Dual anti-HER2 Blockade Research Articles

Does definitive local therapy have a role in select HER2+ de novo metastatic breast cancer patients treated with dual anti-HER2 blockade?

The role of surgery with curative intent in HER2+ de novo metastatic breast cancer (dnMBC) is uncertain in the era of dual antibody therapy. We sought to determine from existing retrospective data current practice patterns and if an association exists between surgery to the primary tumor and improved survival in HER2+ dnMBC patients treated with dual anti-HER2 blockade, accounting for selection bias. This study employed data from the National Cancer Database (NCDB) from the years 2013 to 2015. Study inclusion was limited to adult women with HER2+ dnMBC, who received immunotherapy/biologic response modifier drugs (BRM) as a first line treatment. Patients who received both systemic therapy and surgery to the primary breast tumor and patients who received systemic therapy alone were analyzed in two groups. Chi-square test for discrete variables and Wilcox on Rank-Sum test for numeric variables was used to compare the two groups based on patient, tumor, and treatment characteristics. The primary endpoint was overall survival from the time of diagnosis to the time of death. 928 women with HER2+ dnMBC treated with BRM were identified with 43.5% (n = 404) receiving surgery and 56.5% (n = 524) receiving systemic therapy alone. The 3-year overall survival was superior for the surgery group (74.1%, 95% CI 67.9-79.2%) compared to the no surgery group (53.3%; 95% CI 47.6-58.6%). The no surgery group had median overall survival of 39.8months (95% CI 34.1-44.9), while the surgery group had not yet reached median overall survival. In a group of HER2+ dnMBC patients receiving systemic treatment in the era of dual antibody therapy, patients who underwent surgery had a superior 3-year survival rate than those who did not. There may be a role for a prospective trial in HER2+ dnMBC patients with an excellent response to dual HER2 blockade to investigate the contribution of curative intent local therapy to the primary tumor compared to systemic therapy alone.

Suggested Modifications to the Management of Patients With Breast Cancer During the COVID-19 Pandemic: Web-Based Survey Study.

BackgroundManagement of patients with cancer in the current era of the COVID-19 pandemic poses a significant challenge to health care systems. Breast cancer is the most common cancer internationally. Breast cancer is a disease that involves surgery, chemotherapy, hormonal therapy, targeted therapy, radiotherapy, and, more recently, immunotherapy in its management plan. The immune system requires months to recover from these medications, and this condition is even worse in patients with metastatic breast cancer who need ongoing treatment with these drugs. Some of these drugs, such as inhibitors of cyclin-dependent kinases 4 and 6, can cause rare but life-threating lung inflammation. Patients with breast cancer who have metastatic disease to the lungs can experience deterioration of disease symptoms with COVID-19 infection. Oncologists treating patients with breast cancer are facing a difficult situation regarding treatment choice. The impact that COVID-19 has had on breast cancer care is unknown, including how to provide the best care possible without compromising patient and community safety.ObjectiveThe aim of this study was to explore the views of oncologists regarding the management of patients with breast cancer during the COVID-19 pandemic.MethodsA web-based SurveyMonkey questionnaire was submitted to licensed oncologists involved in breast cancer management in Saudi Arabia, Egypt, and United Arab Emirates. The survey focused on characteristics of the participants, infection risk among patients with cancer, and possible treatment modifications related to different types of breast cancer.ResultsThe survey was completed by 82 participants. For early hormone receptor (HR)–positive, human epidermal growth factor receptor 2 (HER2)–negative breast cancer, 61 of the 82 participants (74%) supported using neoadjuvant hormonal therapy in selected patients, and 58% (48/82) preferred giving 6 over 8 cycles of adjuvant chemotherapy when indicated. Only 43% (35/82) preferred inhibitors of cyclin-dependent kinases 4 and 6 with hormonal therapy as the first-line treatment in all patients with metastatic HR-positive disease. A total of 55 of the 82 participants (67%) supported using adjuvant trastuzumab for 6 instead of 12 months in selected patients with HER2-positive breast cancer. For metastatic HER2-positive, HR-positive breast cancer, 80% of participants (66/82) supported the use of hormonal therapy with dual anti-HER2 blockade in selected patients. The preferred choice of first-line treatment in metastatic triple negative patients with BRCA mutation and programmed cell death 1 ligand 1 (PD-L1) <1% was poly(adenosine diphosphate–ribose) polymerase inhibitor according to 41% (34/82) of the participants, and atezolizumab with nab-paclitaxel was preferred for PD-L1 >1% according to 71% (58/82) of the participants.ConclusionsSeveral modifications in breast cancer management were supported by the survey participants. These modifications need to be discussed on a local basis, taking into account the local infrastructure and available resources.

Cardiac safety of dual anti-HER2 blockade with pertuzumab plus trastuzumab (P+T) in the APHINITY trial.

510 Background: Trastuzumab (T) increases the incidence of cardiac events (CEs) in patients (pts) with early breast cancer (BC). Dual blockade with P+T improves BC outcomes and is the standard of care for high-risk HER2-positive BC pts following the phase 3 APHINITY trial that evaluated the addition of P or placebo (Pla) to T and chemotherapy (CT). We analyzed the cardiac safety of P+T in APHINITY. Methods: APHINITY eligibility required a left ventricular ejection fraction (LVEF) ≥55% at study entry. LVEF assessment was performed every 3 months (mos) during treatment, every 6 mos up to month 36, and yearly thereafter. Primary CE was defined as heart failure (HF) class III/IV and a significant decrease in LVEF of at least 10 percentage points from baseline and to &lt;50%, or cardiac death. Secondary CE was defined as a confirmed significant decrease in LVEF or CEs confirmed by the cardiac advisory board. Results: The safety analysis population consists of 4,769 pts. With 74 mos median follow-up (FU), CEs were observed in 159 pts (3.3%): 83 (3.5%) in the P+T and 76 (3.2%) in Pla+T arms, respectively. Most CEs occurred during anti-HER2 therapy: 123/159 (77.4%) and were asymptomatic or mildly symptomatic LVEF decrease (133/159; 83.6%) (Table 1). There were 2 cardiac deaths in each arm (0.1%). More CEs occurred in pts receiving an anthracycline-based CT compared to those receiving non-anthracycline CT (139 vs. 20 CEs, respectively). Acute recovery from a CE based on subsequent LVEF values was observed in 127/155 pts (81.9%). Conclusions: Dual blockade with P+T does not increase the risk of CE compared to Pla+T alone. The use of anthracycline-based CT increases the risk of a CE; hence non-anthracycline CT may be considered particularly in pts with other cardiovascular risk factors. Clinical trial information: NCT01358877. [Table: see text]

EXPERIENCE OF USING PERTUZUMAB IN ANTICANCER THERAPY FOR HER2-POSITIVE BREAST CANCER

Background . Breast cancer is one of the most common malignancies and one of the leading causes of cancer deaths among women in the Russian Federation. The prognosis of the disease is largely determined by the biological subtype of the tumor. Her2-positive breast cancer is characterized by an aggressive course and unfavorable prognosis. The use of pertuzumab, a recombinant humanized monoclonal antibody to the human epidermal growth factor receptor 2, significantly improved immediate and long-term treatment outcomes. The aim of the study was to evaluate treatment outcomes in patients with Her2-positive molecular subtype of breast cancer receiving chemotherapy combined with a dual anti-Her2 blockade, and to assess the intensity and incidence of side effects. Material and methods . Between 2015 and 2018, 37 patients with Her2-positive breast cancer received chemotherapy combined with a dual anti-HER2 blockade (docetaxel 75 mg/m2 i/v on day 1 + trastuzumab 6 mg/kg (loading dose 8 mg/kg) i/v on day 1 + pertuzumab 420 mg (loading dose 840 mg) i/v on day 1 once every 3 weeks). The mean age of the patients was 45.6 ± 11.6 years. Results. Neoadjuvant pertuzumab in combination with trastuzumab and docetaxel resulted in pathological complete response in 12 % of patients and pathological partial response in 36 % of patients. Among patients who received the above neoadjuvant therapy regimen, disease progression was observed in 4 % of patients. The most common side effects were weakness and fatigue (5.4 % of cases) and grade I–II leukopenia (5.4 %). Conclusion. The study demonstrated the efficacy of antitumor therapy with pertuzumab in combination with trastuzumab and docetaxel as well as the absence of severe side effects associated with this treatment regimen in patients with Her2-positive breast cancer.

LBA2 Impact of RNA expression signatures and tumour infiltrating lymphocytes (TILs) for pathological complete response (pCR) and survival after 12 week de-escalated neoadjuvant pertuzumab + trastuzumab ± paclitaxel in the WSG-HER2+/HR- ADAPT trial

Limited data are available on predictive biomarkers for dual anti-HER2 blockade in HER2+/HR- early breast cancer (BC). The present analysis aimed to identify associations of biological signatures and stromal TILs (sTILs) with pCR and survival in phase II WSG-ADAPT HER2+/HR- trial (NCT01779206).

The Pan-Immune-Inflammation-Value Predicts the Survival of Patients with Human Epidermal Growth Factor Receptor 2 (HER2)-Positive Advanced Breast Cancer Treated with First-Line Taxane-Trastuzumab-Pertuzumab.

Simple SummaryAlthough taxane-trastuzumab-pertuzumab combinations in the first-line treatment setting significantly improved clinical outcomes in patients with Human Epidermal growth factor Receptor 2 positive (HER2+) advanced breast cancer (aBC), their clinical efficacy is highly heterogeneous, and reliable biomarkers of benefit from this treatment are lacking. Different peripheral blood parameters have emerged as prognostic biomarkers in breast cancer, but their predictive role in HER2+ BC patients receiving dual anti-HER2 blockade remains unclear. In this work, we identified the Pan-Immune-Inflammatory Value (PIV), a recently defined parameter, taking into account peripheral blood neutrophil, platelet, monocyte and lymphocyte counts, as an independent predictor of worse OS in patients with HER2+ aBC receiving first line trastuzumab-pertuzumab biochemotherapy. The PIV outperforms other well-known peripheral blood parameters, thus potentially representing a new tool to improve the prognostic stratification of HER2+ aBC patients in a first-line treatment setting.Different peripheral blood parameters have emerged as prognostic biomarkers in breast cancer (BC), but their predictive role in Human Epidermal growth factor Receptor 2 positive (HER2+) advanced BC (aBC) patients receiving dual anti-HER2 blockade remains unclear. We evaluated the impact of the Pan-Immune-Inflammatory Value (PIV), defined as the product of peripheral blood neutrophil, platelet, and monocyte counts divided by lymphocyte counts, on the prognosis of HER2+ aBC patients treated with first line trastuzumab-pertuzumab-based biochemotherapy. We also evaluated the association between the neutrophil-to-lymphocyte ratio (NLR), the platelet-to-lymphocyte ratio (PLR), and the monocyte to lymphocyte ratio (MLR) and clinical outcomes. Cox regression models were used to estimate the impact of these variables, as well as of other clinically relevant covariates, on patient survival. We included 57 HER2+ aBC patients treated with taxane-trastuzumab-pertuzumab in our Institution. High baseline MLR, PLR, and PIV were similarly predictive of worse PFS at univariate analysis, but only high PIV was associated with a trend toward worse PFS at multivariable analysis. Regarding OS, both high PIV and MLR were associated with significantly worse patient survival at univariate analysis, but only the PIV was statistically significantly associated with worse overall survival at multivariable analysis (HR 7.96; 95% CI: 2.18–29.09). Our study reveals the PIV as a new and potent predictor of OS in HER2+ aBC patients treated with first line trastuzumab-pertuzumab-containing biochemotherapy. Prospective studies are needed to validate this new prognostic parameter in HER2+ aBC.

De-escalated chemotherapy versus endocrine therapy plus pertuzumab+ trastuzumab for HR+/HER2+ early breast cancer (BC): First efficacy results from the neoadjuvant WSG-TP-II study.

515 Background: HR+/HER2+ breast cancer (BC) is a distinct entity associated with better prognosis compared to HR-/HER2+ BC. However, combination of chemotherapy (CT) with (dual) anti-HER2 blockade is standard in HER2+ early BC (EBC), irrespective of HR-status. Despite of some promising data on combination of endocrine therapy (ET) with dual anti-HER2 blockade in EBC and metastatic HR+/HER2+ BC, no prospective comparison of neoadjuvant CT vs. ET + dual HER2-blockade has yet been performed. Methods: In the prospective WSG TP-II phase II-trial (NCT03272477; Sponsor: Palleos GmbH, Wiesbaden, Germany), 207 patients (pts) (257 screened; 40 centers) with centrally confirmed HR+/HER2+ EBC were randomized to 12 weeks of standard ET (n=100) vs. paclitaxel 80 mg/m2 weekly (n=107) +trastuzumab+pertuzumab q3w for all pts. Primary endpoint was pCR (ypT0/is/ypN0). Secondary endpoints include safety, disease-free and overall survival, translational research, and quality of life (QoL). Omission of further CT was allowed in all pts with pCR; dual HER2-blockade was administered in the adjuvant setting in all pts. Results: Baseline characteristics were well balanced between the arms. Median age was 53 years; 58% had cT2-4, 28% had cN+; 43% had G3 tumors. pCR data were available in 198 pts (ET: n=96; Pac: n=102). pCR was observed in 24% (95% CI: 16-34%) with ET+T+P vs. 57% (95% CI:47-67%) with Pac+T+P (OR 0.24, 95% CI: 0-0.46, p&lt;0.001). In multivariable logistic regression analysis and corresponding sensitivity analysis (bootstrap/subsample inclusion frequencies and lasso regression) including study arm, BMI, menopausal, cT, and cN status, histological grade, HER2-status, Ki67, ER, PR as continuous variables, only study arm and HER2 3+ status were significantly associated with pCR. Neoadjuvant treatment was well tolerated in both study arms and completed per protocol in 93/92 (ET+P+T/Pac+P+T) patients. Only 9/13 SAEs (ET+P+T/Pac+P+T) were reported during neoadjuvant therapy. PAM50 and QoL analysis are ongoing. Conclusions: WSG TP-II is the first randomized prospective trial comparing two neoadjuvant de-escalation treatments in HR+/HER2+ EBC. The excellent pCR rate of 57% after only 12 weeks of Pac+P+T was clearly superior to the still promising 24% pCR rate in pts treated by ET+P+T. In both arms, treatment efficacy was most pronounced in HER2 3+ tumors. Survival results need to be awaited before definite recommendations for a de-escalated regimen in HR+/HER2+ EBC can be made. Clinical trial information: 2016-005157-21 .

New potential therapeutic-sequence strategies of TDM1 in the revolutionary era of metastatic HER2-positive breast cancer treatment: A monocentric retrospective experience.

e13014 Background: EMILIA study showed benefits in terms of both progression free survival (PFS) and overall survival (OS) administering Ado-trastuzumab emtansine (T-DM1) vs lapatinib-capecitabine in HER2+ mBC patients (pts) treated at least with a previous trastuzumab-taxane-based therapy. However a paucity of data is available on TDM1 efficacy after dual anti HER2 blockade with pertuzumab and trastuzumab (PT). Instead TH3RESA trial revealed the positive impact on OS of T-DM1 also in heavily pre-treated (at least 2 lines of T, lapatinib and taxanes regimens) pts. We conducted a retrospective analysis reporting innovative findings on the sequence of anti-HER2 treatments and how it could be potentially optimized. Methods: Between June 15, 2014 and January 31, 2020 we identified HER2+ (IHC: 3+ or 2+/FISH amplified) mBC pts treated with T-DM1, either as second-line after progression on dual blockade PT (Cohort PT) or after ≤ 3 anti her2-combined regimens (trastuzumab o lapatinib plus chemotherapy) (Cohort T). 74 pts received T-DM1: Cohort T n = 34 (all females, median age = 52,7), Cohort PT n = 40 (39 females, 1 male, median age = 52,2). Within Cohort T: 64,7 % of pts (n = 22) received T-DM1 after 1 previous anti her2-combined regimen, 20,6 % (n = 7) and 14,7 % (n = 5) in third and fourth lines, respectively. Instead, the whole Cohort PT received second line T-DM1 after pertuzumab/trastuzumab. Results: Median progression- free survival was 10,2 in Cohort T and 3,7 months in Cohort PT. As regards the best response rate, 8,8 % (n = 3/34) and 52,5 % (n = 21/40) of pts reported a progressive disease (PD) into the Cohorts T and PT, respectively: stable disease (SD) 38,2 % (n = 13/34) versus 15 % (n = 6/40); partial response (PR) 23,5 % (n = 8/34) vs 15 % (n = 6/40); complete response (CR) 23,5 % (n = 8/34) vs 12,5 % (n = 5/40). Almost 2/3 (n = 21/34) of Cohort T and half (n = 20/40) of Cohort PT pts had a 3+ IHC status. Conclusions: Our data suggest a lower efficacy of T-DM1 after progression on dual HER2-blockade PT. After all, EMILIA trial did not robustly evaluate the role of T-DM1 in this specific subset of pts. Obviously, larger prospective studies are necessary in order to optimize the best sequence strategy in the treatment of metastatic HER2+ BC, in light of the increasingly innovative anti-HER2 agents.

Abstract PD5-10: Impact of immune markers on response to neoadjuvant de-escalated T-DM1 or trastuzumab with/or without endocrine therapy in HR+/HER2+ early breast cancer: A translational subproject of the WSG-ADAPT-HER2+/HR+ trial

Abstract Background: Among patients with highly heterogeneous HER2+ breast cancer (BC), pathological complete response (pCR) (ypT0/is/ypN0) is associated with improved prognosis. The prospective, phase-II neoadjuvant 3-arm WSG HER2+/HR+ trial (ADAPT-TP) showed pCR rates of about 41.0% after 4xT-DM1+/-ET and 15% after trastuzumab+ET. Pre-planned translational analysis of ADAPT-TP has revealed several biomarkers with impact on pCR, such as PIK3CA mutation status, HER2-enriched subtype (by PAM50), Bcl-2 and most notably immune biomarkers (e.g.CD8/tumor center). In particular, higher CD8 protein expression values either at baseline and/or after one cycle (3w) of neoadjuvant therapy were favorable for pCR. Moreover, CD8 and PDL1 dynamics were indicators of early therapy response, and dynamical response was itself favorable for pCR. The impact of immune biomarkers suggests that tumor infiltrating lymphocytes (TILs) could serve as predictive markers for de-escalated anti-HER2 therapy, in particular T-DM1. Methods: Semi-quantitative, triplicate TIL measurements were performed in tissue obtained at baseline (TIL-0) and at 3 weeks (TIL-3). At each timepoint, the median of the three measurements was used for analysis. CD8 and PD-L1 expression measurements were obtained by mRNA at baseline at both time points by immunohistochemistry (IHC). Associations of semiquantitative TIL-0/TIL-3 levels with pCR and with other clinical/pathological measurements were analyzed using logistic regression, rank correlations, t and chi-square statistics. Results: TIL-0 and TIL-3 were available in 355/375 and 301/375 randomized patients, respectively. Associations of TIL-0, TIL-3 and TIL-dynamics (increase from TIL-0 to TIL-3) with CD8 and PD-L1 (including dynamics) and with clinical factors (tumor size, nodal status, ER and PR status, grade, patient age, Ki67 and menopausal status) revealed several prominent relationships: Both TIL-0 and TIL-3 were at least moderately correlated with IHC measurements of CD8 (at center, not at invasive margin) and of PD-L1 at both timepoints. At cycle 2, the correlation of TILs and CD8 was strong, particularly in the T-DM1 arms (r=.7, p&amp;lt;.001). CD8 by mRNA was moderately correlated with TIL-0. Correlations between clinical factors and TILs at both timepoints were weak. These associations with known factors influencing pCR suggest a possible direct association of TILs with pCR; logistic regression using standardized TIL-0 revealed a modest (standardized) odds ratio of about 1.4 for pCR for TIL-0 in the T-DM1 arms, though not in the whole cohort. In particular, patients receiving T-DM1 with TIL0≥40% (about 8%) had pCR of 70% vs. 40% pCR for others (p=.016). We observed a dynamic increase of TILs during T-DM1 treatment of about 10 percentage points. However, neither these dynamics nor TIL-3 were significantly associated with pCR (in contrast to CD8 protein expression at cycle 2). Interpretation: To the best of our best knowledge, these are the first prospective data regarding the predictive value of TILs and TIL dynamics in HR+/HER2+ BC treated with de-escalated anti-HER2 therapy. Very high TIL levels (&amp;gt;40%) were associated with an excellent pCR rate of 70% in TDM1treated patients. However, CD8 expression and dynamics of CD8 were more strongly predictive for efficacy of de-escalated treatment than TILs – despite promising data on baseline and/or on-treatment TILs as markers for improved prognosis and higher sensitivity to (dual) anti-HER2 blockade (with or without chemotherapy) in unselected HER2+ BC. Further research on static and dynamic immune markers (according to HR+ and HR-/HER2+ subtypes) is needed prior to final conclusions regarding the clinical impact of TILs in early HER2+ BC. Citation Format: Claudia Biehl, Cornelia Kolberg-Liedtke, Oleg Gluz, Friedrich Feuerhake, Matthias Christgen, Ronald Kates, Eva-Maria Grischke, Helmut Forstbauer, Michael Braun, Mathias Warm, John Hackmann, Christoph Uleer, Bahriye Aktas, Claudia Schumacher, Sherko Kuemmel, Sanne L de Haas, Regula Deurloo, Rachel Wuerstlein, Ulrike Nitz, Hans H. Kreipe, Nadia Harbeck, West German Study Group. Impact of immune markers on response to neoadjuvant de-escalated T-DM1 or trastuzumab with/or without endocrine therapy in HR+/HER2+ early breast cancer: A translational subproject of the WSG-ADAPT-HER2+/HR+ trial [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 PD5-10.

Updated Bayesian Network Meta-Analysis of Adjuvant Targeted Treatment Regimens for Early Human Epidermal Growth Factor Receptor-2 Positive Breast Cancer.

PurposeCombining targeted agents with adjuvant chemotherapy prolongs survival in human epidermal growth factor receptor 2 (HER2)-positive breast cancer patients, but also increases the risk of adverse effects. The updated results of 3 randomized controlled trials (RCTs) were reported in 2019. Given the lack of adequate head-to-head pairwise assessment for anti-HER2 agents, network meta-analysis facilitates obtaining more precise inference for evidence-based therapy.MethodsRCTs comparing at least 2 anti-HER2 regimens in an adjuvant setting for HER2-positive early-stage breast cancer (EBC) were included. Hazard ratios for overall survival (OS) and disease free survival (DFS), with respective 95% confidence intervals were pooled for assessment of efficacy. A Bayesian statistical model was used, and odds ratios (ORs) for adverse events (AEs) were used to pool effect sizes.ResultsWe demonstrated that 1-year trastuzumab plus chemotherapy had increased efficacy compared to shorter or longer treatment duration. The OR of cardiac events gradually increased from 6 months to 1 and 2-year trastuzumab arms, relative to chemotherapy only. Compared to trastuzumab plus chemotherapy, dual HER2-targeting therapies increased DFS, especially for hormone receptor negative patients. Dual anti-HER2 blockade regimens revealed an increased probability of gastrointestinal reactions. As a second agent, pertuzumab showed significantly higher DFS and OS.ConclusionWe conclude that 1-year adjuvant trastuzumab should remain as the standard treatment for HER2-positive EBC patients, as it has greater efficacy and a manageable proportion of AEs. Clinical efficacy can be increased for hormone receptor-negative tumors by including a second HER2-targeted agent to the treatment regimen. For hormone receptor-positive cases with basal disease, it is acceptable to reduce the risk of cardiotoxicity by shortening the duration of trastuzumab.

T-DM1 Efficacy in Patients With HER2-positive Metastatic Breast Cancer Progressing After a Taxane Plus Pertuzumab and Trastuzumab: An Italian Multicenter Observational Study

BackgroundT-DM1 improves progression-free survival (PFS) and overall survival (OS) in patients with metastatic human epidermal growth factor receptor 2-positive (HER2+) breast cancer progressing on prior trastuzumab plus a taxane. A paucity of data is available on T-DM1 efficacy after dual anti-HER2 blockade with pertuzumab and trastuzumab plus a taxane, which represents the current first-line standard of care. The present study is a retrospective/prospective evaluation of the efficacy and activity of second-line T-DM1 after front-line pertuzumab-based therapy. Patients and MethodsEligible patients were identified within the Gruppo Italiano Mammella (GIM) 14/BIOMETA study, a retrospective/prospective multicenter study on treatment patterns and outcomes of patients with metastatic breast cancer (ClinicalTrials.gov Identifier: NCT02284581). We searched for patients who received second-line T-DM1 after taxane plus trastuzumab and pertuzumab between November 15, 2013 and May 31, 2018. We calculated median PFS, median time to treatment failure (TTF), prolonged duration of therapy (PDT), objective response rate (ORR), and 1-year OS. ResultsOf 445 patients with HER2+ metastatic breast cancer, 77 were eligible for the analysis. At a median follow-up of 7 months, median PFS was 6.3 months (95% confidence intervals [CI], 4.8-7.7 months), and median TTF was 6.2 months (95% CI, 4-8.6 months). More than one-third of patients (37.6%; n = 29) experienced PDT with an ORR of 27.1%. At data cutoff, the median OS was not reached, and the 1-year OS was 82%. ConclusionsOur results show meaningful activity of T-DM1 after front-line pertuzumab plus trastuzumab and a taxane, with about 27% of patients having an objective response and 40% of patients achieving durable disease control.

A Study With Pembrolizumab in Combination With Dual Anti-HER2 Blockade With Trastuzumab and Pertuzumab in Early Breast Cancer Patients With Molecular HER2-enriched Intrinsic Subtype (Keyriched-1)

A Study With Pembrolizumab in Combination With Dual Anti-HER2 Blockade With Trastuzumab and Pertuzumab in Early Breast Cancer Patients With Molecular HER2-enriched Intrinsic Subtype (Keyriched-1)

P360 - Single center outcome analysis of dual anti-Her2 blockade using trastuzumab and pertuzumab in early and advanced Her2-overexpressing breast cancer

P360 - Single center outcome analysis of dual anti-Her2 blockade using trastuzumab and pertuzumab in early and advanced Her2-overexpressing breast cancer

Oncofertility counselling in premenopausal women with HER2-positive breast cancer.

A complete oncofertility counselling should be offered to all premenopausal patients before the administration of anticancer treatments. This important discussion is a crucial step for allowing them to take fully informed decisions about the proposed therapy and its potential long-term consequences as well as on their need and interest of accessing the available strategies for ovarian function and/or fertility preservation. In premenopausal women with HER2-positive early breast cancer, limited evidence exists to counsel them about the potential added gonadotoxicity of targeted agents beyond the damage already caused by chemotherapy. In addition, the prognostic role of treatment-induced amenorrhea in this setting was unknown. In our exploratory analysis within the ALTTO (BIG 2-06) trial, we have recently described the rates of treatment-induced amenorrhea after chemotherapy plus trastuzumab and/or lapatinib and the prognostic value of developing this side effect according to the hormone receptor status of their tumours. We observed similar rates of treatment-induced amenorrhea in the four anti-HER2 treatment arms. The lack of an increased rate of treatment-induced amenorrhea in the dual anti-HER2 blockade arm suggests the possible gonadal safety of these agents. In addition, women with HER2-positive/hormone receptor-positive tumours showed significantly better survival outcomes if they developed treatment-induced amenorrhea, while no difference was observed for those with HER2-positive/hormone receptor-negative disease. Future research efforts are needed to address the gonadotoxicity of the new available targeted agents as well as to elucidate which is the best adjuvant endocrine therapy in premenopausal women with HER2-positive/hormone receptor-positive disease.

Efficacy of Anti-HER2 Agents in Combination With Adjuvant or Neoadjuvant Chemotherapy for Early and Locally Advanced HER2-Positive Breast Cancer Patients: A Network Meta-Analysis.

Several (neo)adjuvant treatments for patients with HER2-positive breast cancer have been compared in different randomized clinical trials. Since it is not feasible to conduct adequate pairwise comparative trials of all these therapeutic options, network meta-analysis offers an opportunity for more detailed inference for evidence-based therapy. Phase II/III randomized clinical trials comparing two or more different (neo)adjuvant treatments for HER2-positive breast cancer patients were included. Relative treatment effects were pooled in two separate network meta-analyses for overall survival (OS) and disease-free survival (DFS). 17 clinical trials met our eligibility criteria. Two different networks of trials were created based on the availability of the outcomes: OS network (15 trials: 37,837 patients); and DFS network (17 trials: 40,992 patients). Two studies-the ExteNET and the NeoSphere trials-were included only in this DFS network because OS data have not yet been reported. The concept of the dual anti-HER2 blockade proved to be the best option in terms of OS and DFS. Chemotherapy (CT) plus trastuzumab (T) and lapatinib (L) and CT + T + Pertuzumab (P) are probably the best treatment options in terms of OS, with 62.47% and 22.06%, respectively. In the DFS network, CT + T + Neratinib (N) was the best treatment option with 50.55%, followed by CT + T + P (26.59%) and CT + T + L (20.62%). This network meta-analysis suggests that dual anti-HER2 blockade with trastuzumab plus either lapatinib or pertuzumab are probably the best treatment options in the (neo)adjuvant setting for HER2-positive breast cancer patients in terms of OS gain. Mature OS results are still expected for the Aphinity trial and for the sequential use of trastuzumab followed by neratinib, the treatment that showed the best performance in terms of DFS in our analysis.

Abstract P2-09-01: T-cell receptor beta chain variable region (TRBV) expression patterns predict response to combined trastuzumab/lapatinib treatment in the NeoALTTO/BIG-1-06 trial

Abstract Background: Dual anti-HER2 blockade resulted in increased pathologic complete response rate (pCR) in the 3 arm NeoALTTO trial. High immune gene expression and the absence of PIK3CA pathway mutations are predictive of pCR in all treatment arms but no markers were identified that could predict which patients require dual HER2 targeted therapy. The goal of this analysis was to examine if TRBV expression could add to the predictive function of previously identified immune markers. Patients and Methods: We analyzed RNA and Whole Exome sequencing data from 245 cancers (54% of all patients) included in the trial. The TRBV reference sequences were obtained from the International ImMunoGeneTics information system. Reads were aligned using a custom BLAST mapping pipeline and normalized by the total number of aligned reads in each sample. We calculated 3 T cell receptor metrics for each tumor including (i) total TRBV chain expression level, (ii) Shannon entropy of the normalized unique TRBV-expression frequencies which reflect TCR diversity and (iii) we also used non-negative matrix factorization (NMF) to define TRBV co-expression metagenes (TRBVMG). We evaluated correlation between these metrics and immune and proliferation gene expression signatures and genomic features of the cancer including clonal heterogeneity and mutation load. We assessed association between TRBV and pCR using multivariate logistic regression. Results: 65 distinct TRBV variants showed heterogeneous expression levels across cancers with strong co-expression patterns. Total TRBV expression correlated strongly with immune metagene expression (Spearman's ρ=0.93, P&amp;lt;0.001), but entropy had a weaker, inverse correlation with immune metagene expression (Spearman's ρ=-0.40, P&amp;lt;0.001). Associations between TRBV metrics and mutation load and clonal heterogeneity were weak. pCR correlated with higher total TRBV expression (Spearman's ρ=0.17, P&amp;lt;0.05). Correlation between entropy and pCR was non-significant (odds ratio (OR) for regressing entropy with pCR was &amp;lt;1). NMF identified 4 distinct TRBVMGs that showed substantial expression variation within immune cell rich cancers. ER-status, proliferation and immune-gene expression adjusted logistic regression analysis including a treatment-arm interaction term revealed that TRBVMG-2, characterized by high expression of TRBV4.3, TRBV6.3 and TRBV7.2 variants, was associated with higher pCR rate in patients treated with trastuzumab plus lapatinib (Interaction OR=3.23 adjusted P=0.03). In immune-rich cancers, TRBVMG-2 expression above the median was associated with higher pCR rate in the dual HER2 targeted treatment arm compared to the other arms (68% vs 21%, Fisher exact test P&amp;lt;0.001). Patients with immune cell rich cancers but TRBVMG-2 expression below the median had similar pCR rates in all arms (42% monotherapy vs. 28% dual therapy, P=0.46). Conclusions: TRBV expression pattern can provide predictive information beyond known immune gene expression signatures. High expression of TRBV4.3, TRBV6.3 and TRBV7.2 variants is associated with higher pCR rate with dual HER2 targeted and paclitaxel neoadjuvant therapy. Citation Format: Powles R, Redmond D, Sotiriou C, Loi S, Fumagalli D, Nuciforo P, Harbeck N, de Azambuja E, Sarp S, Di Cosimo S, Huober J, Baselga J, Piccart-Gebhart M, Elemento O, Hatzis C, Pusztai L. T-cell receptor beta chain variable region (TRBV) expression patterns predict response to combined trastuzumab/lapatinib treatment in the NeoALTTO/BIG-1-06 trial [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P2-09-01.

Abstract P4-21-05: Neoadjuvant non-pegylated liposomal doxorubicin plus paclitaxel, trastuzumab and pertuzumab in patients with HER2+ breast cancer – Final results of the SOLTI OPTI-HER HEART study

Abstract INTRODUCTION Targeting HER2 by dual blockade with trastuzumab (T) and pertuzumab (P) in a taxane-based regimen is an active neoadjuvant treatment (NAT) of HER2+ early breast cancer (EBC). Addition of an anthracycline could further enhance this response, but potential cardiac toxicity is a concern. The Opti-HER HEART trial (NCT01669239) aims to optimize neoadjuvant treatment while minimizing cardiac risk, by combining T+P with a taxane and non-pegylated liposomal doxorubicin (NPLD). MATERIAL AND METHODS Phase II open-label, single-arm study of six 21-day cycles of NPLD (50mg/m2 D1), paclitaxel (80mg/m2 D1,8,15), T (4mg/kg C1D1, followed by 2mg/kg weekly), and P (840mg C1D1, followed by 420mg C2-6D1) as NAT for patients (pts) with stage II-IIIB HER2+ BC. Primary objective was to evaluate cardiac safety of the combination, measured by the incidence of type A (symptomatic congestive heart failure ) or type B [asymptomatic reduction of Left Ventricular Ejection Fraction (LVEF) value: ≥10% absolute decrease and LVEF&amp;lt;50%, LVEF&amp;lt;40% or any absolute decrease ≥20%] events, during NAT. Eighty-three pts were required to reject with 80% confidence the null hypothesis that the combination increases the incidence of cardiac events above the historical control of 18% (3% type A; 15% type B). RESULTS Between June 2013 and January 2015, 83 pts with HER2+ EBC (stage II 78%, stage III 22%) and adequate cardiac function (LVEF≥55%) were enrolled. Mean age was 50 years, N+ 47%, hormone receptor (HR) positive 71% and median baseline LVEF 66%. Eighty-five percent of pts completed 6 cycles of NAT, whereas 15% discontinued NAT due to toxicity. Adverse events (AEs) leading to dose adjustments/temporary interruptions and discontinuation of at least 1 drug occurred in 70% and 21% of pts, respectively. Primary objective was met with an incidence of cardiac events during NAT of 4% (95%CI 1-10, 3pts, all type B). Cardiac events until study completion (1 year) were 8% (all type B). All (but 2 cases with no follow-up data) were reversible and only 1 pt presented an asymptomatic LVEF&amp;lt;40%. Neutropenia (45%) was the most frequent hematological toxicity (G3/4 34%; febrile neutropenia 6%), less frequent in the 71% of pts that received primary G-CSF prophylaxis (G3/4 25% vs. 67%). Common non-hematological toxicities were diarrhea (74%; G3 7%), asthenia (78%; G3 11%) and neurotoxicity (52%; G3/4 10%). Pathological complete response (pCR) in breast+axilla (ypT0/is ypN0) was 60% (87% in HR-) and 69% in breast (91% in HR-). TOTALHR-HR+% ypT0/is (95% CI)69 (58-79)91 (72-99)61 (47-74)% ypT0/is ypN0 (95% CI)60 (46-71)87 (66-97)50 (36-64) CONCLUSIONS The neoadjuvant combination of T+P, paclitaxel and NPLD does not increase the risk for cardiac events in HER2+ BC pts. Since cardiac toxicities may present later, long-term cardiac monitoring is essential. Efficacy in terms of pCR was remarkable, being higher to historical values of combinations with dual anti-HER2 blockade and one of the highest reported among HR-HER2+ BC. This regimen administered with primary G-CSF prophylaxis and cardiac function monitoring may be an effective and secure option for early and locally advanced HER2+ pts with good cardiac function. Citation Format: Gavilá J, Perez-Garcia J, Calvo I, Ciruelos E, Muñoz M, Virizuela JA, Ruiz I, Andrés R, Morales S, Perelló A, Sánchez P, Garcia-Saenz JA, Quero Guillen JC, González-Santiago S, Garau Llinas I, González-Martín A, Cantos Sánchez de Ibargüen B, Zaragoza K, de la Peña L, Llombart-Cussac A, Oliveira M. Neoadjuvant non-pegylated liposomal doxorubicin plus paclitaxel, trastuzumab and pertuzumab in patients with HER2+ breast cancer – Final results of the SOLTI OPTI-HER HEART study [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P4-21-05.

Does dual HER-2 blockade treatment increase the risk of severe toxicities of special interests in breast cancer patients: A meta-analysis of randomized controlled trials.

Although dual HER-2 blockade treatment could offer greater clinical efficacy in breast cancer, the risk of severe toxicities of special interest related to this combined regimen in breast cancer remained unknown. We systematically searched public databases (MEDLINE, EMBASE, Cochrane library) to identify relevant studies that comparing anti-HER2 monotherapy (lapatinib or trastuzumab or pertuzumab) with dual HER-2 blockade treatment (pertuzumab plus trastuzumab or trastuzumab plus lapatinib) in breast cancer. A total of 11,941 breast cancer patients from 9 trials were included for analysis. Meta-analysis showed that dual HER2 blockade treatment significantly increased the risk of severe diarrhea (OR 2.52, p<0.001) and treatment discontinuation (OR 1.52, p=0.014), but not for severe rash (OR 1.06, p=0.81), liver toxicities (OR 1.16, p=0.28), CHF (OR 1.46, p=0.09), LVEF decline (OR 1.09, p=0.40) and FAEs (OR 0.97, p=0.91). Similar results were observed in sub-group analysis according to anti-HER2 regimens in terms of severe diarrhea and treatment discontinuation. Additionally, trastuzumab plus lapatinib significantly increased the risk of LVEF decline in comparison with lapatinib alone (OR 1.48, p=0.002). Our analysis indicated that dual anti-HER2 blockade treatment significantly increased the risk of developing severe diarrhea and treatment discontinuation in comparison with anti-HER2 monotherapy. These were no evidence of an increased risk of fatal adverse events with dual-HER2 blockade treatment.

Final analysis of WSG-ADAPT HER2+/HR- trial: Efficacy, safety, and predictive markers for 12-weeks of neoadjuvant dual blockade with trastuzumab + pertuzumab ± weekly paclitaxel in HER2+/HR- early breast cancer (EBC).

518Background: In HER2+ EBC pCR rates after neoadjuvant chemo (CT)+/- anti-HER2 therapy differ according to hormone receptor (HR) status. The neoadjuvant ADAPT HER2+/HR- phase II trial aims to iden...

Abstract P4-13-20: Activity of HP-based therapies as third and later lines for the treatment of HER2-positive metastatic breast cancer: A retrospective study from a single institution

Abstract Background: Dual anti-HER2 blockade with trastuzumab and pertuzumab (HP) plus chemotherapy is an effective therapy (Rx) in the 1st-line setting for HER2-positive metastatic breast cancer (MBC). Our single arm phase II study included patients (pts) treated with HP plus paclitaxel in the 2nd-line setting with progression-free survival (PFS) benefit. Recently, we reported results from a retrospective study of pts treated at our institution, suggesting a longer PFS for those who received HP-based Rxs when compared to any other anti-HER2 based Rxs in the 2nd-line setting. To further assess the activity of this combination in later Rx lines, we conducted a retrospective analysis of pts with HER2-positive MBC who had progressive disease after 2nd-line and were treated with HP-based Rxs in the 3rd and later lines at MSKCC. Historically, the median (med) PFS in this setting with trastuzumab-based Rx is about 3-4 months. Methods: Pts diagnosed with HER2-positive MBC and treated with HP-based Rxs at MSKCC between 1-1-2011 and 03-30-2015 and who progressed on 2nd-line Rx were identified through an institutional database. Primary endpoint was PFS in 3rd and later treatment lines. Results: 70 pts who received any HP-based Rx in the 3rd or later lines of treatment were eligible. The med number of prior anti-HER2 Rx was 3. The baseline characteristics and Rxs are summarized in Table 1. The med PFS for the entire cohort was 5.7 months (95% CI, 4.8-6.5). Conclusions: In this retrospective analysis involving heavly pretreated patients, HP-based Rx appears to be an active regimen and compares favorably to historical data. This supports the NCCN endorsement of HP-based Rx in later lines if HP has not been delivered previously. Baseline Characteristics and treatments (n=70)Characteristic(n)(%)Age Median56 Range27-83 Gender Female70100.0Male00.0Race Black1014.3White5477.1Other68.6Ethnicity Non Hispanic6694.3Hispanic45.7ER/PR status ER and PR negative2738.6ER and/or PR positive4361.4Type of disease Non visceral1622.9Visceral5477.1Visceral CNS2130.0Anti-HER2 in early stage Yes2941.4No4158.6Line of therapy 3rd line1927.14th line1521.45th line912.96th line912.97th line811.48th line and beyond1014.3HP-based regimens Chemotherapy + HP5477.1Endocrine therapy + HP57.1HP alone912.9Other22.9 Citation Format: Argolo D, Friedman M, Smyth L, Iyengar N, Singh J, Patil S, Norton L, Baselga J, Hudis C, Dang C. Activity of HP-based therapies as third and later lines for the treatment of HER2-positive metastatic breast cancer: A retrospective study from a single institution. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P4-13-20.