Therapy For HER2-positive Metastatic Breast Cancer Research Articles

The MiR-200c/FOXP3 Network: A Promising Biomarker for Predicting Trastuzumab Response in HER2-Positive Breast Cancer.

Purpose: Resistance to Trastuzumab is a significant challenge in the management of HER2-positive Metastatic Breast cancer (HER2-MBC), and a better understanding of the molecular causes of resistance is required to develop more effective treatment plans. While elevated plasma levels of miR-200 and FOXP3 have been linked to breast cancer progression and treatment response, no clinical studies have confirmed these results. Methods: The study involved 40 patients with HER2-positive metastatic breast cancer (HER2-MBC). The expression levels of miR-200c-3p and the FOXP3 gene were assessed in plasma samples at two time points: baseline (BL) and after the consent completion of one cycle of Trastuzumab, utilizing quantitative polymerase chain reaction (qPCR). Clinical response to Trastuzumab was evaluated 12 months post-therapy and correlated with the time to progression (TTP) through Kaplan-Meier analysis. Results: Low plasma expression level of miR-200c-3p was detected before therapy in HER2-MBC, compared to healthy controls, and decreased dramatically in the follow-up sample at disease progression, while increased after one cycle of Trastuzumab therapy in patients who were sensitive to Trastuzumab. At baseline, a low expression level of miR-200c was significantly associated with overexpression of FOXP3, poor prognosis, and shorter time to progression. Conclusions: The findings suggest that miR-200c-3p may be a promising biomarker for predicting the response to Trastuzumab in HER2-MBC patients.

The efficacy of pyrotinib-based therapy in lapatinib-resistant metastatic HER2-positive breast cancer.

Human epidermal growth factor receptor 2 (HER2)-positive breast cancer tends to metastasize and is associated with poor prognosis. Anti-HER2 treatment combined with chemotherapy or endocrine therapy is often used for HER2-positive metastatic breast cancer (MBC). For later lines of therapy in HER2-positive MBC, there is no standard treatment. We investigated the efficacy of pyrotinib, a new irreversible tyrosine kinase inhibitor (TKI) targeting epidermal growth factor receptor, HER2, and HER4, in lapatinib-resistant HER2-positive MBC patients. This is a retrospective observational study including lapatinib-resistant HER2-positive MBC patients who received pyrotinib-based treatment. We used the Kaplan-Meier method for the survival analyses. A total of 31 patients were included. Concurrent treatments included cytotoxic chemotherapy (29 patients, 93.6%), endocrine therapy (1 patient, 3.2%), and another targeted therapy (1 patient, 3.2%). The objective response rate (ORR) was 25.8% and the median progression-free survival in the study population was 4.5 months (95% CI: 3.1-5.9 months). The treatment-related adverse events (AEs) included diarrhea, neutropenia, vomiting, fatigue, and thrombocytopenia. Dose reduction to 320 mg was conducted in 19.4% of all cases due to severe AEs. Pyrotinib-based treatment was effective and generally well tolerated in lapatinib-resistant HER2-positive MBC for later line treatment.

Trastuzumab, Pertuzumab, and Docetaxel as the First Line for HER-2-Positive Metastatic Breast Cancer among Arabs

Introduction: Human epidermal growth factor receptor 2 (HER-2) targeted therapy regimens can improve tumor response in HER-2-positive metastatic breast cancer (MBC), with overall survival benefits. Objective: We evaluated the efficacy of dual HER-2 blockade combined with chemotherapy for HER-2-positive MBC patients as a first-line therapy in our patient population. Patients and Methods: We identified 75 patients at King Faisal Specialist Hospital and Research Center that received trastuzumab, pertuzumab, and docetaxel as a first-line therapy in HER-2 positive MBC in 2013–2016. Results: Median age at diagnosis was 45 years; 54.7% were estrogen receptor (ER)-positive. 10% of patients presented with only bone metastasis. The median follow-up time was 36 months with an objective response rate of 74.7% (complete response [CR] 18.7%; partial response [PR] 56%). The 5-year progression-free survival (PFS) and overall survival (OS) were 21% and 71.9% respectively, with a median PFS of 36 months (95% confidence interval [CI] 23.6–48.4). The 5-year OS for ER-negative and ER-positive patients was 93.9% and 59.4% respectively (p = 0.189); 23 patients experienced grade 1/2 toxicity and 2 patients had grade 3/4 toxicity. In terms of OS and PFS, the site of metastasis did not make any significant difference. Conclusions: First line pertuzumab, trastuzumab, and docetaxel for HER-2-positive MBC patients was found to be an effective and safe therapy in the Saudi population. This finding was consistent with the results seen in the CLEOPATRA trials.

Advances in anti-HER2 therapy in metastatic breast cancer.

Though most patients with breast cancer are cured, there are still many patients progressed to metastatic breast cancer (MBC) and some are diagnosed as MBC. Human epidermal growth factor receptor 2 (HER2) is positive in about 20% all breast cancer patients and considered as a poor prognostic factor. The advent of ant-HER2 therapy has prominently prolonged the time of disease progression and survival for HER2-positive MBC patients. This review summarizes the advance in anti-HER2 therapy in HER2-positive MBC according to the phase III clinical trials, and briefly discusses some new agents and anti-HER2 therapy for HER2 low-or non-expression breast cancer patients.

Eribulin in combination with pertuzumab plus trastuzumab for HER2-positive advanced or recurrent breast cancer (JBCRG-M03).

1025 Background: Pertuzumab (P) provided overall and progression-free survival (PFS) benefits in HER2-positive metastatic breast cancer (MBC) in the CLEOPATRA study as a first-line therapy. However, long-term administration of intravenous docetaxel at a dose of 75 mg/m2 every 3 weeks in MBC patients is difficult. Eribulin (E) is a well-tolerated cytotoxic agent. We report the efficacy and safety of E in combination with trastuzumab (T) plus P as first- and second-line therapy for metastatic or advanced BC in a multicenter, open-label phase II study (UMIN000012232). Methods: HER2-positive advanced or recurrent BC patients with no or a single prior therapy as advanced or recurrent chemotherapy were enrolled. All patients were administered T and taxane as adjuvant or first-line chemotherapy. Treatment consisted of E 1.4 mg/m2 on days 1 and 8 of a 21-day cycle and T (8 mg/kg loading dose > 6 mg/kg) plus P (840 mg loading dose > 420 mg) once every 3 weeks, all given intravenously. The primary end point was PFS. Results: From November 2013 to April 2016, 50 patients were enrolled. Forty-nine patients were eligible for safety analysis; full analysis set (FAS) includes 46 patients. The median patient age was 56 years (range 23–70), and 8 (16%) and 41 (84%) patients were treated in first- and second-line settings, respectively. Twenty-eight patients out of 49 patients (57%) continued the protocol therapy at the end of 8 cycles and median PFS was not yet reached. The response rate by RECIST ver.1.1 was 56.5% in FAS. The relative dose intensity of E, T, and P were 93.3% (range 77.0%–100%), 100% (range 96.0%–100%) and 100% (range 89.7%–100%), respectively in FAS. The grade 3/4 adverse effects (AE) were neutropenia in 5 patients (10.2%) including 2 patients (4.1%) with febrile neutropenia, hypertension in 3 patients (6.1%), and other AEs in only one patient. Average of the ejection fraction did not decrease significantly. Symptomatic left ventricular systolic dysfunction was not observed. Conclusions: E in combination with T plus P was well-tolerated and could be an alternative to docetaxel-based combination therapy for HER2-positive MBC. Clinical trial information: 000012232.

Trastuzumab combined with doublet or single-agent chemotherapy as a first-line treatment for HER2-positive metastatic breast cancer.

e12511 Background: To investigate the efficacy and safety of doublet vs. single-agent chemotherapy (CT) plus trastuzumab as first-line treatments for human epidermal growth factor 2 receptor (HER2)-positive metastatic breast cancer (MBC). Methods: We searched for randomized clinical trials (RCTs) that investigated the treatment effects of single-agent or doublet CT+H as first-line therapies for HER2-positive MBC. The main outcome measures for this analysis included the overall response rate (ORR), progression-free survival (PFS), and overall survival (OS). Meta-analyses and trial sequential analyses (TSA) were conducted. The study quality was evaluated using the GRADE framework. The PROSPERO registry number is CRD42016043766. Results: The results from four RCTs that included 1,044 participants were pooled. Moderate-quality evidence indicated that doublet CT+H better correlated with prolonged PFS (hazard ratio [HR] = 0.69, 95% confidence interval (CI) 0.63 to 0.75, P < 0.0001) and OS (HR = 0.90, 95% CI 0.88 to 0.92, P < 0.0001) than did single-agent CT+H; however, moderate-quality evidence indicated there was no significant difference between the two drug regimens regarding the ORR (relative risk [RR] = 1.07, 95% CI 0.98 to 1.17, P = 0.157), as confirmed by TSA, which indicated that the cumulative Z-curve entered the futility area. There was moderate-quality evidence that the treatment-related grade 3 to 4 toxicities of thrombocytopenia (RR = 4.08, P = 0.000; number needed to treat to harm (NNTH) = 20), nausea/vomiting (RR = 4.26, P = 0.002; NNTH = 25), diarrhea (RR = 2.81, P = 0.002; NNTH = 25), and stomatitis (RR = 5.02, P= 0.003; NNTH = 25) were more frequent with doublet CT+H than single-agent CT+H. Conclusions: Doublet CT+H is associated with longer PFS and OS than single-agent CT+H when used as a first-line therapy for HER2-positive MBC.

Effects of hormone receptor status on the durable response of trastuzumab-based therapy in metastatic breast cancer.

Trastuzumab-based treatment is the standard care for patients with HER2+ metastatic breast cancer (MBC). About 10% of HER2+ MBC showed a long-term durable response (progression-free survival, PFS>3years) to trastuzumab-based therapy. The aim of this study is to identify clinico-pathologic factors for a durable response to trastuzumab-based therapy in HER2-positive MBC. In the Yonsei Breast Cancer MBC Database, we identified 1218 MBC patients who were diagnosed from 2006 to 2015. Among them, 294 had HER2+ disease, and 153 received trastuzumab plus taxane chemotherapy as first-line treatment. Clinico-pathologic factors, such as hormone receptor (HR) status and metastatic sites, were reviewed. To evaluate a durable response, landmark analysis was performed. The median follow-up time was 28months (95% CI 4.4-83.0months). Of 153 HER2+ patients, there were 73 HR- patients (47.7%), and bone was the most common metastatic site. The median PFS and overall survival (OS) were 12 and 39months, respectively. HR- patients showed a tendency toward longer PFS (median, 13 vs. 11months, P=0.160) compared with HR+ patients. Patients with non-visceral metastases had longer median PFS and OS than those with visceral disease (median PFS, 15 vs. 11months, P=0.012; median OS, 75 vs. 34months, P=0.03). Landmark analysis at 9months suggested that the PFS of HR- patients was significantly longer than that of HR+ patients (median, 19 vs. 9months, P=0.008). Among patients with HER2+ MBC, HR status is a possible predictive biomarker of a durable response to trastuzumab-based therapy.

PHEREXA: A phase III study of trastuzumab (H) + capecitabine (X) ± pertuzumab (P) for patients (pts) who progressed during/after one line of H-based therapy in the HER2-positive metastatic breast cancer (MBC) setting.

504Background: P provides a progression-free and overall survival (PFS, OS) benefit in HER2-positive MBC, and is standard of care in the 1st line. Continuing H post-progression on 1st-line H improves response and time to progression. H + X is well tolerated and more effective than X in these pts, and dual P + H anti-HER2 therapy has activity in this population. However, efficacy and safety of P + H + X is unknown. We report the primary analysis of a multicenter, open-label randomized study of H + X vs P + H + X (NCT01026142). Methods: Pts who received a prior taxane and progressed during/after 1st-line H-based therapy for HER2-positive MBC were randomized to intravenous (IV) H 8 mg/kg then 6 mg/kg q3w + oral X 1250 mg/m2 twice daily (2 weeks on, 1 week off q3w; Arm A) or IV P 840 mg then 420 mg q3w + IV H per Arm A + oral X per Arm A but at 1000 mg/m2 (Arm B). The primary endpoint was independent review facility-assessed PFS (IRF PFS). The secondary endpoints of OS and safety are also reported. Hierarchic...

Abstract P5-11-05: Making a difficult conversation easier: Estimating and explaining scenarios for survival time in patients with HER2 positive, metastatic breast cancer

Abstract Aim Advances in the treatment of HER2 positive metastatic breast cancer (MBC) have resulted in significant improvements in survival time. Therefore, when estimating survival time, HER2 positive MBC now needs to be considered as a separate entity to HER2 negative MBC. Using data from trials of HER2 targeted therapies for HER2 positive MBC, we aimed to estimate worst-case, typical, and best-case scenarios for survival time to provide oncologists with a simple method to estimate and explain survival time to their patients in this situation. Method We sought randomised trials of HER2 targeted therapies in MBC published from 2001 to 2014. We recorded median progression free survival (PFS), median overall survival (OS), and extracted the following percentiles (represented scenario) from each OS curve: 90th (worst-case), 75th (lower-typical), 25th (upper-typical), and 10th (best-case). We also estimated these scenarios for each OS curve by multiplying its median by four simple multiples: 0.25 (worst-case), 0.5 (lower-typical), 2 (upper-typical), and 3 (best-case). Estimates were deemed accurate if within 0.75 to 1.33 times the actual value. Results We reviewed 10 first-line and 5 subsequent-line trials of HER2 targeted therapies: 8 of trastuzumab, 6 of lapatinib, 2 of trastuzumab-emtansine (TDM-1), 1 of pertuzumab and 1 of neratinib. The mean for median PFS was 11.1 months (interquartile range [IQR], 8.1 – 12.9) for first-line trials and 5.6 months (IQR 3.6 -6.6) for subsequent-line trials. The scenarios for overall survival are tabulated. Follow-up was insufficient for the best-case scenario (10th percentile) to be extracted from any curve. Simple multiples of the median OS provided accurate estimates of the worst-case scenario in 75% of OS curves, lower-typical in 100% and upper-typical in 88%. Characteristics associated with a longer median OS in first-line trials were: dual HER2 targeted therapy (adding a second agent increased the median OS by 25 months [95% CI 12-38, p = 0.001), and more recent year of publication (for each 1 year increase in year of publication, median OS increased by 1 month, [95% CI 0.2 to 2, p=0.02] Table 1: Scenarios for overall survival Mean(IQR) in monthsTreatment Group(n)Worst-caseLower-typicalMedian OSUpper-typicalBest-case1st-line HER2 trials26769.4 (7.7-11.0)18.8 (16.4 - 20.8)34.2 (29.1-38.4)56.2 (47.1-63.3)Not evaluableSubsequent-line HER2 trials21225.7 (4.1-7.3)10.7 (8.6-12.8)19.9 (15.2-24.4)21.7 (20.0-23.0)Not evaluable Conclusions The median OS for women starting first-line HER2 targeted therapies for HER2 positive MBC was on average 34 months. For most OS curves, simple multiples of the median provided accurate estimates of the worst-case (one-quarter of the median) and typical (half to double the median) scenarios for survival. Longer follow-up is needed to determine the best-case scenario, which is likely to be greater than triple the median OS. For a woman starting first-line HER2 targeted therapy, survival time could be explained as a worst-case scenario of less than 9 months, typical scenario of 18 months to 4.5 years, and a best-case scenario of 8 years or longer. This framework will help oncologists discuss survival times with their patients. Citation Format: Vasista A, Stockler M, West T, Wilcken N, Kiely B. Making a difficult conversation easier: Estimating and explaining scenarios for survival time in patients with HER2 positive, metastatic breast cancer. [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 P5-11-05.

Trastuzumab emtansine (T-DM1) in previously treated HER2-positive metastatic breast cancer (MBC): Results from an expanded access study.

166 Background: T-DM1 is an antibody-drug conjugate composed of trastuzumab, a stable linker, and the cytotoxic agent DM1. Few T-DM1 data are available in settings approximating clinical practice. We present safety and efficacy data from T-PAS, an expanded access study of T-DM1 in patients (pts) with previously treated HER2-positive MBC. Methods: T-PAS is a US multicenter study of T-DM1 (3.6 mg/kg q3w) in HER2-positive (IHC 3+ or FISH/CISH+) locally advanced or MBC. Key eligibility criteria: prior anthracycline and taxane; prior capecitabine or 5-FU and ≥2 HER2-directed agents (including trastuzumab and lapatinib) for MBC; LVEF ≥50%. Primary endpoint: safety; secondary endpoint: investigator-assessed objective response rate (ORR) in pts with measurable disease. Safety was assessed on day 1 of each cycle; ECHO/MUGA scans were every 12 weeks. Results: This analysis includes 215 pts enrolled in May 2010–Sep 2011 (data cutoff 7/31/2012). Pts received a median of 7 prior systemic MBC therapies (range 1–23) with a median cumulative anthracycline dose of 240 mg/m2(range 6–2645). At baseline, median LVEF was 60% and 50% of pts had investigator-reported cardiovascular disease. Median follow-up was 5.9 months (range 0.1–25.3); median T-DM1 duration was 5.0 months (range 0–23) with 15.8% receiving >18 cycles. ORR was 25.6% (42/164). Rate of grade ≥3 AEs was 43.7% and of SAEs of any grade was 18.1%. Most common all-grade AEs were fatigue (50.7%), nausea (36.3%), and headache (24.2%). Most common grade ≥3 AEs were thrombocytopenia (7.9%), fatigue (4.7%), and increased aspartate aminotransferase and anemia (each 3.7%). There were no grade ≥3 bleeding events. Cardiac dysfunction (primarily asymptomatic decreases in LVEF) was reported in 8 pts (3.7%); 4 were grade ≥3, 3 resulting in T-DM1 discontinuation. Conclusions: In this study that more closely reflects the real-world setting, the safety profile of T-DM1 was similar to that previously reported in conventional clinical trials, with no new safety signals. In this pretreated population (median of 7 prior therapies for HER2-positive MBC), significant activity was observed. Clinical trial information: NCT01120561.

A Phase II Trial of Oxaliplatin and Trastuzumab in the Treatment of HER2-Positive Metastatic Breast Cancer

ABSTRACTWe investigated the feasibility/efficacy of oxaliplatin in combination with trastuzumab as first-/second-line treatment of HER2-positive metastatic breast cancer (MBC). Patients received oxaliplatin/trastuzumab every 21 days and were evaluated every 6 weeks using RECIST criteria. The study closed early due to slow accrual. Twenty-five patients were evaluable; of these, 5 (20%) had objective responses to oxaliplatin/trastuzumab. Therapy was well tolerated (no grade-4 and gastrointestinal grade-3 toxicity in 4% of patients), but had only modest activity (median time-to-progression 1.8 months). Substitution of oxaliplatin for cisplatin or carboplatin, in combination with trastuzumab, does not appear to improve first-/second-line therapy in HER2-positive MBC.

Trastuzumab (T) treatment beyond progression in metastatic breast cancer (MBC): Patterns of care in Swiss clinical practice.

1146 Background: T is an established therapy for HER2-positive MBC as monotherapy or as part of combination with several chemotherapies (CT). T beyond progression (after first-line T-based therapy) seems to be a frequently used treatment option. We analyzed treatment strategies in pts with HER2-positive MBC over several lines of therapy. Methods: Six Swiss breast cancer centers participated in this retrospective cohort study. Pts with HER2-positive MBC progressing after T (January 2006 to December 2007) were eligible. Data collection included type and duration of anti-HER2 therapy and time to progression (TTP) for each line. Results: All 72 pts (median age 58 years, range 28-81) received T as first anti-HER2 therapy. Combination therapy with T/CT was preferred over T monotherapy (49 vs. 23 pts). T was combined with vinorelbine in 23, with taxanes in 22 and with other CT in 4 pts. In first- line, TTP for both nontaxane and taxane combinations was 35 weeks. After progression, 67 pts received second-line T-b...