HER2-overexpressing Metastatic Breast Cancer Research Articles

Abstract PS09-03: Neoadjuvant zanidatamab for stage I node negative HER2 positive breast cancer

Abstract Background: The addition of trastuzumab+/-pertuzumab to chemotherapy has changed the natural history of earlyHER2+ breast cancer. However, trials with targeted therapy alone are needed to avoid acute and chronic toxicities of chemotherapy. Zanidatamab is a novel, humanized, bispecific, immunoglobulin G isotype 1-like, monoclonal antibody directed against the juxtamembrane extracellular and dimerization domains (ECD2, ECD4) of HER2. The biparatopic nature of zanidatamab results in HER2 clustering that modulates signaling and leads to immune activation. Zanidatamab has demonstrated antitumor activity in heavily pre-treated HER2 overexpressing metastatic breast cancer with an acceptable safety profile. We hypothesized that zanidatamab would be a safe and effective regimen for women with node negative stage I HER2+ BC. Methods: Patients with 1-3 cm, clinically node negative HER2+ BC were enrolled in a single-institution investigator-initiated clinical trial. Patients had HER2+ breast cancer: HER2 3+ by IHC or IHC 2+ and ISH +. Patients received six to ten doses of zanidatamab, 20 mg/kg IV every 2 weeks prior to surgery. Patients with ER+ tumors also received neoadjuvant endocrine therapy. Post-menopausal patients received letrozole 2.5 mg daily, and pre-menopausal patients received tamoxifen 20 mg daily or GNRH and letrozole 2.5 mg. The primary objective was to evaluate efficacy as determined by pathologic complete response (pCR). Secondary objectives included pathologic response by residual cancer burden (RCB), radiological response, and safety profile of zanidatamab. Results: Twenty patients with HER2+ breast cancer were enrolled. Median age was 62 years old (range 30-73). Fifteen patients had HER2 3+, and 5 HER2 2+/ISH+ tumors with a median size of 1.95 cm (range 1-3 cm) and 10 patients had tumors >2 cm. Seven patients were pre-menopausal. Six received tamoxifen and 8 letrozole. Eleven patients completed 6 cycles and 9 patients will receive 10 cycles of zanidatamab. Eleven patients already had surgery the remainder patients will have surgery by Oct 30, 2023. Four (36%) had pCR, 3 RCB1 (28%) and 4 RCB2 (36%). Treatment was tolerated well. There were no grade 3 or 4 toxicities. One patient had minor infusion related reaction and grade 2 acne, and 2 grade 2 diarrhea. Conclusions: Neoadjuvant zanidatamab demonstrates significant preliminary efficacy, (pCR/RCB-1 64%) with a good safety profile in patients with stage I node negative HER2+ BC. An update of efficacy and safety of all patients will be presented at the time of meeting Citation Format: Vicente Valero, Jason Mouabbi, Heather Alonzo, Paula Pohlmann, Adaeze Lheme, Amy Hassan, Rashmi Murthy, Xuelin Huang, Wei Qiao, Miral Patel, Gaiane Rauch, Cristina Checka, W. Fraser Symmans, Kelly Hunt, Debu Tripathy, Funda Meric-Bernstam. Neoadjuvant zanidatamab for stage I node negative HER2 positive breast cancer [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PS09-03.

Abstract CT265: Trastuzumab emtansine in patients (pts) with HER2 mutation-positive (HER2mut) tumors: TAPISTRY study

Abstract Background: HER2 point mutations are found in ~1.4% of solid tumors, but prevalence varies across tumor types. Trastuzumab emtansine is an antibody-drug conjugate approved in HER2-overexpressing metastatic breast cancer. Here we present efficacy and safety data of trastuzumab emtansine in pts with HER2mut advanced/metastatic solid tumors (excluding HER2 amplifications) from Cohort F of the TAPISTRY trial (NCT04589845). Methods: TAPISTRY is a phase II, global, open-label, multi-cohort basket trial evaluating the efficacy and safety of multiple therapies in pts with advanced/metastatic solid tumors. Pts in Cohort F were ≥12 years old, with tumors harboring an activating HER2 mutation identified by NGS, and measurable disease by RECIST v1.1. Trastuzumab emtansine 3.6 mg/kg IV was administered every 21 days; tumor assessments were performed at screening, every 6 weeks from day 1/cycle 1 for one year, and every 9 weeks thereafter. Primary endpoint: objective response rate (ORR) by independent review committee (IRC). Key secondary endpoints: ORR by investigator; duration of response; progression-free survival; overall survival; safety. Results: At data cut-off (16 Jul 2023), 35 pts with 10 different tumor types were efficacy evaluable; the most common tumor type was non-small cell lung cancer (NSCLC; 31%). Baseline characteristics and key outcomes are presented in the Table. After a median follow-up of 7 months, ORR by IRC in efficacy-evaluable pts was 14.3% (n/N=5/35; 95% CI 4.8-30.3]). Responses were observed in 3 tumor types: NSCLC (n/N=1/11), breast (n/N=3/5), endometrial (n/N=1/1). The most frequent adverse events were decreased appetite, fatigue, and nausea (25.7% each). No new safety signals were identified. Conclusions: Trastuzumab emtansine in pts with HER2mut tumors (excluding HER2 amplifications) did not meet its primary endpoint. Trastuzumab emtansine was generally well tolerated and the safety profile was consistent with the known profile of the drug. TABLE 1. NAND Baseline characteristics Trastuzumab emtansine N=35 Median age, years (range) 67 (29-83) Female, n (%) 22 (62.9) Prior lines of therapy, n (%) - No prior lines of therapy/1 prior line of therapy/≥2 prior lines of therapy 1 (2.9)/8 (22.9)/26 (74.3) Efficacy N=35 Objective response rate by IRC, n (%) [95% CI] 5 (14.3)* [4.8-30.3] Complete response 0 Partial response 5 (14.3) Stable disease 14 (40.0) Progressive disease 10 (28.6) Missing† 6 (17.1) Clinical benefit rate by IRC, n (%)‡ 8 (22.9) Objective response rate by investigator, n (%) 2 (5.7) Median duration of response, months (95% CI) - By IRC/By investigator 9.4 (2.8-NE)/11.8 (8.3-NE) Median progression-free survival, months (95% CI) - By IRC/By investigator 3.3 (1.4-4.3)/2.7 (1.5-3.9) Median overall survival, months (95% CI) 10.0 (6.2-13.4) Safety, n (%) N=35 ≥1 AE 33 (94.3) Grade 3-5 AEs 19 (54.3) AE-related deaths 4 (11.4) Serious AEs 13 (37.1) AEs leading to withdrawal from study 4 (11.4) Treatment-related AEs 25 (71.4) Treatment-related AEs leading to withdrawal from study 1 (2.9) *By tumor type: non-small cell lung cancer (n=1), breast (n=3), and endometrial (n=1); †Six patients had missing data due to: death (n=4), clinical progression (n=1), or withdrawal of consent (n=1) prior to first scan; ‡Criteria for clinical benefit: either a response (confirmation not required) and/or stable disease or better for at least 24 weeks. AE, adverse event; CI, confidence interval; NE, not estimable. Citation Format: Jeong Eun Kim, David Thomas, Shirish Gadgeel, Marcelo Corassa, Tira J. Tan, Eugenia Girda, Donald Richards, Sabine Tejpar, David Chen, Junhan Fang, Sid Patel, Timothy R. Wilson, Fabrice Barlesi. Trastuzumab emtansine in patients (pts) with HER2 mutation-positive (HER2mut) tumors: TAPISTRY study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr CT265.

Trastuzumab deruxtecan in metastatic breast cancer with variable HER2 expression: the phase 2 DAISY trial.

The mechanisms of action of and resistance to trastuzumab deruxtecan (T-DXd), an anti-HER2-drug conjugate for breast cancer treatment, remain unclear. The phase 2 DAISY trial evaluated the efficacy of T-DXd in patients with HER2-overexpressing (n = 72, cohort 1), HER2-low (n = 74, cohort 2) and HER2 non-expressing (n = 40, cohort 3) metastatic breast cancer. In the full analysis set population (n = 177), the confirmed objective response rate (primary endpoint) was 70.6% (95% confidence interval (CI) 58.3-81) in cohort 1, 37.5% (95% CI 26.4-49.7) in cohort 2 and 29.7% (95% CI 15.9-47) in cohort 3. The primary endpoint was met in cohorts 1 and 2. Secondary endpoints included safety. No new safety signals were observed. During treatment, HER2-expressing tumors (n = 4) presented strong T-DXd staining. Conversely, HER2 immunohistochemistry 0 samples (n = 3) presented no or very few T-DXd staining (Pearson correlation coefficient r = 0.75, P = 0.053). Among patients with HER2 immunohistochemistry 0 metastatic breast cancer, 5 of 14 (35.7%, 95% CI 12.8-64.9) with ERBB2 expression below the median presented a confirmed objective response as compared to 3 of 10 (30%, 95% CI 6.7-65.2) with ERBB2 expression above the median. Although HER2 expression is a determinant of T-DXd efficacy, our study suggests that additional mechanisms may also be involved. (ClinicalTrials.gov identifier NCT04132960 .).

Efficacy and Safety of Trastuzumab as a Single Agent in First-Line Treatment of HER2-Overexpressing Metastatic Breast Cancer.

To evaluate the efficacy and safety of first-line, single-agent trastuzumab in women with HER2-overexpressing metastatic breast cancer. One hundred fourteen women with HER2-overexpressing metastatic breast cancer were randomized to receive first-line treatment with trastuzumab 4 mg/kg loading dose, followed by 2 mg/kg weekly, or a higher 8 mg/kg loading dose, followed by 4 mg/kg weekly. The objective response rate was 26% (95% confidence interval [CI], 18.2% to 34.4%), with seven complete and 23 partial responses. Response rates in 111 assessable patients with 3+ and 2+ HER2 overexpression by immunohistochemistry (IHC) were 35% (95% CI, 24.4% to 44.7%) and none (95% CI, 0% to 15.5%), respectively. The clinical benefit rates in assessable patients with 3+ and 2+ HER2 overexpression were 48% and 7%, respectively. The response rates in 108 assessable patients with and without HER2 gene amplification by fluorescence in situ hybridization (FISH) analysis were 34% (95% CI, 23.9% to 45.7%) and 7% (95% CI, 0.8% to 22.8%), respectively. Seventeen (57%) of 30 patients with an objective response and 22 (51%) of 43 patients with clinical benefit had not experienced disease progression at follow-up at 12 months or later. The most common treatment-related adverse events were chills (25% of patients), asthenia (23%), fever (22%), pain (18%), and nausea (14%). Cardiac dysfunction occurred in two patients (2%); both had histories of cardiac disease and did not require additional intervention after discontinuation of trastuzumab. There was no clear evidence of a dose-response relationship for response, survival, or adverse events. Single-agent trastuzumab is active and well tolerated as first-line treatment of women with metastatic breast cancer with HER2 3+ overexpression by IHC or gene amplification by FISH.

Flashback Foreword: Activity of First-Line Trastuzumab

Article Tools FLASHBACK FOREWORD Article Tools OPTIONS & TOOLS Export Citation Track Citation Add To Favorites Rights & Permissions COMPANION ARTICLES Efficacy and Safety of Trastuzumab as a Single Agent in First-Line Treatment of HER2-Overexpressing Metastatic Breast Cancer. March 15, 2023 JCO Flashback: Trastuzumab Monotherapy for HER2-Positive Breast Cancer (2002). March 15, 2023 ARTICLE CITATION DOI: 10.1200/JCO.22.02843 Journal of Clinical Oncology - published online before print March 15, 2023 PMID: 36921334 Flashback Foreword: Activity of First-Line Trastuzumab Jennifer J. Griggs, MD, MPH1xJennifer J. GriggsSearch for articles by this author Show More 1Journal of Clinical Oncology, Alexandria, VA https://doi.org/10.1200/JCO.22.02843 First Page Full Text PDF Figures and Tables © 2023 by American Society of Clinical OncologyTHE TAKEAWAYIn 2002, Vogel et al1 demonstrated that single-agent trastuzumab in people with human epidermal growth factor receptor 2–positive metastatic breast cancer yielded a response rate rivaling chemotherapy and a nonprogression rate of more than 50% at 12 months in people who had declined chemotherapy as first-line therapy. The effect of this trial was the demonstration of activity of single-agent trastuzumab in people with breast cancer who decline chemotherapy and to further illustrate the predictive importance of high levels of overexpression and overamplification of human epidermal growth factor receptor 2.AUTHOR'S DISCLOSURES OF POTENTIAL CONFLICTS OF INTERESTFlashback Foreword: Activity of First-Line TrastuzumabThe following represents disclosure information provided by the author of this manuscript. All relationships are considered compensated unless otherwise noted. Relationships are self-held unless noted. I = Immediate Family Member, Inst = My Institution. Relationships may not relate to the subject matter of this manuscript. For more information about ASCO's conflict of interest policy, please refer to www.asco.org/rwc or ascopubs.org/jco/authors/author-center.Open Payments is a public database containing information reported by companies about payments made to US-licensed physicians (Open Payments).Jennifer J. GriggsEmployment: Anglona CorporationStock and Other Ownership Interests: Anglona CorporationNo other potential conflicts of interest were reported. Companion Efficacy and Safety of Trastuzumab as a Single Agent in First-Line Treatment of HER2-Overexpressing Metastatic Breast Cancer JCO Flashback: Trastuzumab Monotherapy for HER2-Positive Breast Cancer (2002)

Multinational Study of the Efficacy and Safety of Humanized Anti-HER2 Monoclonal Antibody in Women Who Have HER2-Overexpressing Metastatic Breast Cancer That Has Progressed After Chemotherapy for Metastatic Disease.

Overexpression of the HER2 protein occurs in 25% to 30% of human breast cancers and leads to a particularly aggressive form of the disease. Efficacy and safety of recombinant humanized anti-HER2 monoclonal antibody as a single agent was evaluated in women with HER2-overexpressing metastatic breast cancer that had progressed after chemotherapy for metastatic disease. Two hundred twenty-two women, with HER2-overexpressing metastatic breast cancer that had progressed after one or two chemotherapy regimens, were enrolled. Patients received a loading dose of 4 mg/kg intravenously, followed by a 2-mg/kg maintenance dose at weekly intervals. Study patients had advanced metastatic disease and had received extensive prior therapy. A blinded, independent response evaluation committee identified eight complete and 26 partial responses, for an objective response rate of 15% in the intent-to-treat population (95% confidence interval, 11% to 21%). The median duration of response was 9.1 months; the median duration of survival was 13 months. The most common adverse events, which occurred in approximately 40% of patients, were infusion-associated fever and/or chills that usually occurred only during the first infusion, and were of mild to moderate severity. These symptoms were treated successfully with acetaminophen and/or diphenhydramine. The most clinically significant adverse event was cardiac dysfunction, which occurred in 4.7% of patients. Only 1% of patients discontinued the study because of treatment-related adverse events. Recombinant humanized anti-HER2 monoclonal antibody, administered as a single agent, produces durable objective responses and is well tolerated by women with HER2-overexpressing metastatic breast cancer that has progressed after chemotherapy for metastatic disease. Side effects that are commonly observed with chemotherapy, such as alopecia, mucositis, and neutropenia, are rarely seen.

Flashback Foreword: Anti-HER2 Monoclonal Antibody as a Single Agent

Article Tools FLASHBACK FOREWORD Article Tools OPTIONS & TOOLS Export Citation Track Citation Add To Favorites Rights & Permissions COMPANION ARTICLES Multinational Study of the Efficacy and Safety of Humanized Anti-HER2 Monoclonal Antibody in Women Who Have HER2-Overexpressing Metastatic Breast Cancer That Has Progressed After Chemotherapy for Metastatic Disease. February 28, 2023 ARTICLE CITATION DOI: 10.1200/JCO.22.02679 Journal of Clinical Oncology - published online before print March 7, 2023 PMID: 36881997 Flashback Foreword: Anti-HER2 Monoclonal Antibody as a Single Agent Pamela J. Goodwin , MD, MSc1,2xPamela J. GoodwinSearch for articles by this author Show More 1Department of Medicine, Sinai Health System, University of Toronto, Toronto, Ontario, Canada2Former Associate Editor, Journal of Clinical Oncology, Alexandria, VA https://doi.org/10.1200/JCO.22.02679 First Page Full Text PDF Figures and Tables © 2023 by American Society of Clinical OncologyTHE TAKEAWAYIn 1999, Cobleigh et al1 demonstrated important activity of a single-agent recombinant humanized monoclonal antibody (now known as trastuzumab) targeting the human epidermal growth factor receptor (HER2) in women with pretreated metastatic HER2-positive breast cancer. This, along with subsequent studies of trastuzumab and other agents targeting HER2 in the metastatic and (neo)adjuvant settings, has revolutionized the management of HER2-positive breast cancer, leading to dramatic improvements in outcomes in both the early and metastatic settings.AUTHOR'S DISCLOSURES OF POTENTIAL CONFLICTS OF INTERESTFlashback Foreword: Anti-HER2 Monoclonal Antibody as a Single AgentThe following represents disclosure information provided by the author of this manuscript. All relationships are considered compensated unless otherwise noted. Relationships are self-held unless noted. I = Immediate Family Member, Inst = My Institution. Relationships may not relate to the subject matter of this manuscript. For more information about ASCO's conflict of interest policy, please refer to www.asco.org/rwc or ascopubs.org/jco/authors/author-center.Open Payments is a public database containing information reported by companies about payments made to US-licensed physicians (Open Payments).Pamela J. GoodwinResearch Funding: Epic Sciences (Inst)No other potential conflicts of interest were reported. Companion Multinational Study of the Efficacy and Safety of Humanized Anti-HER2 Monoclonal Antibody in Women Who Have HER2-Overexpressing Metastatic Breast Cancer That Has Progressed After Chemotherapy for Metastatic Disease

LBA72 Unraveling the mechanism of action and resistance to trastuzumab deruxtecan (T-DXd): Biomarker analyses from patients from DAISY trial

T-DXd is an anti-HER2 antibody-drug conjugate that demonstrated high efficacy in patients with HER2-overexpressing and HER2-low metastatic breast cancer (mBC). We aimed to explore the mechanism of action and resistance to T-DXd in patients from DAISY trial. DAISY is a phase II, multicenter, open-label trial (NCT04132960) that assessed T-DXd efficacy in three cohorts of patients with mBC according to HER2 expression and performed biomarker analyses. Efficacy and biomarker results have been reported previously (Dieras et al, SABCS 2021; Mosele et al, ESMO BREAST 2022). To further explore the mechanism of action of T-DXd, we assessed the spatial genomic response according to HER2 expression by GeoMx in biopsies at D2-4 after cycle 1 of T-DXd (n=8). In addition, biopsies at baseline with no detection of HER2 by IHC were assessed by RT-PCR (n=36). Finally, primary and secondary resistance were explored by whole-exome sequencing in biopsies at baseline (n=88) and at progression (n=20); and T-DXd distribution was assessed by IHC in biopsies at ≤6 weeks after last infusion at progression (n=6). Serotonin receptor pathways in HER2-overexpressing and interferon alpha pathways in HER2-negative area were activated after T-DXd administration. No association between ERBB2 expression and clinical response to T-DXd was observed. No recurrent driver alteration was associated with resistance. ERBB2 hemizygous deletion was detected in 5 out of 88 (6%) patients at baseline; four of them did not respond to T-DXd. SLX4 mutation was acquired in 2 biopsies out of 10 pairs (20%) at progression and was found in 2 samples unmatched with baseline (20%). In two BC cell lines, SLX4 silencing mediated resistance to DXd. T-DXd distribution was observed in 4 out of 6 patients at progression. T-DXd could trigger anti-tumor immune response in HER2-negative mBC. No recurrent drivers were identified at resistance. ERBB2 hemizygous deletion seems to be associated with T-DXd upfront resistance. SLX4 could induce secondary resistance; however, it needs to be confirmed. T-DXd uptake is not suggested to be a mechanism of resistance.

In Memoriam: José Baselga's Journey in Cancer Medicine.

In Memoriam: José Baselga's Journey in Cancer Medicine.

Abstract P1-18-22: Unlocking Her2 as a target in invasive lobular cancer and endocrine resistant invasive ductal carcinoma

Abstract Background: Invasive Lobular Carcinoma (ILC) is a molecular subtype of breast cancer that is usually hormone receptor (HR) positive and E-cadherin negative. Ninety percent of ILC carry CDH1 mutations. Although ILC patients have a seemingly favorable outlook at diagnosis, they suffer from late recurrences and hence the long-term outcomes are not as favorable suggesting resistance to conventional therapies. In vitro and in vivo studies have demonstrated cross talk between EGFR/HER2 with HR in inducing endocrine resistance1. Increase in HER2 expression at the time of recurrence has been reported, while HER2 activating mutations occur in approximately 15.4% of ILC’s2. Importantly, HER2 mutations are associated with significantly worse prognosis in patients with CDH1 mutated ILC3. We believe that HER2 is a viable target in ILC, and endocrine resistant IDC when combined with endocrine therapy. HER2 targeted therapy, such as Trastuzumab is not currently used to treat patients with normal HER2 expression as a recent clinical trial NSAPB B-47 found that Trastuzumab has very little effect on these patients. We hypothesize that ONT-380 (Tucatinib), a tyrosine kinase inhibitor (TKI) that is currently in clinical trials for HER2 overexpressing metastatic breast cancer, will be effective in treating normal HER2 expressing ILC and HR positive IDC that are relatively endocrine resistant. Combined treatment with TKI and anti-estrogen could improve responses to endocrine therapy. Methods: We have studied effects of ONT-380 in combination with Tamoxifen on cell proliferation using in vitro cell culture models. We used ERα positive cell lines with varying levels of HER2 expression BT474 (HER2+), and cell lines expressing basal level of HER2, ZR-75-1 (IDC), T47D (IDC), SUM44PE (ILC), and MDA-MB-134-VI (ILC) to understand the effects of simultaneous targeting of HER2 and ERα. We have used MTT assay (Promega) to compare cell proliferation in drug treated and untreated cells. Western blot analysis was used to measure the levels of pHER2Y877, pHER2Y1221/1222,pAKTS473, total HER2 and total AKT. Basal level and drug induced alteration in phosphorylation status of downstream targets of HER2 and ERα signaling will be assessed using Human RTK (Receptor Tyrosine Kinase) phosphorylation antibody array (Abcam). Results: Western blot analysis of whole cell extracts showed that the designated HER2 positive cells (BT474) have higher level of HER2 protein, while the other cells (ZR-75-1, T47D, SUM44PE, MDA-MB-134) have significantly lower level of HER2 protein. HER2 was not detectable in MCF7 cells. Similarly, pAKT, a downstream effector of EGFR/ HER2 signaling was higher in the HER2 positive cell lines. Treatment of ILC cell line MDA-MB-134-VI with ONT-380 (100nM) or Tamoxifen (10 μM) alone or in combination showed additive inhibition of cell proliferation when the two drugs were combined as opposed to single drug treatment. We have observed similar effect of ONT-380 and Tamoxifen on SUM44PE, BT474 and ZR-75-1 cells. Furthermore, treatment of ZR-75-1 cells with ONT-380 and Tamoxifen markedly reduced pAKT level, while the effect of treatment with individual drugs was barely detectable. Similar studies are underway for endocrine resistant ILC and additional IDC cell lines. Conclusion: Targeting HER2 kinase activity in normal HER2 expressing ILC and endocrine resistant IDC with small molecule inhibitors of tyrosine kinase could be a viable option for treating these cancers. Further in vitro and in vivo studies are underway to study the efficacy of this drug combination. 1. Schafer et.al. 2002 (PMID: 12650703) 2. Deniziaut et.al. 2016 (PMID: 27602491) 3. Ping et.al. 2016 (PMID: 27811364) Citation Format: Nikhil Pramod, Sivanesan Dhandayuthapani, Sarmila Majumder, Bhuvaneswari Ramaswamy. Unlocking Her2 as a target in invasive lobular cancer and endocrine resistant invasive ductal carcinoma [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 P1-18-22.

Predictive and prognostic value of circulating blood lymphocyte subsets in metastatic breast cancer.

The treatment of breast cancer (BC) has improved greatly in recent years, however, the limitations of current therapeutic modalities underscore the need to define new prognostic tools and develop highly targeted therapies. The aims of the present study were to explore the effects of circulating blood lymphocyte subsets on the survival of metastatic breast cancer (MBC) patients and to evaluate their predictive and prognostic value. The clinical data of 482 patients with MBC were retrospectively analyzed, and patients were grouped according to molecular types of BC. The distribution of peripheral blood lymphocyte subsets at the time of first metastasis was examined by flow cytometry, and the distribution of lymphocyte subsets in each group was categorized into ‘‘high or low’’ subgroups using the upper quartile point as the cutoff. The relationship between the distribution of lymphocyte subsets and progression‐free survival (PFS) as well as overall survival (OS) was evaluated in diverse molecular MBCs. In multivariate analysis, CD4+ was a negative independent predictor of PFS (hazard ratio [HR] = 0.538, 95% confidence interval [CI] = 0.313‐0.926, P = 0.025) and CD3+ was a poor independent prognostic factor for OS (HR = 0.437, 95% CI = 0.248‐0.772, P = 0.004) in the human epidermal growth factor receptor 2 (HER2)‐positive group. Neither the CD8+, CD19+, and CD56+ lymphocyte subsets nor the CD4+/CD8+ ratio in peripheral blood was significant predictive or prognostic factors. In conclusion, higher circulating levels of CD4+ and CD3+ at first diagnosis in HER2‐overexpressing MBC were significantly associated with worse survival outcomes. Low levels of plasma CD4+ and CD3+ were associated with increased anti‐HER2 benefit in HER2‐positive MBC. The present results indicate that these factors can be used as predictive and prognostic indicators of the outcome of patients with MBC.

Longer follow-up on clinical outcomes of weekly paclitaxel with trastuzumab and pertuzumab in patients with HER2 overexpressing metastatic breast cancer.

e13005Background: Favorable progression-free survival (PFS) and overall survival (OS) results were previously reported on a phase II trial of patients with human epidermal growth factor receptor 2 ...

VP09 Trastuzumab For Metastatic Breast Cancer Access Assessment In Brazil

Introduction:Trastuzumab is the most recent biological therapy incorporated by the Brazilian Health Ministry for HER-2 overexpressed metastatic breast cancer treatment (2012). The aim of this study was to investigate if access to this technology is appropriate.Methods:We performed a web-based questionnaire, which received answers from October 2016 to April 2017. Oncologists that work in the care of patients with overexpressed HER-2 metastatic breast cancer were the focus of the survey. Forty-three professionals informed work location, sector (public, private or both) and trastuzumab access. This research was approved by Brazilian Ethics Committee (CAE 59076316300005260).Results:Among 43 valid answers, nine informed they work in the public sector, 10 in the private sector and 24 in both sectors. In total, 33 reported to work in public and 34 in private sector. We observed that 17 (51.5 percent) participants who work in the public sector do not have access to trastuzumab, while in private sector only one participant (2.9 percent) reported the lack of access to this technology for HER-2 overexpressed metastatic breast cancer treatment. Regarding the respondents who informed the lack of access, six (33.3 percent) work in Northeast Brazilian region, six (33.3 percent) in Southeast, two (11.1 percent) in South, one (5.6 percent) in Central-West and three (16.7 percent) did not give this information. Eleven respondents reported they do not have another treatment option for these patients, while seven informed access only to chemotherapy without biological therapy.Conclusions:Trastuzumab is a biological therapy that can increase HER-2 overexpressed metastatic breast cancer patients overall survival by nine months on average. The questionnaire results indicate that its access in Brazil is still irregular, mainly in public sector, even five years after its incorporation by the Brazilian Health Ministry. Although universal access is one of Brazilian Public Health System main directives, there is evidence of a serious issue regarding its services equity.

Hersintuzumab: A novel humanized anti-HER2 monoclonal antibody induces potent tumor growth inhibition

Humanized monoclonal antibodies (mAbs) against HER2 including trastuzumab and pertuzumab are widely used to treat HER2 overexpressing metastatic breast cancers. These two mAbs recognize distinct epitopes on HER2 and their combination induces a more potent blockade of HER2 signaling than trastuzumab alone. Recently, we have reported characterization of a new chimeric mAb (c-1T0) which binds to an epitope different from that recognized by trastuzumab and significantly inhibits proliferation of HER2 overexpressing tumor cells. Here, we describe humanization of this mAb by grafting all six complementarity determining regions (CDRs) onto human variable germline genes. Humanized VH and VL sequences were synthesized and ligated to human γ1 and κ constant region genes using splice overlap extension (SOE) PCR. Subsequently, the humanized antibody designated hersintuzumab was expressed and characterized by ELISA, Western blot and flow cytometry. The purified humanized mAb binds to recombinant HER2 and HER2-overexpressing tumor cells with an affinity comparable with the chimeric and parental mouse mAbs. It recognizes an epitope distinct from those recognized by trastuzumab and pertuzumab. Binding of hersintuzumab to HER2 overexpressing tumor cells induces G1 cell cycle arrest, inhibition of ERK and AKT signaling pathways and growth inhibition. Moreover, hersintuzumab could induce antibody-dependent cell cytotoxicity (ADCC) on BT-474 cells. This new humanized mAb is a potentially valuable tool for single or combination breast cancer therapy.

A phase I open-label dose-escalation study of the anti-HER3 monoclonal antibody LJM716 in patients with advanced squamous cell carcinoma of the esophagus or head and neck and HER2-overexpressing breast or gastric cancer

BackgroundHuman epidermal growth factor receptor 3 (HER3) is important in maintaining epidermal growth factor receptor-driven cancers and mediating resistance to targeted therapy. A phase I study of anti-HER3 monoclonal antibody LJM716 was conducted with the primary objective to identify the maximum tolerated dose (MTD) and/or recommended dose for expansion (RDE), and dosing schedule. Secondary objectives were to characterize safety/tolerability, pharmacokinetics, pharmacodynamics, and preliminary antitumor activity.MethodsThis open-label, dose-finding study comprised dose escalation, followed by expansion in patients with squamous cell carcinoma of the head and neck or esophagus, and HER2-overexpressing metastatic breast cancer or gastric cancer. During dose escalation, patients received LJM716 intravenous once weekly (QW) or every two weeks (Q2W), in 28-day cycles. An adaptive Bayesian logistic regression model was used to guide dose escalation and establish the RDE. Exploratory pharmacodynamic tumor studies evaluated modulation of HER3 signaling.ResultsPatients received LJM716 3–40 mg/kg QW and 20 mg/kg Q2W (54 patients; 36 patients at 40 mg/kg QW). No dose-limiting toxicities (DLTs) were reported during dose-escalation. One patient experienced two DLTs (diarrhea, hypokalemia [both grade 3]) in the expansion phase. The RDE was 40 mg/kg QW, providing drug levels above the preclinical minimum effective concentration. One patient with gastric cancer had an unconfirmed partial response; 17/54 patients had stable disease, two lasting >30 weeks. Down-modulation of phospho-HER3 was observed in paired tumor samples.ConclusionsLJM716 was well tolerated; the MTD was not reached, and the RDE was 40 mg/kg QW. Further development of LJM716 is ongoing.Trial registrationClinicaltrials.gov registry number NCT01598077 (registered on 4 May, 2012).

PTEN expression as a predictor for the response to trastuzumab-based therapy in Her-2 overexpressing metastatic breast cancer.

BackgroundEven though trastuzumab is an effective therapy in early stage Her-2+ breast cancer, 40–50% of advanced Her-2+ breast cancer patients develop trastuzumab resistance. A potential resistance mechanism is aberrant downstream signal transmission due to loss of phosphatase and tensin homologue (PTEN). This study investigated the relationship between the expression of PTEN and trastuzumab response in Her-2 overexpressing metastatic breast cancer patients.MethodsBetween 2000 and 2007, 164 patients with Her-2+ metastatic breast cancer received trastuzumab-based therapy in our institution. We analyzed PTEN status by immunohistochemistry of 115 available tumor tissues and analyzed associations with other histopathological parameters, response rate, progression free survival (PFS) and overall survival (OS) with a median follow-up of 60 months.ResultsEighty patients were PTEN positive (69.6%) and 35 patients PTEN negative (30.4%). We found a significant association of the expression of PTEN and p53 (p = 0.041), while there was no association with grading, hormone receptor status, IGFR or MIB. We found significantly more cases with progressive disease under trastuzumab-based therapy in patients with PTEN positive breast cancers (p = 0.018), while there was no significant correlation with PFS or OS.ConclusionIn Her-2-positive metastatic breast cancers, PTEN positivity was significantly associated with progressive disease, but not with PFS or OS.

Brain metastasis in patients with metastatic breast cancer in the real world: a single-institution, retrospective review of 12-year follow-up.

The data of 589 metastatic breast cancer (MBC) patients in a single institution were reviewed to determine the outcomes of patients with brain metastasis (BM) and assess the efficacy of BM screening. The patients with BM among the 589 MBC patients who underwent treatment at Shizuoka Cancer Center (Shizuoka, Japan) from 09/2002 to 03/2014 were retrospectively analyzed. During the study period, BM developed in 187 (31.7%) patients. The tumor subtypes were as follows: luminal (hormone receptor [HR]+, HER2-), 44.9%; luminal-HER2 (HR+, HER2+), 14.9%; HER2 (HR-, HER2+), 21.3%; and triple-negative (TN), 16.0%. BM was detected in 48.6% of the patients by screening MRI. While 137 of 187 patients underwent local therapy, whole-brain irradiation was the most frequently applied therapy (63.5%). The median overall survival from the diagnosis of BM was as follows: luminal, 7.0months (M); luminal-HER2, 13.3M; HER2, 17.7M; TN, 4.2M. The HER2 status (hazard ratio [HR]: 0.58, 95% confidence interval [CI] 0.38-0.88) and nonprogressive extracranial lesion(s) (HR: 0.45, 95% CI 0.29-0.71) were identified as prognostic factors in a multivariate analysis. When limited to HER2-overexpressed MBC patients, the multivariate analysis revealed that non-progressive extracranial lesion(s) (HR: 0.20, 95% CI 0.088-0.47) and stereotactic irradiation (STI) as an initial treatment (HR: 0.18, 95% CI 0.061-0.56) were prognostic factors. Our retrospective review showed that early detection of BM by screening MRI, followed by STI, improved the prognosis of HER2-overexpressed MBC patients with BM. A further prospective randomized study is needed to confirm our findings.

Complete remission in metastatic breast cancer: expecting the unexpected-results of a cross-sectional study.

Complete response (CR) in metastatic breast cancer (MBC) is rare. This study aims at analyzing the characteristics and outcome of MBC patients achieving CR. We performed a cross-sectional analysis of clinical data from a consecutive series of MBC patients admitted at the Division of Medical Oncology of Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy, achieving CR following treatment for systemic disease and with at least 2years of follow-up. Seventy-six MBC patients with CR were identified during a calendar year. 47 patients (61.8%) achieved CR more than once, for a total of 123 cases. Median age at MBC diagnosis was 56years (range 30-76). 52 patients (68.4%) presented with recurrent disease, 24 (31.6%) with de novo metastatic disease. The majority of patients (80.3%) had hormone receptor (HR) positive and 26 (34.2%) had HER2 overexpressing MBC. 54 patients (71.1%) had only one site of metastatic disease. 33 patients (43.4%) received a local approach as part of their treatment and 67 (54.5%) achieved CR during maintenance therapy. CRs were durable, as after a median follow-up of 8.3years (interquartile range 5.8-11.0years) 42 patients (55.3%) were alive with no evidence of disease. Durable CRs can occur after systemic therapy alone or after combined systemic and local treatments. Most cases presented CR in the presence of limited disease spreading, not necessarily on first-line therapy. Our study highlights the crucial role of multidisciplinary approach to MBC and the benefit of maintenance treatment.

Continuation of trastuzumab beyond disease progression in HER2-positive metastatic gastric cancer: the MD Anderson experience.

Despite the wide spread use of trastuzumab in human epidermal growth factor receptor 2 (HER2) overexpressing metastatic gastric cancer patients, its optimal duration of administration beyond first-line disease progression is unknown. In HER2 overexpressing metastatic breast cancer, trastuzumab continuation beyond first-line disease progression has shown improvement in time to progression (TTP) without an increased risk of treatment related toxicity. HER2-overexpressing metastatic gastric cancer patients were identified from our database between January 2010 and December 2014. We retrospectively reviewed the medical records of 43 patients who received trastuzumab in combination with chemotherapy as first-line and continued trastuzumab beyond disease progression. Forty-three cases were identified, 27 males (62.8%), median age of the patients was 58 years. Thirty-five (81.4%) presented with stage 4 as their initial presentation. Eighty one percent had 3+ HER2 overexpression by immunohistochemistry (IHC) and 18% had 2+ HER2 overexpression confirmed by fluorescence in situ hybridization (FISH). Thirteen (52%) were moderately differentiated, 16 (37.1%) were poorly differentiated. The most common sites of metastasis were liver 35 (81.4%) and lung 14 (32.5%). The most commonly used first-line regimen was oxaliplatin, 5-fluorouracil (5-FU), and trastuzumab in 22 (51.1%) patients. Twenty-five (58.1%) patients received irinotecan, 5-FU and trastuzumab in the second-line. Progression-free survival (PFS) was 5 months (95% CI: 4.01-5.99 months). Five patients are still alive and excluded from calculating the median overall survival (OS) which was 11 months (range, 5-53 months) for the remaining 20 subjects of this second-line group. Trastuzumab was not discontinued due to side effects in any of the study population. In conclusion, this retrospective analysis suggests that continuation of trastuzumab beyond disease progression in patients with HER2-overexpressing metastatic gastric cancer is feasible and safe. Randomized studies are warranted.

Abstract P6-11-01: Cost-effectiveness of pertuzumab in HER2+ metastatic breast cancer

Abstract Purpose The Clinical Evaluation of Pertuzumab and Trastuzumab (CLEOPATRA) study showed a 15.7-month survival benefit with the addition of pertuzumab (P) to docetaxel and trastuzumab (TH) as first-line treatment for patients with HER2 overexpressing metastatic breast cancer. We performed a cost-effectiveness analysis to assess the value of the addition of pertuzumab to docetaxel and trastuzumab. Patient and Methods We developed a decision-analytic Markov model to evaluate the cost-effectiveness of TH with or without P in U.S. patients with metastatic breast cancer. The model followed patients weekly over their remaining lifetimes. Health states included: stable disease, progressing disease, hospice, and death. Transition probabilities were based on the CLEOPATRA study. Costs reflected the 2014 Medicare rates. Health state utilities were the same as those used in other recent cost-effectiveness studies of trastuzumab and pertuzumab. Outcomes included health benefits expressed as discounted quality-adjusted life-years (QALYs), costs in U.S. dollars, and cost-effectiveness expressed as an incremental cost-effectiveness ratio. One-way and multi-way deterministic and probabilistic sensitivity analyses explored the effects of specific assumptions. Results Modeled median survival was 39.4 months (TH) and 56.9 months (THP). The addition of pertuzumab resulted in an additional 1.81 life years gained (0.62 QALYs) at a cost of $472,668 per QALY gained. Deterministic sensitivity analysis showed that THP is unlikely to be cost-effective even under the most favorable assumptions, and probabilistic sensitivity analysis predicted 0% chance of cost-effectiveness at a willingness-to-pay of $100,000 per QALY gained. Conclusion The addition of pertuzumab to docetaxel and trastuzumab in patients with metastatic HER2+ breast cancer is unlikely to be cost-effective in the United States. Citation Format: Qian Y, Durkee BY, Pollom EL, King M, Dudley SA, Shaffer JB, Chang DT, Gibbs IC, Goldhaber-Fiebert JD, Horst KC. Cost-effectiveness of pertuzumab in HER2+ 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 P6-11-01.