anti-HER2 Agents Research Articles

The role of radiation therapy and systemic therapies in elderly with breast cancer.

The focus of this review deals with the management of elderly patients with early stage breast cancer, discussing the role of systemic therapies [endocrine therapy (ET), chemotherapy, novel agents] and radiation therapy (RT). Several studies have evaluated in elderly low risk patients the possibility of omitting the RT but, at the same time, higher locoregional relapse (LR) rates without significant impact on overall survival (OS) were observed in all studies when RT was excluded. Technological improvements [intensity-modulated RT (IMRT), volumetric modulated arc therapy (VMAT), high dose brachy therapy (HDBT)] are very useful in order to reduce cosmetic outcome and improve quality of life of frail patients. The optimal sequence of ET, concomitant or sequential to RT, is currently under investigation, and specifically in the elderly it is questioned the possible choice of prolonged therapy after standard 5 years. Data regarding chemotherapy suggesting no benefit of OS in endocrine responsive diseases, whereas endocrine non-responsive breast cancer still showed a better outcome. Cyclophosphamide, methotrexate and 5-fluorouracil (CMF) regimen is recognized as the standard protocol, although age-dependent increase in therapy related mortality was reported. Neoadjuvant chemotherapy in elderly showed a lower ratio of pathological complete response in comparison to younger patients, but triple negative breast cancer patients showed a good prognosis regarding OS, comparable to younger patients. The risk of cardiotoxicity seems to increase with age, so the use trastuzumab in this setting is much debated. Currently, other anti-HER2 agents (pertuzumab, lapatinib) are used in neoadjuvant setting, but the data on elderly are still premature. Novel molecules are rapidly changing the clinical management of breast cancer patients but are tested especially in locally advanced and metastatic setting. Among these, particularly interesting are inhibitors of CDK4 and 6, alpelisib (PI3K enzymes mutations), immune checkpoint (PD1, PDL1, CTLA4) inhibitors, atezolizumab. Elderly patients are under-represented in clinical trials, although ageing can be frequently correlated with a decrease in the effectiveness of the immune system. For elderly women, treatment decisions should be individually decided, taking into account the geriatric assessment and limited life expectancy and tumor characteristics.

Gastrointestinal Adverse Effects of Immunotherapeutic Agents: A Systematic Review

The utilization of immunotherapy is increasing to the point of becoming the fifth pillar of management alongside surgical intervention, chemotherapy, radiotherapy and targeted therapy. However, gastrointestinal adverse effects and toxicities have been frequently cited with its use. As per literature, the most common adverse effect of immune checkpoint inhibitors is watery and non-bloody diarrhea. Adoptive cell therapy can lead to delayed, on-target but off-tumor adverse effects which are unknown and may be life-threatening. The use of anti-angiogenic monoclonal antibodies can lead to bowel perforations, whereas epidermal growth factor receptor inhibitors and anti-HER2 agents are frequently associated with diarrhea. Minimal adverse effects have been associated with therapeutic cancer vaccines; however, additional studies are needed to determine their efficacy and potential toxicities. To provide an in-depth review of the gastrointestinal side effects of immunotherapeutic agents, we performed a thorough literature search using multiple online search engines such as PubMed, Google Scholar and Ovid MEDLINE, along with a review of the guidelines from the United States Food and Drug Administration (FDA) and the Cancer Research Institute on immunotherapy. In this systematic review, we detail the gastrointestinal adverse effects of immunotherapy and describe their management. With the advent of newer immunotherapeutic agents and the consistent approval of current agents by FDA for a wide spectrum of cancers, it is vital for physicians to familiarize themselves with their adverse effects for prompt diagnosis and early intervention to decrease adverse outcomes.

Breast cancer in twin pregnancy

Introduction: Breast cancer is the most common neoplasm among pregnant women, and occurs in up to 0.04% of pregnancies. There are only few short and long term results about the intrauterine exposure to antineoplastic agents, and treatment should follow the same guidelines as the one for non-pregnant women. Surgery is possible during the entire pregnancy. Radiotherapy is not indicated in pregnancy, but it is possible for selected patients. Chemotherapy is usually safe during the second and third trimesters, with interruption of the treatment three weeks before the probable date of birth; however, hormone therapy and anti-HER2 agents are contraindicated during pregnancy, and can be postponed until after birth. Objective: To report the case of a patient with breast cancer in the first trimester of a monochorionic diamniotic twin pregnancy, 13 years after thoracic radiotherapy due to Hodgkin's lymphoma. Methods: Medical chart review, interview with the patient, photographic record and literature review. Results: Thirty-four year old Japanese descendant woman, born in São Paulo, nutritionist, married, primiparous. In the eighth week of spontaneous twin pregnancy, she complained of a palpable, fast-growth nodule in the left breast superomedial quadrant. She took combined hormonal contraceptives from the ages of 17 to 33 years. Negative family history for neoplasms. Physical examination showed a nodule in the left breast superomedial quadrant measuring 9.0x7.5 cm – T3N0 (initial clinical staging IIB). Propedeutics: Obstetric ultrasound with topic monochorionic diamniotic twin pregnancy, compatible with 13 weeks and 5 days; breast US showed a complex irregular nodule in the left breast at 9h, measuring 54x40x40 mm: Birads 4. The ultrasound-guided percutaneous biopsy showed invasive carcinoma without expression of hormone receptors, negative HER2, 95% KI67 (triple negative). Negative staging for metastasis. She was referred to clinical oncology: received five sessions of Carboplatin (AUC 2) and Paclitaxel (80mg/m2). Despite the treatment, the tumor progressed to 12x10.5 cm, with large areas and negative axilla. The choice was for mastectomy with axillary lymphadenectomy. Anatomopathological: absence of residual neoplastic cells and neoplasm in axillary nodes (0/8): pathological complete response. A Cesarean section was performed after 36 weeks of pregnancy, and two female infants were born, weighing 2030g and 2455g, Apgar 8/9 and 9/9, respectively. Conclusion: Breast cancer diagnosis and prognosis during pregnancy are not well established. Considering that, this study collaborates with others that were conducted to better understand this pathology in twin pregnancies.

An overview of immune checkpoint inhibitors in breast cancer.

Although breast cancer is not traditionally considered an immunogenic type of tumor, the combination of immunotherapy and chemotherapy has recently emerged as a novel treatment option in triple-negative subtype in the advanced setting and other similar combinations of immune checkpoint inhibitors with chemotherapy are expected to become part of the neoadjuvant management in the near future. In addition, encouraging results have been observed with the combination of immune checkpoint blockade with diverse biological agents, including anti-HER2 agents, CDK 4/6 inhibitors, PARP-inhibitors. The present review summarized the available evidence coming from clinical trials on the role of immune checkpoint inhibitors in the management of breast cancer, both in advanced and early setting.

Targeted lapatinib anti-HER2/ErbB2 therapy resistance in breast cancer: opportunities to overcome a difficult problem.

Approximately 20% of invasive breast cancers have upregulation/gene amplification of the oncogene human epidermal growth factor receptor-2 (HER2/ErbB2). Of these, some also express steroid receptors (the so-called Luminal B subtype), whereas others do not (the HER2 subtype). HER2 abnormal breast cancers are associated with a worse prognosis, chemotherapy resistance, and sensitivity to selected anti-HER2 targeted therapeutics. Transcriptional data from over 3000 invasive breast cancers suggest that this approach is overly simplistic; rather, the upregulation of HER2 expression resulting from gene amplification is a driver event that causes major transcriptional changes involving numerous genes and pathways in breast cancer cells. Most notably, this includes a shift from estrogenic dependence to regulatory controls driven by other nuclear receptors, particularly the androgen receptor. We discuss members of the HER receptor tyrosine kinase family, heterodimer formation, and downstream signaling, with a focus on HER2 associated pathology in breast carcinogenesis. The development and application of anti-HER2 drugs, including selected clinical trials, are discussed. In light of the many excellent reviews in the clinical literature, our emphasis is on recently developed and successful strategies to overcome targeted therapy resistance. These include combining anti-HER2 agents with programmed cell death-1 ligand or cyclin-dependent kinase 4/6 inhibitors, targeting crosstalk between HER2 and other nuclear receptors, lipid/cholesterol synthesis to inhibit receptor tyrosine kinase activation, and metformin, a broadly inhibitory drug. We seek to facilitate a better understanding of new approaches to overcome anti-HER2 drug resistance and encourage exploration of two other therapeutic interventions that may be clinically useful for HER+ invasive breast cancer patients.

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.

Biomarkers of response and resistance to PI3K inhibitors in estrogen receptor-positive breast cancer patients and combination therapies involving PI3K inhibitors.

In this review, we discuss biomarkers of response and resistance to PI3K inhibitors (PI3Ki) in estrogen receptor-positive breast cancer, both in the early and advanced settings. We analyse data regarding PIK3CA mutations, PI3K pathway activation, PTEN expression loss, Akt signalling, insulin levels, 18FFDG-PET/CT imaging, FGFR1/2 amplification, KRAS and TP53 mutations. Most of the discussed data comprise retrospective and exploratory studies, hence many results are not conclusive. Therefore, among all of these biomarkers, only PIK3CA mutations have proved to have a predictive value for treatment with the α-selective PI3Ki alpelisib (SOLAR-1 trial) and the β-sparing PI3Ki taselisib (SANDPIPER trial) in the advanced setting. Since the accuracy of current individual biomarkers is not optimal, a composite biomarker, including DNA, RNA and protein expression data, to more precisely assess the PI3K/AKT/mTOR pathway activation status, may arise as a promising approach. Finally, we describe the rational for new combination therapies involving PI3Ki and anti-HER2 agents, chemotherapy, CDK4/6 inhibitors, mTOR inhibitors or new endocrine treatments and discuss the ongoing trials in this field.

Randomised Phase 2 study of lapatinib and vinorelbine vs vinorelbine in patients with HER2\u2009+\u2009metastatic breast cancer after lapatinib and trastuzumab treatment (KCSG BR11-16)

BackgroundThe continuum of anti-HER2 agents is a standard treatment of HER2 + metastatic breast cancer (MBC). This study evaluated the efficacy of lapatinib plus vinorelbine in patients progressed on both trastuzumab and lapatinib treatments.MethodsA total of 149 patients were randomly assigned to lapatinib with vinorelbine (LV) (n = 75; lapatinib, 1000 mg daily; vinorelbine 20 mg/m2 D1, D8 q3w) or vinorelbine (V) (n = 74; 30 mg/m2 D1, D8 q3w). The primary endpoint was progression-free survival (PFS) rate at 18 weeks.ResultsThe median number of previous anti-HER2 therapies was 2 (range 2–5). There was no significant difference in PFS rate at 18 weeks between LV and V arms (45.9% vs 38.9%, p = 0.40). ORR was 19.7% in LV arm, and 16.9% in V arm (p = 0.88). PFS and OS did not differ between two arms (LV vs V; median PFS, 16 vs 12 weeks, HR = 0.86, 95% CI 0.61–1.22; median OS, 15.0 vs 18.9 months, HR = 1.07, 95% CI 0.72–1.58). Toxicity profiles were similar in both arms and all were manageable.ConclusionsLapatinib plus vinorelbine treatment was tolerable; however, it failed to demonstrate the clinical benefits over vinorelbine alone in patients with HER2 + MBC after progression on both trastuzumab and lapatinib.Clinical trial registrationClinicalTrials.gov number NCT01730677.

Role of dose-dense chemotherapy in high-risk early breast cancer.

Adjuvant chemotherapy for breast cancer significantly reduces the risk of recurrence and improves overall survival (OS). The purpose of the current article is to review available evidence on dose-dense chemotherapy, also focusing on special population, including premenopausal women and those with HER2-positive disease. A recent patient-level meta-analysis showed that the use of dose-dense chemotherapy is associated with significant reduction in disease recurrence, breast cancer mortality and improvement in OS. The benefit of dose-dense chemotherapy is irrespective from HER2 status, although women with HER2-positive disease enrolled in trials included in the meta-analysis did not receive the current standard of treatment with anti-HER2 agents. Among premenopausal women, dose-dense chemotherapy improved OS, and thus should be considered standard of care for them. In conclusion, high-risk early stage breast cancer patients should be treated with (neo)adjuvant dose-dense anthracycline-based chemotherapy followed by paclitaxel. In the era of trastuzumab, the benefit of dose-dense chemotherapy is still unclear for patients with HER2-positive breast cancer.

Breast Cancer during Pregnancy-Current Paradigms, Paths to Explore.

Breast cancer is the most common form of malignancy in pregnant women. The prevalence of pregnancy-associated breast cancer (PABC) is up to 0.04% of pregnancies and is expected to rise in developed countries. PABC represents a unique clinical scenario which requires a delicate balance of risks and benefits for both maternal and fetal well-being. Currently, there is paucity of data regarding the short- and long-term outcomes of in-utero exposure to anti-neoplastic agents. In general, when possible, treatment for PABC should follow the same guidelines as in non-pregnant patients. Surgery, including sentinel lymph node biopsy, is possible during all trimesters of pregnancy. Radiotherapy is contraindicated during pregnancy, although it might be considered in highly selected patients based on risk–benefit assessment. Evidence supports that administration of chemotherapy may be safe during the second and third trimesters, with cessation of treatment three weeks prior to expected delivery. Currently, hormonal therapy and anti-HER2 agents are contraindicated during pregnancy and should be postponed until after delivery. Prematurity is associated with worse neonatal and long-term outcomes, and thus should be avoided. While current data on the long-term effects of anti-neoplastic treatments are reassuring, grade of evidence is lacking, hence additional large prospective studies with long-term follow-up are essential to rule out any treatment-induced adverse effects.

Prognostic Factors in HER2-Positive Primary Breast Cancer Patients Treated Using Neoadjuvant Chemotherapy Plus Trastuzumab

Background: It is unclear for whom new anti-human epidermal growth factor receptor 2 (anti-HER2) agents, such as pertuzumab and T-DM1, should be considered. We investigated prognostic factors before neoadjuvant chemotherapy (NAC) among HER2-positive invasive breast cancer patients and those after NAC among patients who did not achieve pathological complete response (pCR) using conventional adjuvant trastuzumab. Methods: HER2-positive primary breast cancer patients treated using NAC containing trastuzumab were enrolled between September 2006 and June 2017 at the Osaka Breast Clinic. Patients with distant metastasis or using NAC containing pertuzumab were excluded. The main outcome was disease-free survival (DFS). We investigated pre- and post-NAC prognostic factors using the log-rank test and Cox proportional hazards model. Results: In total, 157 patients were included. Among the pre-NAC prognostic factors, younger age (under 40 years old) and positive clinical nodal status were significantly poorer prognostic factors (hazard ratio [HR] 3.47, 95% CI 1.06–10.12, p = 0.041 and HR 3.32, 95% CI 1.03–14.78, p = 0.045) by multivariate analysis. Among the post-NAC prognostic factors, patients with non-pCR (3-year DFS; 85 vs. 96%, p = 0.022) had a poorer DFS than patients with pCR. DFS was assessed for non-pCR patients (n = 64). High post-NAC Ki-67 status (≥20%; HR 6.73, 95% CI 1.82–31.93, p = 0.004) was a significant and large post-NAC tumor size (≥2 cm; HR 3.65, 95% CI 0.97–14.71, p = 0.056) was a marginally significant prognostic factor by multivariate analysis. After having combined them, high post-NAC Ki-67 status or large post-NAC tumor size was also a significant prognostic factor (HR 5.75, 95% CI 1.32–16.12, p = 0.017). Conclusions: Positive clinical nodal status and young age were found to be prognostic factors before NAC in HER2-postive invasive breast cancer patients. A high post-NAC Ki-67 status and large post-NAC tumor size were significant and marginally significant prognostic factors, respectively, after NAC in patients who did not achieve pCR. New anti-HER2 agents, such as pertuzumab and T-DM1, should be considered for the patients with those prognostic factors.

Systemic therapy for metastatic breast cancer

Abstract For metastatic breast cancer (MBC), many drugs including chemotherapy, endocrine therapy, and molecular-targeted therapy have been widely used, and there remain many clinical questions on optimal use of these agents. In patients with HER2-positive MBC, anti-HER2 agents such as trastuzumab, lapatinib, pertuzumab, and trastuzumab emtansine (T-DM1) are used, and trastuzumab + pertuzumab + taxane (HPT) for first-line treatment and T-DM1 for second-line treatment have been established as the standard of care by CLEOPATRA study and EMILIA study, respectively. New anti-HER2 agents such as neratinib, margetuximab, and anti-HER2 antibody-drug conjugates (ADC) are under development. In patients with HER2-negative, estrogen receptor (ER)-positive MBC, many molecular-targeted agents such as CDK4/6 inhibitors, mTOR inhibitors, PI3K inhibitors, Akt inhibitors, and HDAC inhibitors are studied in combination with endocrine therapy. Also in patients with triple negative breast cancer (TNBC), many promising agents are under development. Although TNBC is defined by the of expression of ER and HER2, from now on, we should not treat this subtype as disease characterized by lack but disease characterized by gain. The third or more targets other than ER and HER2 have been suggested and many drugs designed to affect such targets have been studied. Immune checkpoint inhibitors and PARP inhibitors have been investigated mostly in TNBC. Among each subtype, several smaller subtypes have been identified and found to differentially respond to specific drugs. We must efficiently develop appropriate classification and treatment to establish In this education lecture, I want to discuss current standard of care, perspectives of new drug development, and future direction of precision medicine.

1189PD - Determinants of response of HER2+ gastric cancer (GC) vs gastroesophageal junction adenocarcinoma (GEJ) to margetuximab (M) plus pembrolizumab (P) post trastuzumab (T)

1189PD - Determinants of response of HER2+ gastric cancer (GC) vs gastroesophageal junction adenocarcinoma (GEJ) to margetuximab (M) plus pembrolizumab (P) post trastuzumab (T)

Trastuzumab and pertuzumab in circulating tumor DNA ERBB2-amplified HER2-positive refractory cholangiocarcinoma

Cholangiocarcinoma is a heterogeneous and target-rich disease with differences in actionable targets. Intrahepatic and extrahepatic types of cholangiocarcinoma differ significantly in clinical presentation and underlying genetic aberrations. Research has shown that extrahepatic cholangiocarcinoma is more likely to be associated with ERBB2 (HER2) genetic aberrations. Various anti-HER2 clinical trials, case reports and other molecular studies show that HER2 is a real target in cholangiocarcinoma; however, anti-HER2 agents are still not approved for routine administration. Here, we show in a metastatic cholangiocarcinoma with ERBB2 amplification identified on liquid biopsy (circulating tumor DNA (ctDNA) testing), a dramatic response to now over 12 months of dual-anti-HER2 therapy. We also summarize the current literature on anti-HER2 therapy for cholangiocarcinoma. This would likely become another treatment option for this target-rich disease.

Towards precision oncology for HER2 blockade in gastroesophageal adenocarcinoma.

Gastroesophageal adenocarcinoma (GEA) represents a very heterogeneous disease and patients in advanced stages have a very poor prognosis. Although several molecular classifications have been proposed, precision medicine for HER2-amplified GEA patients still represents a challenge. Despite improvement in clinical outcomes obtained by adding trastuzumab to first-line platinum-based chemotherapy, no other anti-HER2 agents used first-line or beyond progression have demonstrated any benefit. Several factors contribute to this failure. Among them, variable HER2 amplification assessment, tumour heterogeneity, molecular mechanisms of resistance and microenvironmental factors could limit the effectiveness of anti-HER2 blockade. Identifying the factors responsible for both primary and acquired resistance is a priority for providing an improved, personalised approach. In this review, we examine current treatments for HER2-amplified GEA, their potential mechanisms of resistance and the ways to overcome them, investigating the most relevant translational studies with anti-HER2 agents in GEA, as well as novel agents under development in this field.

Body Mass Index and Hormone Receptor Status Influence Recurrence Risk in HER2-Positive Early Breast Cancer Patients

IntroductionA reliable risk stratification on the basis of tumor biology and host factors of HER2-positive (HER2+) early breast cancer (eBC) patients is needed. The aim of our study was to assess the prognostic role of body mass index (BMI) and hormone receptor (HR) expression in this setting. Patients and MethodsWe retrospectively evaluated 238 women with stage I to III HER2+ breast cancer who completed adjuvant chemotherapy (CHT) and 1 year of treatment with trastuzumab. The end point was 3-year distant disease-free survival (3yDDFS). Survival analysis was evaluated using the Kaplan–Meier method. Multivariate analysis was performed using Cox proportional-hazards model adjusting for HR status, BMI, tumor staging, size, nodal status, and type of adjuvant CHT. Association among categorical variables was assessed using χ2 test. ResultsThe early recurrence rate after 3 years resulted as 4.2% (40% HR+ patients and 60% HR− patients). Neither HR status nor BMI alone showed an association with 3yDDFS in multivariate analysis. However, the hazard ratios for patients with HR− tumors who had also BMI ≥25 (3yDDFS 86.9%; 95% confidence interval [CI], 75.0%-97.7%) were amplified compared with patients with HR+ tumors and with BMI <25 (3yDDFS 98%; 95% CI, 94.8%-100.0%) and other subgroups (P = .003). This observation was confirmed in multivariate analysis (hazard ratio, 1.79; 95% CI, 1.04-3.07; P = .03). ConclusionOur real-life data highlight a different risk of eBC recurrence after grouping patients according to HR status and BMI. These results might help clinicians to identify correct treatment strategies. Patients who are HR− and have BMI ≥25 might benefit from escalation approaches, whereas those who are HR+ and have BMI <25 might be eligible for a shorter duration of adjuvant treatment with anti-HER2 agents.

Abstract 3132: Immune regulatory gene expression and clinical outcome in the NeoALTTO trial

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&amp;lt;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.

Plasma miRNA Levels for Predicting Therapeutic Response to Neoadjuvant Treatment in HER2-positive Breast Cancer: Results from the NeoALTTO Trial.

To investigate the potential of circulating-miRNAs (ct-miRNA) as noninvasive biomarkers to predict the efficacy of single/dual HER2-targeted therapy in the NeoALTTO study. Patients with plasma samples at baseline (T0) and/or after 2 weeks (T1) of treatment were randomized into training (n = 183) and testing (n = 246) sets. RT-PCR-based high-throughput miRNA profiling was employed in the training set. After normalization, ct-miRNAs associated with pathologic complete response (pCR) were identified by univariate analysis. Multivariate logistic regression models were implemented to generate treatment-specific signatures at T0 and T1, which were evaluated by RT-PCR in the testing set. Event-free survival (EFS) according to ct-miRNA signatures was estimated by Kaplan-Meier method and Cox regression model. In the training set, starting from 51 ct-miRNAs associated with pCR, six signatures with statistically significant predictive capability in terms of area under the ROC curve (AUC) were identified. Four signatures were confirmed in the testing set: lapatinib at T0 and T1 [AUC 0.86; 95% confidence interval (CI), 0.73-0.98 and 0.71 (0.55-0.86)], respectively; trastuzumab at T1 (0.81; 0.70-0.92); lapatinib + trastuzumab at T1 (0.67; 0.51-0.83). These signatures were confirmed predictive after adjusting for known variables, including estrogen receptor status. ct-miRNA signatures failed to correlate with EFS. However, the levels of ct-miR-140-5p, included in the trastuzumab signature, were associated with EFS (HR 0.43; 95% CI, 0.22-0.84). ct-miRNAs discriminate patients with and without pCR after neoadjuvant lapatinib- and/or trastuzumab-based therapy. ct-miRNAs at week two could be valuable to identify patients responsive to trastuzumab, to avoid unnecessary combination with other anti-HER2 agents, and finally to assist deescalating treatment strategies.

Abstract 850: Evaluating preclinical efficacy of anti-HER2 drug combinations using ER+/HER2 mutant models

Abstract Targeting HER2 is one of the greatest successes in oncology, and has resulted in the generation of a wide array of HER2-targeting agents. Our genomic approaches are revealing other mechanisms of HER2 activation, such as our discovery of activating HER2 mutations in different cancer types. From initial breast cancer and SUMMIT trial data, the pan-HER drug neratinib as monotherapy showed initial clinical response in ER+ breast cancer, but with frequent early relapse. This study investigates the preclinical efficacy of anti HER2 agents alone or in combination with endocrine therapy agents or in combination with CDK4/6 inhibitors using ER+/HER2 mutant cell lines and ex vivo HER2 mutant patient derived xenograft (PDX) model. ER+ breast cancer cell lines (T47D and MCF7) stably expressing HER2V777L, and ER+/HER2 mutant PDX model (HER2G778_P780 dup) were used to examine HER2 signaling. We found that MCF7/T47D cells expressing HER2V777L and HER2G778_P780 dup PDX tumors showed strongly activated autophosphorylation of HER2 and increased expression of CDK4, CDK6, phospho-Rb, and cyclin D1 as compared to MCF7/T47D cells expressing HER2WT or ER+/non-HER2mut PDX model, suggesting that HER2 mutations preferentially depend on CDK4/6 signaling for cell growth. Additionally, we showed that activating MCF7 HER2V777L cause resistance to endocrine therapy treatment (fulvestrant IC50 &amp;gt;5μM). Further, we show that neratinib alone is effective at higher concentrations (IC50 &amp;lt; 2μM) in MCF7/HER2V777L cells. Next we showed that abemaciclib alone exhibited moderate activity against MCF7 HER2V777L cells (IC50 &amp;lt; 0.4μM) and additional activity in combination with neratinib (IC50 &amp;lt; 0.06μM) was seen. Moreover, ex vivo HER2G778_P780 dup cells are relatively resistant to fulvestrant alone (IC50 &amp;lt; 0.2μM), neratinib alone (IC50 &amp;lt; 0.006μM), abemaciclib alone (IC50 &amp;lt; 0.04μM), and neratinib in combination with abemaciclib (IC50 &amp;lt; 0.005μM), suggesting that patients harboring ER+/HER2-mutant tumors may benefit from neratinib in combination with abemaciclib. Therefore, we propose that simultaneous targeting of both HER2 and the CDK4/6 axis is required for maximal inhibition of ER+ breast cancers harboring HER2 activating mutations. Citation Format: Vaishnavi Devarakonda, LaTerrica Williams, Sinem Seker, Jonathan T. Lei, Purba Singh, Airi Han, Meenakshi Anurag, Kimberly R. Holloway, Alana L. Welm, Matthew J. Ellis, Shyam M. Kavuri. Evaluating preclinical efficacy of anti-HER2 drug combinations using ER+/HER2 mutant models [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 850.

Risk of Cardiomyopathy in Breast Cancer: How Can We Attenuate the Risk of Heart Failure from Anthracyclines and Anti-HER2 Therapies?

To review cardiotoxicity of and strategies to prevent cardiotoxicity from anthracyclines and anti-HER2 agents used to treat breast cancer. Although not common, cardiotoxicity from anthracyclines and anti-HER2 therapies is a major consideration in the use of these agents, especially in the adjuvant setting. Modifications in anthracycline agent, dosing, or schedule or use of Dexrazoxane have been shown to ameliorate the mostly irreversible cardiotoxicity from anthracyclines. Dose delays have been the primary means of addressing the possibly reversible cardiotoxicity from the anti-HER2 agent, trastuzumab, whereas the other anti-HER2 therapies, pertuzumab, lapatinib, and neratinib, are relatively nontoxic to the myocardium. Data from recent randomized clinical trials suggest that the use of angiotensin-converting enzyme inhibitors (ACEi), angiotensin receptor blockers (ARBs), and beta blockers may prevent subclinical cardiotoxicity, as measured by decline in the left ventricular ejection fraction, associated with these agents. Longer-term follow-up will be needed to confirm their role in prevention of symptomatic cardiomyopathy and subsequent cardiovascular disease in women with breast cancer. Preliminary evidence suggests that the use of ACEi, ARB, and beta blockers during treatment with anthracyclines and trastuzumab may prevent subsequent cardiomyopathy. Larger trials with meaningful clinical endpoints are needed.