Werner, Olena

Abstract Background: In HER2-positive breast cancer patients, timing from the end of (neo)adjuvant trastuzumab (T)-based therapy to diagnosis of metastatic breast cancer is the key factor in determining the optimal first-line treatment. There is currently lack of clear evidence to support the possible prognostic role of this interval and 12 months has been mostly empirically used. The present analysis aimed to investigate patterns of relapse, first-line choice and survival outcomes of patients with HER2-positive early breast cancer who relapsed after adjuvant T-based therapy depending on T-free interval (TFI, i.e. timing from end of adjuvant T to diagnosis of distant metastases). Methods: In ALTTO, HER2-positive early breast cancer patients were randomized to 1 year of either T alone, lapatinib (L) alone, their sequence (T–>L) or their combination (T+L). This exploratory analysis included only pts in the T or T+L arms who experienced a distant disease-free survival (DDFS) event. Two cohorts of patients were defined depending on TFI: group A (TFI of <12 months) and group B (>12 months). Baseline characteristics, patterns of relapse, first-line choice and overall survival (OS) were compared. OS was defined as time between date of DDFS event to death; age at diagnosis, tumor size and hormone receptor status were the variables included in the final multivariate models. Results: Out of 8,381 patients included in ALTTO, 404 patients in the T and T+L arms developed a DDFS event, of whom 201 occurred <12 months (group A) and 203 >12 months (group B) after the end of adjuvant T. Patients in group A were older (p=0.013), had larger tumors (p=0.004) and more frequently hormone receptor-negative disease (p<0.001). No significant difference in patterns of first DDFS event was observed (p=0.073); however, a numerically higher number of patients in group A compared to group B developed brain metastasis (26% vs. 15%). First-line anti-HER2 therapy was received by 57% of the patients. Choice of first-line anti-HER2 therapy was different between the two groups (p=0.022): the majority of patients received T in both groups (61% vs. 65% in groups A and B, respectively), while more patients in group A received L (25% vs. 11%) and less received pertuzumab (8% vs. 17%). OS survival was significantly shorter in group A compared to group B: median OS was 18.4 and 29.3 months in groups A and B, respectively (adjusted HR 0.69; 95% CI 0.54-0.89; p=0.004). Similar results were observed after the exclusion of patients treated with first-line pertuzumab-based therapy (n=29): median OS was 18.2 and 26.8 months in groups A and B, respectively (adjusted HR 0.66; 95% CI 0.51-0.86; p=0.002). Better outcomes in terms of OS for patients in group B was observed across all analyzed subgroups with no interaction according to hormone receptor status (p=0.814) nor type of adjuvant anti-HER2 treatment (p=0.233): hormone receptor-positive (adjusted HR 0.69; 95% CI 0.48-0.99), hormone receptor-negative (adjusted HR 0.68; 95% CI 0.48-0.98), T+L arm (adjusted HR 0.55; 95% CI 0.38-0.80) and T arm (adjusted HR 0.80; 95% CI 0.55-1.17). Conclusions: In the ALTTO trial, HER2-positive early breast cancer patients who experienced shorter TFI (i.e. <12 months vs. >12 months) following adjuvant T-based therapy had inferior OS after the diagnosis of distant recurrence. Given its prognostic value, TFI can help to individualize clinical recommendations and to design future trials in the metastatic setting for patients relapsing after prior exposure to anti-HER2 therapy for early disease. Citation Format: Matteo Lambertini, Dominique Agbor-Tarh, Otto Metzger-Filho, Noam Ponde, Francesca Poggio, Florentine Hilbers, Larissa A Korde, Saranya Chumsri, Olena Werner, Lucia Del Mastro, Rafael Caparica, Volker Moebus, Alvaro Moreno-Aspitia, Martine Piccart, Evandro de Azambuja. Prognostic role of distant disease-free interval from completion of adjuvant trastuzumab in HER2-positive early breast cancer: Analysis from the ALTTO (BIG 2-06) trial [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PD3-04.

11553 Background: Little is known about the toxicity of trastuzumab (T) or of trastuzumab + lapatinib (T + L), approved in the advanced setting, in older pts. We have performed a sub-analysis of the Adjuvant Lapatinib and/or Trastuzumab Treatment Optimisation (ALTTO) trial focused on treatment completion and toxicity of T and T+L in older pts (aged ≥65 years (yr)). Methods: The ALTTO trial (NCT00490139, NCCTG N063D) randomised 8381 pts with early HER2+ BC into 4 arms and we included the T and T+L arms in our analysis. Eligible pts for our study were those having received at least one dose of assigned treatment. Treatment completion was evaluated through the rate of temporary treatment interruptions (TTI), permanent treatment discontinuations (PTD) and lapatinib dose reductions (LDR). Toxicity was evaluated via a selected set of adverse events of interest (AEIs). Risk factors for TTI, PTD, LDR and AEIs were assessed, including comorbidities and polypharmacy at baseline (defined as use 5 or more co-medications) and AEIs during treatment. Results: A total of 430 pts≥65-year-old were identified for this sub-analysis, out of a total of 4190 pts with a median age of 68 yrs (range 65-80). Older pts were more likely to have comorbidities (70% vs 38%). Treatment completion was worse among older pts in the T+L arm but not in the T arm (Table). AEIs were more common in the T+L arm in all patients, with older patients having higher AEI rates (78.04% in older vs 63.38% in younger), particularly diarrhea (60.75% vs 38.0%). Identified risk factors (multivariate) for worse treatment completion in the T and T+ L arms included concomitant use of chemotherapy and the occurrence of grade 3 adverse events, among others. Conclusions: T + L has worse treatment completion and is more toxic in older patients, while T was well tolerated. Identifiable risk factors at baseline and during the course of treatment could be used to aid in regimen selection and management for both T and T + L in their respective indications. Support: UG1CA189823, Novartis;https://acknowledgments.alliancefound.org. [Table: see text]

Abstract Background: The level of immune suppression in an individual breast cancer (BC) patient is relevant for having a major benefit from treatments that act via or are directed to the immune response, such as anti-HER2 agents and immune checkpoint molecules, respectively. The link(s) between the tumor immune microenvironment and treatment responses has been investigated in HER2-positive BC. This study analyzed the association between baseline expression of genes regulating T cell activities (PD1, CTLA4, LAG3, TIM3, PDL1, PDL2, FOXP3, IL10, TGFβ (1-3), FOXP1 and other related genes) and pathologic complete response (pCR) rates in the NeoALTTO trial. Methods: NeoALTTO randomized early-stage HER2-positive BC patients to neoadjuvant trastuzumab (T), lapatinib (L) or T+L for 6 weeks followed by 12 weeks of concurrent paclitaxel. Anthracyclines were given after surgery (FEC). Patients with RNA sequencing data from their baseline tumor samples (N=254 patients out of 455 from the original cohort) were included in the current study. The primary endpoint, pCR, was defined as ypT0/is ypN0. Logistic regression was used for analysis of pCR. Cox regression univariate and multivariate (adjusted for clinicopathological parameters and treatment arms) analyses were performed. Results: In the total cohort analyzed, high PD1 (odds ratio, OR: 1.4, P=0.03), PDL2 (OR: 1.4, P=0.04), CTLA4 (OR: 1.4, P=0.03) and TGFβ3 (OR: 1.4, P=0.02) expression was associated with an increased probability of achieving pCR at the multivariate analysis. ERBB2 (HER2) expression was associated with pCR in the three arms (T: OR: 2.7, P=0.02; L: OR: 2.3, P=0.01; T+L: OR: 5, P<0.001). Additionally in the T+L arm, PAM50 HER2-enriched subtype (OR: 2.9, P=0.03), as well as immune genes PD1 (OR: 2.1, P=0.01), PDL1 (OR: 1.8, P=0.03) and CTLA4 (OR: 2; P=0.01), were also associated with pCR. Conclusions: In the NeoALTTO population examined, PD1, PDL2, CTLA-4 and TGFβ3 expression at diagnosis were all associated with improved pCR rates after anti-HER2 treatment. The effect of these treatments seemed to be dependent on HER2 expression levels, which was particularly relevant in the T+L arm. These observations confirm previous findings that link immune infiltrates to higher pCR rates, demonstrate the clinical significance of the PD-1 pathway and additionally show that CTLA-4 and TGFβ3 could also be important in early stage HER2-positive BC. The association of tumors linked with immune regulatory gene expression with positive responses to neoadjuvant anti-HER2 agents suggests that they act in a way that reinvigorates the antitumor immunity in the face of tumor-mediated suppression. Patients whose tumors highly express these genes may be good candidates for immunotherapy before the start or after the neoadjuvant treatment when residual disease is detected at surgery, although these hypotheses require further confirmation. Citation Format: Cinzia Solinas, Pushpamali De Silva, David Venet, Soizic Garaud, Chunyan Gu-Trantien, Florentine Hilbers, Evandro de Azambuja, Olena Werner, Lorena De la Peña, Amylou Dueck, Serena Di Cosimo, Istvan Lang, Jens Huober, Sherko Küemmel, Carsten Denkert, Roberto Salgado, Christos Sotiriou, Martine Piccart-Gebhart, Debora Fumagalli, Karen Willard-Gallo. Immune regulatory gene expression and clinical outcome in the NeoALTTO trial [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3132.