 0.502, p< 0.001 in the GIADA trial; Pearson correlation 0.373, p=0.002 in the LETLOB trial) and lower levels of CES (Pearson correlation -0.422, p=0.005 in the GIADA trial; Pearson correlation -0.763, p< 0.001 in the LETLOB trial), indicative of higher chemosensitivity. In the GIADA trial, higher levels of HRD signature (p=0.018) and RBloss signature (p=0.073) and lower levels of CES (p=0.007) were associated with higher pCR rates after chemo, endocrine and immunotherapy. In the LETLOB trial, lower levels of HRD signature (p=0.068) and RBloss signature (p=0.042) and higher levels of CES (p=0.050) were associated with higher sensitivity to endocrine treatment (lower PEPI scores, 0 vs 1-3 vs 4 or more, after neoadjuvant letrozole). Conclusions: In HR+/HER2- early BC, HRD gene signatures, RB-loss gene signatures and non-luminal (especially Basal-like) intrinsic subtyping are associated with each other and associated with higher sensitivity to chemotherapy-based therapy and lower sensitivity to endocrine treatment. These observations might help correctly tailor systemic therapy, including biologic agents, in patients with HR+/HER2- early and advanced BC. Citation Format: Gaia Griguolo, Federica Miglietta, Laia Paré, Daniele G. Generali, Antonio Frassoldati, Antonino Musolino, Simon Spazzapan, Grazia Vernaci, Tommaso Giarratano, Marcello Lo Mele, Giancarlo Bisagni, Federico Piacentini, Enrico Tagliafico, Katia Cagossi, Francesca Schiavi, Claudia Pinato, Aleix Prat, Valentina Guarneri, Maria Vittoria Dieci. Homologous recombination deficiency, RB-loss gene signatures, intrinsic subtype and response to neoadjuvant treatment in HR+/HER2- early breast cancer: a correlative analysis of two phase II trials [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P4-02-13.

Background: Trastuzumab + pertuzumab + taxane and ado-trastuzumab emtansine (T-DM1) are standard first and second-line therapies for HER2+ metastatic breast cancer. Lapatinib is approved in combination with capecitabine in trastuzumab-resistant patients and in combination with letrozole in hormone receptor positive HER2+ pts for whom endocrine treatment is indicated. In Italy, L is also approved in combination with trastuzumab for hormone receptor-negative HER2+ pts. There are only few data on the activity of lapatinib in pts who received prior pertuzumab and /or T-DM1. Methods: We retrospectively analysed HER2+ metastatic breast cancer pts who received lapatinib after prior pertuzumab and/or T-DM1 from July 2013 to June 2018. Objective response rate (ORR) was assessed according to RECIST 1.1. Progression-free survival (PFS) was calculated from lapatinib-based therapy starting to disease progression (PD) or last follow-up. Overall Survival (OS) was calculated from lapatinib-based therapy starting to death or last follow up. Results: Data from 32 HER2+ mBC treated with lapatinib-based therapy were recorded: 30 pts (94%) received lapatinib combined with capecitabine, 1 pt received lapatinib combined with letrozole and 1 pt received lapatinib combined with trastuzumab. All patients had been treated with prior T-DM1 and 9 (28%) with prior pertuzumab for metastatic breast cancer. Setting of treatment with lapatinib-based therapy was: 2° line (n=2, 6%), 3° line (n=17, 53%) and >4° line (n=13, 41%). Patients characteristics were as follows: median age 55 years (range 35-71), hormone receptor positive 66% (n=21), stage IV at diagnosis 34% (n=11), visceral involvement at lapatinib-based therapy starting 91% (n=29). As of June 2018, lapatinib-based therapy was ongoing for 4 pts and 28 pts discontinued treatment due to disease progression (median number of courses for these pts was 8.5, range 2-27). ORR in evaluable pts was: complete response (n=1, 3%), partial response (n=13, 41%), stable disease (n=9, 28%), disease progression (n=9, 28%). Median PFS was 6.4 months (95% CI 3.0-9.8). As of June 2018, 14 pts (44%) were alive, median OS was 11.8 months (95% CI 9.9-13.6). Conclusion: These results confirm that lapatinib-based therapy retains clinical efficacy in HER2+ metastatic breast cancer pts treated with prior pertuzumab and/or T-DM1 and represents a valid therapeutic option in this setting. Citation Format: Frezzini S, Giarratano T, Dieci MV, Giorgi CA, Griguolo G, Vernaci G, Menichetti A, Mantiero M, Tasca G, Faggioni G, Falci C, Miglietta F, Mioranza E, Angelini S, Ghiotto C, Conte P, Guarneri V. Lapatinib-based therapies after pertuzumab and/or T-DM1 for HER2+ metastatic breast cancer patients [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P6-18-24.

Background: The integration of Residual Cancer Burden (RCB) and post-treatment Ki67 (Residual Proliferative Cancer Burden [RPCB] index) has been proposed as a stronger predictor of long-term outcome in unselected breast cancer (BC) patients undergoing neoadjuvant chemotherapy (NACT), as compared to RCB. However, no specific analysis in the subgroup of patients with hormone-receptor (HR)-positive/HER2-negative BC is available so far. We investigated the prognostic value of RPCB in an independent cohort of hormone-receptor (HR) positive/HER2 negative BC patients treated with NACT at our Institution. Methods: A cohort of 130 stage II-III, HR+/HER2 negative BC patients who underwent NACT between 2000 and 2014 was included. Archival surgical specimens were evaluated for RCB (Symmans et al. J Clin Oncol 2007). RPCB was calculated by combining RCB and Ki67 as previously described (Sheri et al, Ann Oncol 2015). Patients were categorized in 4 RCB categories (pathological complete response -pCR- and RCB tertiles) and 4 RPCB categories (pCR and RPCB tertiles). Disease-free Survival (DFS) and overall Survival (OS) estimates were determined by Kaplan-Meier analysis and compared using the log-rank test. The c-index was used to compare the performance of the prognostic models. Results: Patients characteristics were: ductal histology 70%, Grade 3 41%, Stage III 54%, PgR negative (≤10%) 35%, median Ki67 at diagnosis 25%. Neoadjuvant chemotherapy included both anthracycline and taxane in 92% of cases. The rate of pCR was 8%. The vast majority of patients received adjuvant endocrine therapy (96%), whereas 30% received further adjuvant chemotherapy. Median follow up was 8.5 years (95% CI 8.0-9.0). RCB was calculated for 105 patients and RPCB was calculated for 85 patients. RPCB was better than RCB in predicting both DFS and OS (5-year DFS and 8-year OS according to RPCB and RCB are reported in the Table). The c-index for DFS prediction was numerically higher for RPCB vs RCB (0.4042316 vs 0.3396437, p=0.08). Similar results were observed for OS prediction: c-index 0.3099490 (RPCB) vs 0.2372449 (RCB), p=0.08. Conclusions: This is the first study evaluating RPCB specifically in HR+/HER2- BC patients treated with NACT. In this independent cohort, after a median follow up of 8.5 years, RPCB was a strong predictor of DFS and OS. The better performance of RPCB vs RCB was in part due to the ability of RPCB to discriminate a subgroup of patients with a particularly worse prognosis after NACT, who may be candidate for clinical trials evaluating novel adjuvant treatments. Five-year DFS and eight-year OS according to RPCB and RCB5-year DFSp-value8-year OSp-valueRPCBpCR100%0.041100% Citation Format: Federica Miglietta, Vassilena Tsvetkova, Maria Vittoria Dieci, Gaia Griguolo, Grazia Vernaci, Alice Menichetti, Cristina Falci, Giovanni Faggioni, Tommaso Giarratano, Simona Frezzini, Eleonora Mioranza, Marcello Lo Mele, PierFranco Conte, Valentina Guarneri. Validation of residual proliferative cancer burden (RPCB) as a predictor of long-term outcome following neoadjuvant chemotherapy in hormone-receptor positive/HER2 negative breast cancer patients [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P5-06-12.