Efficacy Of anti-HER2 Therapy Research Articles

New HER2-negative breast cancer subtype responsive to anti-HER2 therapy identified

PurposeHER2 signaling functional activity may be important to measure in addition to HER2 protein quantification when identifying patients eligible for HER2 therapies. A HER2 Signaling Function (CELx HSF) Test for HER2-negative patients uses patient’s live tumor cells on a biosensor to identify patients with abnormally high HER2-related signaling (HSFs+) likely to respond to anti-HER2 therapies.MethodsThe CELx HSF test was employed to: (1) characterize the sensitivity and specificity of the test to detect abnormal levels of HER2 signaling; (2) evaluate the inhibitory effectiveness of five different anti-HER2 therapies; (3) assess the correlation between CELx HSF test detection of abnormal HER2 signaling and response to HER2 therapy using xenograft models; and (4) confirm the prevalence of abnormal HER2 signaling amongst HER2-negative breast cancer patients (HER2−/HSFs+).ResultsHER2−/HSFs+ breast cancer patient samples were identified and showed sensitivity to five approved anti-HER2 therapies. Xenograft studies using both HER2+ and HER2− cell lines confirmed that CELx HER2 signaling status better predicts HER2 inhibitor efficacy than HER2 receptor status. In a study of 114 HER2-negative breast tumor patient samples, 27 (23.7%; 95% CI = 17–32%) had abnormal HER2 signaling (HSFs+). A ROC curve constructed with this dataset projects the CELx HSF Test would have greater than 90% sensitivity and specificity to detect the HER2−/HSFs+ patient population.ConclusionsThe CELx HSF test is a well-characterized functional biomarker assay capable of identifying dynamic HER2-driven signaling dysfunction in tumor cells from HER2-negative breast cancer patients. This test has demonstrated efficacy of various HER2 targeted therapies in live tumor cells from the HSFs+ population and correlated the test result to HER2 drug response in mouse xenograft studies. The proportion of HER2-negative breast cancer patients found to have abnormal HER2 signaling in a 114 patient sample study, 20–25%, is significant. A clinical trial to evaluate the efficacy of anti-HER2 therapies in this patient population is warranted.

The prognostic value of HER2 status and efficacy of anti-HER2 therapy in patients with HR-positive mucinous breast cancer: a nationwide study from the Korean Breast Cancer Society.

The effect of human epidermal growth factor receptor 2 (HER2) status on mucinous carcinoma (MC) of the breast is unknown due to the rarity of HER2-positive cases. We evaluated the prognostic value of HER2 status and the efficacy of anti-HER2 therapy in patients with hormone receptor (HR)-positive MC. From the data of 154,661 patients recorded in the Korean Breast Cancer Registry between January 1990 and August 2016, 3076 (2.0%) were diagnosed with MC. Overall survival (OS) according to HER2 status and anti-HER2 therapy was analyzed using Kaplan-Meier estimates. Multivariate analysis was performed using the Cox proportional hazards model to estimate the adjusted hazards ratio (HR) for clinicopathologic factors. A total of 2716 HR-positive MC patients were enrolled and followed up for a median 100.1months. Of these, 2094 (77.1%) were HER2-negative and 228 (8.4%) were HER2-positive. HR-positive, HER2-positive MC patients had more advanced pathologic tumor stages (T3 or T4) (p = 0.001), more axillary lymph node involvement (p < 0.001), higher nuclear grade (p < 0.001), and more lymphovascular invasion (p = 0.012) than HER2-negative patients. Subgroup analysis of HR-positive, node-positive MC showed that HER2-positive MC was an independent prognostic factor for OS (HR = 2.657; 95% CI, 1.665-4.241; p < 0.001). HR-positive, node-positive, and HER2-negative MC had significantly longer OS than HER2-positive MBC (p = 0.017). The node-positive subgroup that received anti-HER2 therapy had increased OS, although not significantly (p = 0.224). Our nationwide database study revealed that HER2-positive status was associated with worse prognosis in HR-positive and node-positive MC. Anti-HER2 therapy might be beneficial in HR-positive, node-positive, and HER2-positive MC.

Abstract 2615: Heterogeneity of HER2 expression in gastric cancer (GC) leads to high deviation rates between local and central testing and hampers efficacy of anti-HER2 therapy: Survival results from the VARIANZ study

Abstract Background: HER2 is a membrane-bound receptor tyrosine kinase that belongs to the epidermal growth factor receptor family. The anti-HER2 directed monoclonal antibody trastuzumab is approved for 1st-line treatment of stage IV HER2+ GC, while other drugs addressing HER2 (pertuzumab, TDM1, lapatinib) failed to improved survival outcomes. Until today, resistance against HER2-directed treatment of GC is poorly understood. The VARIANZ study aims to assess the biologic background of resistance to anti-HER2 therapy in GC. Methods: This academic network study funded by the German Federal Ministry of Education and Research (BMBF 01ZX1610E) recruited patients (pts) who received medical treatment for stage IV GC in 34 sites. HER2 expression was verified centrally by two dedicated GI pathologists using immunohistochemistry (DCS, HI608C0I) and chromogenic in situ hybridization (Zytomed Systems, C-3022-40). Treatment and survival outcomes were reported by investigators. Results: 502 pts were enrolled from May 2014 to Oct 2017. At present, 442 samples were fully characterized for HER2. According to criteria from the ToGA study, 73 of 442 samples were found HER2+ in central testing. In 57 samples with a HER2+ status diagnosed by local pathologists, HER2 positivity could not be confirmed centrally. Deviation rate between local and central testing was 23%. Centrally confirmed HER2-positive GC displayed a higher percentage of tumor cells staining positive for HER2 (49.72 ± 28.58% [SD] vs. 11.35 ± 17.74% [SD]; p&amp;lt;0.001) and a higher HER2/CEP17 ratio (5.78 ± 2.55 [SD] vs. 1.43 ± 0.41 [SD]; p&amp;lt;0.001). Survival outcomes indicate that only pts with centrally confirmed HER2+ status benefit from trastuzumab with an overall survival of 30.7 months (95%-CI 10.7 - 50.8; n=28) versus 7.9 months (95%-CI 2.8 - 12.9, n=33); HR for death was 3.9 in pts with unconfirmed vs. confirmed HER2+ GC receiving trastuzumab plus chemotherapy; p&amp;lt;0.0001. Conclusions: Variability between local and central HER2 assessment in GC is significant. Pts with centrally unconfirmed HER2+ status have no benefit from anti-HER2 therapy. HER2 status should be assessed in highly qualified laboratories and cut-offs for defining HER2+ should be reconsidered. Alternative treatment options–other than trastuzumab–should be investigated in pts with unconfirmed or borderline HER2 expression. Citation Format: Florian Lordick, Ivonne Haffner, Birgit Luber, Dieter Maier, Elba Raimundez, Jan Hasenauer, Albrecht Kretzschmar, Ludwig Fischer von Weikersthal, Miriam Ahlborn, Jorge Riera Knorrenschild, Gabriele Siegler, Beate Rau, Stefan Fuxius, Thomas Decker, Katrin Schierle, Christian Wittekind. Heterogeneity of HER2 expression in gastric cancer (GC) leads to high deviation rates between local and central testing and hampers efficacy of anti-HER2 therapy: Survival results from the VARIANZ study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2615.

To treat or not to treat: HER2 equivocal is the matter!

With the introduction of the 2013 American Society of Clinical Oncology (ASCO)/College of American Pathologists (CAP) guidelines for human epidermal growth factor receptor type 2 (HER2) testing, some authors noticed an increase in equivocal HER2 determinations. Indeed, many retrospective assessments showed an increase of up to 14% in the number of equivocal cases by immunohistochemistry and fluorescence in situ hybridization. In these cases, if after reflex testing with the same and/or an alternative specimen the HER2 test result is deemed to be equivocal, the ASCO/CAP guidelines recommend to consider HER2-targeted therapy. However, due to the absence of prospective data on the efficacy of anti-HER2 therapy in equivocal HER2 breast cancer (BC), the therapeutic decision is extremely complex, especially in the adjuvant and neoadjuvant settings. In this perspective paper, we analyse the available retrospective data aiming to answer to the dilemma whether to treat or not to treat HER2 equivocal cases with a HER2-targeted therapy.

Analysis of protein overexpression and Her2 gene amplification in gastric adenocarcinoma from Moroccan patients

Background: Gastric cancer is one of the leading causes of cancer death in the world; it is burdened with a poor prognosis. The advent of targeted therapy Herceptin makes the search for new prognostic factors such as the HER2 receptor essential for better management. HER2 overexpression is increasingly recognized as a frequent molecular abnormality, driven as in breast cancer by gene amplification. There is mounting evidence of the role of HER2 overexpression in patients with gastric cancer, and it has been solidly correlated to poor outcomes and a more aggressive disease. Additionally, preclinical data are showing significant antitumor efficacy of anti-HER2 therapies (particularly monoclonal antibodies directed towards the protein) in in vitro and in vivo models of gastric cancer.

Clinical Differences in Triple-Positive Operable Breast Cancer Subtypes in Korean Patients: An Analysis of Korean Breast Cancer Registry Data.

PurposeTriple-positive breast cancer is defined by estrogen receptor, progesterone receptor, and human epidermal growth factor receptor 2 (HER2) positivity. Several systemic breast cancer therapies target hormonal and HER2 responsiveness. We compared clinical outcomes of triple-positive disease with those of HER2-enriched and luminal HER2-negative disease and investigated the clinical efficacy of anti-HER2 therapy for triple-positive disease.MethodsWe retrospectively compared overall and recurrence-free survival among cases included in the Korean Breast Cancer Society (KBCS) and Seoul St. Mary's Hospital breast cancer registries and the therapeutic efficacy of trastuzumab for triple-positive and HER2-enriched cases.ResultsKBCS registry data (2006–2010; median follow-up, 76 months) indicated that patients with triple-positive breast cancer had intermediate survival between those with luminal A and HER2-enriched subtypes (p<0.001). Trastuzumab did not improve overall survival among patients with triple-positive breast cancer (p=0.899) in contrast to the HER2-enriched subtype (p=0.018). Seoul St. Mary's Hospital registry data indicated similar recurrence-free survival outcomes (p<0.001) and a lack of improvement with trastuzumab among patients with triple-positive breast cancer (median follow-up, 33 months; p=0.800). Multivariate analysis revealed that patients with triple-positive breast cancer had better overall survival than those with HER2-enriched disease and similar survival as those with the luminal A subtype (triple-positive: hazard ratio, 1.258, p=0.118; HER2-enriched: hazard ratio, 2.377, p<0.001).ConclusionOur findings showed that anti-HER2 therapy was less beneficial for treatment of triple-positive breast cancer than for HER2-enriched subtypes of breast cancer, and the triple-positive subtype had a distinct prognosis.

De-escalation of treatment in HER2-positive breast cancer: Determinants of response and mechanisms of resistance

Overexpression and/or gene amplification of HER2, a crucial member of the HER family of four receptors, occur in about 15–20% of breast cancers and define an aggressive subtype of the disease. Activated HER homo and heterodimers govern a complex and redundant downstream signaling network that regulates cell survival and metastasis. Despite treatment with effective HER2-targeted therapies, many HER2-positive tumors fail to respond, or initially respond but eventually develop resistance. One of the upfront reasons for this treatment failure is failure to accurately select the tumors that are truly dependent on HER2 for survival and so would benefit the most from HER2-targeted therapy. In these truly HER2-addicted tumors (i.e. physiologically dependent), resistance could be the result of an incomplete inhibition of signaling at the HER receptor layer. In this regard, preclinical and clinical studies have documented the superiority of combination anti-HER2 therapy over single agent therapy to achieve a more comprehensive inhibition of the various HER receptor dimers. HER2 can be further activated or reactivated by mutations or other alterations in HER2 itself, or in other HER family members. Even when a complete and sustained HER inhibition is achieved, resistance to anti-HER therapy can arise by other somewhat dominant mechanisms, including preexisting or emerging alternative signaling pathways such as the estrogen receptor, deregulated downstream signaling components, especially of the PI3K pathway, and the tumor immune microenvironment. Most of the clinical trials that have investigated the efficacy of anti-HER2 therapies took place in the background of aggressive chemotherapy regimens, thus confounding the identification of key factors of resistance to the anti-HER2 treatments. Recent studies, however, have suggested that some HER2-amplified tumors may benefit from anti-HER2 therapy combined with only a single chemotherapy agent or in the absence of any chemotherapy. This de-escalation approach, a promising therapeutic strategy, is currently being explored in the clinic. In this review, we summarize the major molecular determinants that play a crucial role in influencing tumor response and resistance to HER2-targeted therapy, and discuss the growing need for patient stratification in order to facilitate the development of de-escalation strategies using HER2-targeted therapy alone with no chemotherapy.

P-0054 - The Change of Serum HER2 Extra Cellular Domain Concentration Before and After Resection in Operable Gastric Cancer Patients in Japan; Consider Relations with Pathological HER2 Status by IHC and Fish

Introduction: HER2 extra cellular domain (ECD) can be detected in the serum of healthy person, these concentrations are raised in the patients with cancer; this is dependent on tumor HER2 status and tumor burden. In previous reports, serum HER2-ECD status is useful for judgement of efficacy of anti-HER2 therapy in patients with HER2-positive breast cancer. Although, similarly to breast cancer, approximately 20% gastric cancer show HER2 amplification or overexpression and the efficacy of trastuzumab has been reported, we don't have enough date for serum HER2-ECD of gastric cancer patients.

Highlights of This Issue

The HER2 oncogene is amplified in approximately 25–30% of human gastric cancers. Wainberg and colleagues explored the efficacy of anti-HER2 therapies for the treatment of gastric cancer. Using in vitro and in vivo models of gastric cancer, they evaluated the efficacy of lapatinib, a small molecule tyrosine kinase inhibitor of HER2, and trastuzumab, a monoclonal antibody against HER2. The combination of dual HER2 blockade by both trastuzumab and lapatinib demonstrated synergy in both cell lines and gastric cancer animal models. A randomized clinical trial of lapatinib in patients with gastric cancer is ongoing.There is an unmet need for personalized chemotherapy for non–small cell lung cancer (NSCLC) patients, as current regimens have only modest effectiveness and are relatively toxic. Here, Dong and colleagues describe a method for reliably and quickly determining the sensitivity of NSCLC to various drug regimens. Their approach is based on grafting primary NSCLC tissue (as distinct from established tumor lines) under renal capsules of immunodeficient mice. They found that NSCLCs had a high engraftment rate, and xenografts retained the major biological properties of the original cancers. Further, they showed that this approach can be used to assess the responsiveness of a patient's cancer to different chemotherapeutic regimens.CCR4 is expressed on tumor cells from most adult T-cell leukemia/lymphoma (ATLL) patients. Ishii and colleagues developed a humanized defucosylated anti-CCR4 monoclonal antibody, KW-0761. They found that KW-0761 exhibits potent antitumor activity mediated by highly enhanced antibody-dependent cellular cytotoxicity against autologous primary ATLL cells in vitro. Based on these data, a clinical trial of KW-0761 is underway in patients with relapsed CCR4-positive leukemia/lymphoma. The results here may help guide the development of other novel, effective treatment strategies using not only KW-0761, but also other defucosylated monoclonal antibodies.The IDH1 gene has been found mutated in 60–80% of grade II and grade III gliomas. In this prospective randomized study of patients with anaplastic oligodendroglioma, van den Bent and colleagues assessed the prognostic significance of IDH1 mutations, and whether this mutation could predict outcome to procarbazine, CCNU, and vincristine (PCV) chemotherapy. In a multivariate analysis, which included all known prognostic factors, IDH1 mutations were found to be a strong and independent prognosticator for overall survival, but they were not predictive for outcome to PCV chemotherapy. Also, IDH1 mutations were found to correlate with MGMT promoter methylation.