Mechanisms of neratinib resistance in HER2-mutant metastatic breast cancer.
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ABSTRACT:
SUBMITTER: Eli LD
PROVIDER: S-EPMC9771739 | biostudies-literature | 2022
REPOSITORIES: biostudies-literature
Publications
Mechanisms of neratinib resistance in <i>HER2</i>-mutant metastatic breast cancer.
Eli Lisa D LD Kavuri Shyam M SM
Cancer drug resistance (Alhambra, Calif.) 20220901 4
Human epidermal growth factor receptor 2 (HER2) is a major drug target and clinical biomarker in breast cancer treatment. Targeting <i>HER2</i> gene amplification is one of the greatest successes in oncology, resulting in the use of a wide array of HER2-directed agents in the clinic. The discovery of <i>HER2</i>-activating mutations as novel therapeutic targets in breast and other cancers marked a significant advance in the field, which led to the metastatic breast and other solid tumor trials M ...[more]
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Project description:Trastuzumab has been shown to improve the survival outcomes of HER2 positive breast cancer patients. However, a significant proportion of HER2-positive patients are either inherently resistant or develop resistance to trastuzumab. We assessed the effects of neratinib, an irreversible panHER inhibitor, in a panel of 36 breast cancer cell lines. We further assessed its effects with or without trastuzumab in several sensitive and resistant breast cancer cells as well as a BT474 xenograft model. We confirmed that neratinib was significantly more active in HER2-amplified than HER2 non-amplified cell lines. Neratinib decreased the activation of the 4 HER receptors and inhibited downstream pathways. However, HER3 and Akt were reactivated at 24 hours, which was prevented by the combination of trastuzumab and neratinib. Neratinib also decreased pHER2 and pHER3 in acquired trastuzumab resistant cells. Neratinib in combination with trastuzumab had a greater growth inhibitory effect than either drug alone in 4 HER2 positive cell lines. Furthermore, trastuzumab in combination with neratinib was growth inhibitory in SKBR3 and BT474 cells which had acquired resistance to trastuzumab as well as in a BT474 xenograft model. Innately trastuzumab resistant cell lines showed sensitivity to neratinib, but the combination did not enhance response compared to neratinib alone. Levels of HER2 and phospho-HER2 showed a direct correlation with sensitivity to neratinib. Our data indicate that neratinib is an effective anti-HER2 therapy and counteracted both innate and acquired trastuzumab resistance in HER2 positive breast cancer. Our results suggest that combined treatment with trastuzumab and neratinib is likely to be more effective than either treatment alone for both trastuzumab-sensitive breast cancer as well as HER2-positive tumors with acquired resistance to trastuzumab.
| S-EPMC3858548 | biostudies-literature
Project description:BackgroundHER2 mutations are targetable alterations in patients with hormone receptor-positive (HR+) metastatic breast cancer (MBC). In the SUMMIT basket study, patients with HER2-mutant MBC received neratinib monotherapy, neratinib + fulvestrant, or neratinib + fulvestrant + trastuzumab (N + F + T). We report results from 71 patients with HR+, HER2-mutant MBC, including 21 (seven in each arm) from a randomized substudy of fulvestrant versus fulvestrant + trastuzumab (F + T) versus N + F + T.Patients and methodsPatients with HR+ HER2-negative MBC with activating HER2 mutation(s) and prior cyclin-dependent kinase 4/6 inhibitor (CDK4/6i) therapy received N + F + T (oral neratinib 240 mg/day with loperamide prophylaxis, intramuscular fulvestrant 500 mg on days 1, 15, and 29 of cycle 1 then q4w, intravenous trastuzumab 8 mg/kg then 6 mg/kg q3w) or F + T or fulvestrant alone. Those whose disease progressed on F + T or fulvestrant could cross-over to N + F + T. Efficacy endpoints included investigator-assessed objective response rate (ORR), clinical benefit rate (RECIST v1.1), duration of response, and progression-free survival (PFS). Plasma and/or formalin-fixed paraffin-embedded tissue samples were collected at baseline; plasma was collected during and at end of treatment. Extracted DNA was analyzed by next-generation sequencing.ResultsORR for 57 N + F + T-treated patients was 39% [95% confidence interval (CI) 26% to 52%); median PFS was 8.3 months (95% CI 6.0-15.1 months). No responses occurred in fulvestrant- or F + T-treated patients; responses in patients crossing over to N + F + T supported the requirement for neratinib in the triplet. Responses were observed in patients with ductal and lobular histology, 1 or ≥1 HER2 mutations, and co-occurring HER3 mutations. Longitudinal circulating tumor DNA sequencing revealed acquisition of additional HER2 alterations, and mutations in genes including PIK3CA, enabling further precision targeting and possible re-response.ConclusionsThe benefit of N + F + T for HR+ HER2-mutant MBC after progression on CDK4/6is is clinically meaningful and, based on this study, N + F + T has been included in the National Comprehensive Cancer Network treatment guidelines. SUMMIT has improved our understanding of the translational implications of targeting HER2 mutations with neratinib-based therapy.
| S-EPMC11335023 | biostudies-literature
Project description:We report a HER2T798I gatekeeper mutation in a patient with HER2L869R-mutant breast cancer with acquired resistance to neratinib. Laboratory studies suggested that HER2L869R is a neratinib-sensitive, gain-of-function mutation that upon dimerization with mutant HER3E928G, also present in the breast cancer, amplifies HER2 signaling. The patient was treated with neratinib and exhibited a sustained partial response. Upon clinical progression, HER2T798I was detected in plasma tumor cell-free DNA. Structural modeling of this acquired mutation suggested that the increased bulk of isoleucine in HER2T798I reduces neratinib binding. Neratinib blocked HER2-mediated signaling and growth in cells expressing HER2L869R but not HER2L869R/T798I In contrast, afatinib and the osimertinib metabolite AZ5104 strongly suppressed HER2L869R/T798I-induced signaling and cell growth. Acquisition of HER2T798I upon development of resistance to neratinib in a breast cancer with an initial activating HER2 mutation suggests HER2L869R is a driver mutation. HER2T798I-mediated neratinib resistance may be overcome by other irreversible HER2 inhibitors like afatinib.Significance: We found an acquired HER2 gatekeeper mutation in a patient with HER2-mutant breast cancer upon clinical progression on neratinib. We speculate that HER2T798I may arise as a secondary mutation following response to effective HER2 tyrosine kinase inhibitors (TKI) in other cancers with HER2-activating mutations. This resistance may be overcome by other irreversible HER2 TKIs, such as afatinib. Cancer Discov; 7(6); 575-85. ©2017 AACR.This article is highlighted in the In This Issue feature, p. 539.
| S-EPMC5457707 | biostudies-literature
Project description:Acquisition of resistance to targeted therapies remains a major clinical obstacle for the HER2+ subtype of breast cancer. Using an isogeneic progression series of HER2+ breast cancer metastasis we demonstrate that metastatic cells have an increased capacity to acquire resistance to the covalent, pan-ErbB inhibitor, neratinib. RNA sequencing analyses comparing parental and metastatic cells identified upregulation of transglutaminase 2 (TG2). Genetic depletion and overexpression approaches established that TG2 is both necessary and sufficient for acquisition of neratinib resistance. Mechanistically, we describe a pathway in which TG2-mediates activation of NF-κB signaling leading to upregulation of IL-6 in metastatic cells. This autocrine expression of IL-6 functions to maintain enhanced levels of TG2 via JAK:STAT3 signaling. This drug persistence feedback loop can be interrupted through the use of the JAK1/2 inhibitor ruxolitinib. In vivo application of ruxolitinib had no effect on tumor growth under non-treated conditions, but effectively prevented acquisition of resistance, leading to tumor regression upon coadministration with neratinib. Overall, our studies reveal a mechanism in metastatic breast cancer cells that predisposes them to acquisition of resistance to ErbB-targeted therapeutics. Clinically, immediate application of ruxolitinib could prevent acquisition of resistance and improve patient responses to HER2-targeted therapies.
| S-EPMC9213622 | biostudies-literature
Project description:ObjectiveThe tolerability and efficacy of targeted therapy in older adults with cancer has not been adequately studied. Neratinib is a novel HER1, HER2, HER4 tyrosine kinase inhibitor that has recently been granted FDA approval for treatment of breast cancer. The major toxicity of neratinib is diarrhea, which affects up to 90% of patients. This phase II trial evaluates the safety and tolerability of neratinib in adults ≥60.MethodsPatients aged 60 or older with histologically proven metastatic breast cancer and HER2 amplification (defined by ASCO/CAP guideline) or HER2/HER3 activating mutation were enrolled to receive neratinib at 240 mg daily in 28-day cycles. The association between tolerability, defined as dose reduction and number of completed courses, and log2 Cancer and Aging Research Group (CARG) toxicity risk score was assessed using a Student's t-test and linear regression, respectively. Response rate, progression free survival, and overall survival were also evaluated.Results25 patients were enrolled with median age of 66 (range 60-79). Seventy-six percent of patients were white, 16% Asian, and 8% African-American. Seventy-six percent were patients with hormone receptor (HR) positive metastatic breast cancer (MBC) and 24% were patients with HR negative MBC. Median number of prior lines of metastatic therapy were 3 (range 0-11). 20/25 (80%) had worst grade toxicities ≥2. A total of 9/25 (36%) had grade 3 toxicities including 5/20 (20%) diarrhea, 2/20 (8%) vomiting, and 2/20 (8%) abdominal pain. There were no grade 4 or 5 toxicities. A total of 9/25 (36%) had dose reduction, and 2/25 (8%) discontinued therapy due to toxicity. The association between dose reductions and CARG toxicity score reached borderline statistical significance suggesting a trend with participants with higher CARG toxicity risk scores being more likely to require a dose modification (p = 0.054). 1/25 (4%) had a partial response, 11/25 (44%) had stable disease, 12/25 (48%) had progression of disease, and 1/25 (4%) was not assessed. Median progression free survival (PFS) was 2.6 months (95% CI [2.56-5.26]), and median overall survival (OS) was 17.4 months (95% CI [10.3, NA]).ConclusionsNeratinib was safe in this population of older adults with HER2 amplified or HER2/3 mutated metastatic breast cancer (BC). Higher CARG toxicity risk score may be associated with greater need for dose adjustments. Future studies are needed to confirm this finding.
| S-EPMC8580161 | biostudies-literature
Project description:ObjectiveHER2 mutations are associated with poor prognosis and are detected in 3-6% of cervical cancers. Neratinib, an irreversible pan-HER tyrosine kinase inhibitor, had activity in several HER2-mutant cancer types in the phase 2 SUMMIT basket study. We present updated and final results from the cervical cancer cohort of SUMMIT.MethodsEligible patients had HER2-mutant, metastatic or recurrent cervical cancer progressing after platinum-based treatment for advanced/recurrent disease. Patients received neratinib 240 mg/day; loperamide was mandatory during cycle 1. Confirmed objective response rate (ORR) was the primary endpoint. Duration of response (DoR), clinical benefit rate (CBR), progression-free survival (PFS), and safety were secondary endpoints.ResultsTwenty-two patients were enrolled; 18 (81.8%) had endocervical adenocarcinoma; median two prior systemic chemotherapy regimens (range 1-4). The most common HER2 variant was S310F/Y mutation (n = 13; 59.1%). Four patients had confirmed partial responses (ORR 18.2%; 95% CI 5.2-40.3); 6 had stable disease ≥16 weeks (CBR 45.5%; 95% CI 24.4-67.8). Median DoR was 7.6 months (95% CI 5.6-12.3). Median PFS was 5.1 months (95% CI 1.7-7.2). All-grade diarrhea (90.9%), nausea (54.5%), and constipation (54.5%) were the most common adverse events. Five patients (22.7%) reported grade 3 diarrhea. There were no grade 4 adverse events, no diarrhea-related treatment discontinuations, and two grade 5 adverse events, unrelated to neratinib: dyspnea (n = 1) and embolism (n = 1).ConclusionsNeratinib resulted in durable responses and disease control in patients with HER2-mutant metastatic/recurrent cervical cancer in SUMMIT. These findings support next-generation sequencing and tailored therapy for select patients with advanced cervical cancer. All responses occurred in patients with endocervical adenocarcinoma. Further assessment of neratinib in this setting is warranted.Trial registration numberNCT01953926 (ClinicalTrials.gov), 2013-002872-42 (EudraCT).
| S-EPMC10922668 | biostudies-literature
Project description:ObjectiveSomatic HER2 mutations occur in ~5% of cervical cancers and are considered oncogenic and associated with poor prognosis. Neratinib, an irreversible pan-HER tyrosine kinase inhibitor, is active in multiple HER2-mutant cancers. SUMMIT is a phase II basket trial investigating the efficacy and safety of neratinib in solid tumors.MethodsPatients with HER2-mutant, persistent, metastatic/recurrent cervical cancer with disease progression after platinum-based treatment for advanced/recurrent disease received oral neratinib 240 mg/day with mandatory loperamide prophylaxis during cycle 1. The primary endpoint was confirmed objective response rate (ORR). Secondary endpoints included: response duration (DOR); clinical benefit rate (CBR); progression-free survival (PFS); overall survival (OS); safety.ResultsSixteen eligible patients were enrolled; 10 (62.5%) had endocervical adenocarcinoma. The most common HER2 mutation was S310F (63% of patients). Three of 12 RECIST-measurable patients had confirmed partial responses (ORR 25%; 95%CI 5.5-57.2%); 3 had stable disease ≥16 weeks (CBR 50%; 95%CI 21.1-78.9%). DOR for responders were 5.6, 5.9, and 12.3 months. Median PFS was 7.0 months (95%CI 0.7-18.3 months); median OS was 16.8 months (95%CI 4.1-NE months). Diarrhea (75%), nausea (44%), and decreased appetite (38%) were the most common adverse events. One patient (6%) reported grade 3 diarrhea. There were no grade 4 events, and no diarrhea-related treatment discontinuations.ConclusionsNeratinib monotherapy showed evidence of activity in heavily pretreated patients with HER2-mutant cervical cancer, with no new safety signals. Given the few effective options for cervical cancer after platinum-based therapy failure, neratinib warrants further investigation in this molecularly defined patient population.Trial registration numberNCT01953926 (ClinicalTrials.gov), 2013-002872-42 (EudraCT).
| S-EPMC8336424 | biostudies-literature
Project description:IntroductionNeratinib is a potent irreversible pan-ErbB tyrosine kinase inhibitor that has demonstrated antitumour activity and an acceptable safety profile in patients with human epidermal growth factor receptor (HER)-2-positive breast cancer and other solid tumours.MethodsThis was a phase I/II, open-label, two-part study. Part 1 was a dose-escalation study to determine the maximum tolerated dose (MTD) of neratinib plus paclitaxel in patients with solid tumours. Part 2 evaluated the safety, efficacy, and pharmacokinetics of the combination at the MTD in patients with HER2-positive breast cancer.ResultsEight patients were included in the dose-escalation study; no dose-limiting toxicities were observed, and an MTD of oral neratinib 240 mg once daily plus intravenous paclitaxel 80 mg m(-2) on days 1, 8, and 15 of each 28-day cycle was determined. A total of 102 patients with HER2-positive breast cancer were enrolled in part 2. The overall median treatment duration was 47.9 weeks (range: 0.1-147.3 weeks). Common treatment-emergent adverse events (all grades/grade ≥3) included diarrhoea (92%/29%; none grade 4), peripheral sensory neuropathy (51%/3%), neutropenia (50%/20%), alopecia (46%/0%), leukopenia (41%/18%), anaemia (37%/8%), and nausea (34%/1%). Three (3%) patients discontinued treatment due to an adverse event (mouth ulceration, left ventricular ejection fraction reduction, and acute renal failure). Among the 99 evaluable patients in part 2 of the study, the overall response rate (ORR) was 73% (95% confidence interval (CI): 62.9-81.2%), including 7 (7%) patients who achieved a complete response; an additional 9 (9%) patients achieved stable disease for at least 24 weeks. ORR was 71% among patients with 0/1 prior chemotherapy regimen for metastatic disease and no prior lapatinib, and 77% among those with 2/3 prior chemotherapy regimens for metastatic disease with prior lapatinib permitted. Kaplan-Meier median progression-free survival was 57.0 weeks (95% CI: 47.7-81.6 weeks). Pharmacokinetic analyses indicated no interaction between neratinib and paclitaxel.ConclusionThe combination of neratinib and paclitaxel was associated with higher toxicity than that of neratinib as a single agent, but was manageable with antidiarrhoeal agents and dose reductions in general. The combination therapy also demonstrated a high rate of response in patients with HER2-positive breast cancer. A phase III trial is ongoing to assess the benefit and risk of this combination in the first-line setting.
| S-EPMC3670493 | biostudies-literature
Project description:Purpose: Based on promising preclinical data, we conducted a single-arm phase II trial to assess the clinical benefit rate (CBR) of neratinib, defined as complete/partial response (CR/PR) or stable disease (SD) ≥24 weeks, in HER2mut nonamplified metastatic breast cancer (MBC). Secondary endpoints included progression-free survival (PFS), toxicity, and circulating tumor DNA (ctDNA) HER2mut detection.Experimental Design: Tumor tissue positive for HER2mut was required for eligibility. Neratinib was administered 240 mg daily with prophylactic loperamide. ctDNA sequencing was performed retrospectively for 54 patients (14 positive and 40 negative for tumor HER2mut).Results: Nine of 381 tumors (2.4%) sequenced centrally harbored HER2mut (lobular 7.8% vs. ductal 1.6%; P = 0.026). Thirteen additional HER2mut cases were identified locally. Twenty-one of these 22 HER2mut cases were estrogen receptor positive. Sixteen patients [median age 58 (31-74) years and three (2-10) prior metastatic regimens] received neratinib. The CBR was 31% [90% confidence interval (CI), 13%-55%], including one CR, one PR, and three SD ≥24 weeks. Median PFS was 16 (90% CI, 8-31) weeks. Diarrhea (grade 2, 44%; grade 3, 25%) was the most common adverse event. Baseline ctDNA sequencing identified the same HER2mut in 11 of 14 tumor-positive cases (sensitivity, 79%; 90% CI, 53%-94%) and correctly assigned 32 of 32 informative negative cases (specificity, 100%; 90% CI, 91%-100%). In addition, ctDNA HER2mut variant allele frequency decreased in nine of 11 paired samples at week 4, followed by an increase upon progression.Conclusions: Neratinib is active in HER2mut, nonamplified MBC. ctDNA sequencing offers a noninvasive strategy to identify patients with HER2mut cancers for clinical trial participation. Clin Cancer Res; 23(19); 5687-95. ©2017 AACR.
| S-EPMC6746403 | biostudies-literature
Project description:Metastatic breast cancer (mBC) patients have a high risk of progression and face poor prognosis overall, with about one third (34%) surviving five years or more. In rare instances (2-4% of cases) patients with mBC have ERBB2 (HER2) activating mutations but are ERBB2 non-amplified. Neratinib is a potent, irreversible inhibitor that binds HER2 and inhibits downstream signaling. We used the previously validated high-definition single cell assay (HDSCA) workflow to investigate the clinical significance of the liquid biopsy in ERBB2 mutant, non-amplified, post-menopausal mBC patients starting neratinib and fulvestrant combination therapy. Characterization with a comprehensive liquid biopsy methodology (HDSCA) included genomic analysis of both the cell-free DNA (cfDNA) and single circulating tumor cells (CTCs) to monitor tumor evolution and identify potential mutational variants unique to the patient's clinical response. A limited series of five sequentially enrolled patients presented here were from the MutHER ( https://www.clinicaltrials.gov , NCT01670877) or SUMMIT ( https://www.clinicaltrials.gov , NCT01953926) trials. Patients had an average of 5.4 lines of therapy before enrollment, variable hormone receptor status, and ERBB2 mutations at diagnosis and during treatment. CTC enumeration alone was not sufficient to predict clinical response. Treatment pressure was shown to lead to an observable change in CTC morphology and genomic instability (GI), suggesting these parameters may inform prognosis. Single cell copy number alteration (CNA) analysis indicated that the persistence or development of a clonal population of CTCs during treatment was associated with a worse response. Hierarchical clustering analysis of the single cells across all patients and timepoints identified distinct aberrant regions shared among patients, comprised of 26 genes that are similarly affected and may be related to drug resistance. Additionally, the genomic analysis of the cfDNA, identified new mutations in ERBB2, PIK3CA, and TP53 that arose likely due to treatment pressure in a patient with poor response, further providing insights on the dynamics of the cancer genome over the course of therapy. The data presented in this small cohort study demonstrates the feasibility of real-time molecular profiling of the cellular and acellular fractions of the liquid biopsy using the HDSCA methodology. Additional studies are necessary to determine the potential use of morphometric and genomic analysis as a prognostic tool to advance personalized oncology.
| S-EPMC8857263 | biostudies-literature