Treatment Of HER2-negative Breast Cancer Research Articles

Clinicopathological features and prognostic analysis of HER2 low and fibrotic focus in HER2-negative breast cancer.

The aim of this study is to evaluate the clinicopathological features and prognostic significance of HER2 low, fibrotic focus (FF), and tumor-infiltrating lymphocytes (TILs) in patients with HER2-negative breast cancer. We retrospectively reviewed the data of 293 patients with HER2-negative, stage I-II, invasive breast cancer of non-specific types. The HER2-negative cases were classified into HER2 low and HER2 0. Digital analysis of hematoxylin-eosin stained whole slide images was used to evaluate the FF expression. TILs were also evaluated using the Whole Slide Image. Furthermore, the association between HER2 low, FF, and TILs as well as their prognostic significance were analyzed. The study cohort included 178 cases (60.8%) with HER2 low and 115 cases (39.2%) with HER2 0. Older age, lower Nottingham histological grade (NHG), estrogen receptor (ER) positivity, progesterone receptor (PR) positivity, and hormone receptor (HR) positivity were all associated with HER2 low. FF was correlated with older age, intermediate and low NHG, vascular invasion, HR positivity, HER2 low status, high Ki67 expression, and low TILs. Univariate survival analysis showed that FF was significantly associated with shorter progression-free survival (PFS). Stratified analysis indicated that in the HR-negative and HR-positive groups, HER2 status and TILs did not affect PFS. DFS was longer in patients without FF compared to those with FF in the HR-positive (hazard ratio [HR] = 0.313) and HER2 low (HR = 0.272) groups. DFS was also significantly longer in patients without FF compared to those with FF in the HR-negative (HR = 0.069) and HER2 0 groups (HR = 0.129). The results indicated that the HER2 low status and the TILs expression did not impact prognosis. However, patients with FF exhibited distinct biological characteristics and prognostic significance, particularly in the HR-negative and HER2 0 groups. This provides a rationale for accurate diagnosis and treatment of HER2-negative breast cancer.

Nomograms for predicting survival in patients with HER2 negative breast cancer.

e12528 Background: It is increasingly recognized that there is considerable heterogeneity in HER2-negative breast cancer. The clinicopathological characteristics differed between HER2-low and HER2-0 breast cancer evaluated by immunohistochemistry (IHC) or in situ hybridization (ISH). HER2-low breast cancer may benefit from novel antibody-drug conjugates. However, the immunohistochemical agreement of HER2-low is poor. We aimed to construct nomograms to predict the survival of HER2-negative breast cancer and to evaluate the effects of HER2 on survival at the RNA transcript level. Methods: A retrospective analysis was performed on breast cancer patients who were evaluated HER2-negative by IHC or ISH in the TCGA database. Univariate and multivariate cox regression analysis was used to evaluate whether the HER2 RNA transcript level and clinical parameters were independent predictors for overall survival (OS), progression-free survival (PFS), and Disease-Specific Survival (DSS), and nomograms were generated for the prediction of 1-, 2-, 3-, 5-year OS, PFS, and DSS based on significant parameters. Survival curves were drawn using the Kaplan-Meier methods to compare mortality outcomes according to HER2 RNA transcript level (75% vs. 25%). Results: A total of 769 HER2-negative patients were included in the analysis. The median age of patients was 56 years (range 26-30), and the majority were White (80.3%). Univariate and multivariate cox regression analysis showed that age, pN_stage, and pM_stage were independent predictors for OS, but HER2 was not. The C-index of a nomogram based on these three parameters was 0.723 (95%CI, 0.6555-1). HER2, pT_stage, pN_stage, and pM_stage were analyzed as independent predictors of PFS. HER2, pN_stage, and pM_stage were independent predictors of DSS. The C-indexes of established nomograms were 0.734 (95%CI, 0.672-1) and 0.775 (95%CI, 0.686-1) respectively. PFS and DSS were significantly better for patients with high HER2 RNA transcript levels (PFS, log-rank p = 0.00446, HR = 0.352; DSS, log-rank p = 0.0119, HR = 0.247). Conclusions: In the TCGA database, the HER2 RNA transcript level was an independent predictor for PFS and DSS in HER2-negative breast cancer. Stratification of patients at the RNA level can help clinicians optimize treatment for HER2-negative breast cancer.

Intermediate results of the prospective randomized controlled trial VOG-01: "Evaluation of the efficacy of neoadjuvant combination hormone therapy in premenopausal patients with ER+ HER2- breast cancer"

To date, the standard of care for neoadjuvant treatment of HER2-negative breast cancer remains chemotherapy with the inclusion of anthracyclines and taxanes in both luminal and triple-negative tumor subtypes. The purpose of this article was to scientifically substantiate the use of combined hormone therapy at the preoperative treatment of premenopausal patients with ER+ HER2- breast cancer. After analyzing the scientific data presented in scientific databases (PubMed, MEDLINE, BMS), as well as studying active clinical trials on the ClinicalTrials.gov, we concluded that most of the studies where hormone therapy was used in the preoperative regimen were conducted in the postmenopausal patient. In this regard, a randomized controlled clinical trial was initiated to study the efficacy and safety of a new method of preoperative treatment in premenopausal women with ER+ HER2- breast cancer, the preliminary results of which will be reported in this article. Currently, the study included 28 patients, of which 13 patients were analyzed who received the neoadjuvant and surgical stages of complex treatment. The research is ongoing.

New Advances in Targeted Therapy of HER2-Negative Breast Cancer.

Breast cancer has an extremely high incidence in women, and its morbidity and mortality rank first among female tumors. With the increasing development of molecular biology and genomics, molecular targeted therapy has become one of the most active areas in breast cancer treatment research and has also achieved remarkable achievements. However, molecular targeted therapy is mainly aimed at HER2-positive breast cancer and has not yet achieved satisfactory curative effect on HER2-negative breast cancer. This article describes the potential targets that may be used for breast cancer treatment from the aspects of PI3K/AKT signaling pathway, DDR, angiogenesis, the cell cycle, breast cancer stem cells, etc., and explores possible inhibitors for the treatment of HER2-negative breast cancer, such as PI3K inhibitors, AKT inhibitors and m-TOR inhibitors that inhibit the PI3K/AKT signaling pathway, small molecule tyrosine kinase inhibitors that restrain angiogenesis, CDK inhibitors, aurora kinase inhibitors and HDAC inhibitors that block cell cycle, as well as the drugs targeting breast cancer stem cells which have been a hit, aiming to provide a new idea and strategy for the treatment of HER2-negative breast cancer.

MO32-4 A real-world multicentre retrospective study of low-dose apatinib for HER2-negative metastatic breast cancer

There are fewer treatments in for patients with HER2-negative breast cancer than for HER2-positive patients, especially for metastatic breast cancer. Apatinib is a small-molecule tyrosine kinase inhibitor that selectively targets VEGFR-2. Apatinib was prescribed orally at a dose of 250mg once daily. If conditions permitted, patients also received an NGS test before treatment. The median PFS of the 115 patients was 4.0 months. The objective response rate was 25.5%, and the disease control rate was 80.9%. Univariate analysis showed that patients without liver metastases before treatment were given longer PFS (4.4 months vs. 3.0 months, p=0.022), and that patients with hypertension or hand-foot syndrome during treatment had significantly longer PFS (hypertension: 4.4 vs 3.0 months, p=0.010; Hand-foot syndrome: 4.7 vs 3.3 months, p=0.016). NGS found that patients with BRCA mutations had significantly longer PFS (10.5 months versus 2.6 months, p=0.023). In addition, there were 15 patients having continued to treat with apatinib combined with another chemotherapy agent after PD for first time, the PFS slightly extended (5.2 vs. 4.0 months), but no statistical difference (p =6.22). Most of the adverse effects were grade 1 to 2. Low-dose apatinib is a new choice after failure of multi-line treatment for HER2-negative breast cancer, and the adverse reactions are well tolerated. Through NGS detection to find the predictive factors of apatinib, to the first time, we found that patients with BRCA mutations had longer PFS. Moreover, patients without liver metastasis received significantly longer PFS, suggesting the organ selectivity of apatinib treatment. It provides effective evidence for the clinical use of low-dose apatinib in HER2-negative advanced breast cancer. We believe that patients with HER2-negative advanced breast cancer should choose low-dose apatinib to increase the efficacy, especially those with BRCA mutations.

Bevacizumab in the neoadjuvant treatment of human epidermal growth factor receptor 2-negative breast cancer: A meta-analysis of randomized controlled trials.

Several randomized clinical trials have suggested the effectiveness of bevacizumab (Bev) in early and advanced breast cancer; however, due to the increased toxicity and lack of a clear long-term survival benefit, there is currently no defined role for Bev in breast cancer in the USA, while it has been approved in Europe. We herein sought to conduct a meta-analysis of large randomized trials comparing the efficacy and long-term outcome of neoadjuvant chemotherapy with Bev compared with chemotherapy without Bev in human epidermal factor receptor 2 (HER2)-negative breast cancer. A search was conducted through PubMed and Ovid Medline databases. Among the 279 articles identified, 5 met the eligibility criteria and were included in the present analysis. A total of 2,268 patients treated with Bev and 2,278 treated without Bev were analyzed. Pathological complete response (pCR) was obtained in 35% of patients treated with Bev and in 26% of those treated without Bev. A statistically significant increase (26%) in the incidence of pCR was observed in the Bev-treated group. However, patients treated with Bev exhibited no significant difference in the risk of disease recurrence or death. To the best of our knowledge, this is the first meta-analysis addressing the long-term outcomes of Bev in combination with chemotherapy in the neoadjuvant treatment of HER2-negative breast cancer. The results confirmed the significant benefit of Bev combined with chemotherapy compared with chemotherapy alone on breast cancer response, in both triple-negative and hormone receptor-positive cases. However, this benefit does not translate into a long-term disease-free or definitive overall survival advantage. Optimizing patient selection is desirable for maximizing the long-term benefits of Bev, while reducing cost and treatment-related adverse effects. Future efforts directed toward the discovery of predictive markers would be crucial for identifying the subset(s) of breast cancer patients who are most likely to benefit from Bev therapy.

Anthracycline and taxane-based chemotherapy versus docetaxel and cyclophosphamide in the adjuvant treatment of HER2-negative breast cancer patients: a systematic review and meta-analysis of randomized controlled trials.

Standard adjuvant chemotherapy for HER2-negative breast cancer consists generally in an anthracycline and taxane-based regimen (A+T). The TC (docetaxel and cyclophosphamide) regimen arises as a potential alternative, although individual randomized controlled trials (RCTs) could not demonstrate the non-inferiority of TC over A+T. This is a systematic review and meta-analysis of RCTs comparing 6 cycles of TC versus sequential A+T in the adjuvant treatment of HER2-negative breast cancer. A systematic literature search was performed to identify RCTs comparing TC versus A+T. Disease-free survival (DFS) and overall survival (OS) were assessed. Subgroup analyses of DFS according to hormone receptor status,lymph node involvement, and menopausal status were performed. Hazard ratios (HRs) and 95% confidence intervals (CI) for DFS and OSwere extracted from each trial, and a pooled analysis was conducted using the random-effect model. The Higgins' I-Squared Test was used to quantify heterogeneity. Seven RCTs were included (12,741 patients). Overall, no difference was observed between TC and A+T in DFS (HR 1.08, 95% CI 0.96-1.20) and OS (HR 1.05; 95% CI 0.90-1.22). A trend favoring A+T was observed in hormone receptor-negative (HR 1.12, 95% CI 0.93-1.34) and N2 patients (HR 1.25; 95% CI 0.82-1.90). Emesis/vomiting, mucositis, thrombocytopenia and sensory neuropathy were significantly more frequent with A+T. As adjuvant treatment of HER2-negative breast cancer, sequential A+T regimen was associated with increased risk of toxicities and no clear survival benefit as compared to 6 cycles of TC. Higher-risk patients may benefit the most from A+T, whilst TC may be an efficacious and less toxic alternative for lower-risk patients.

The combination of bevacizumab with chemotherapy is more beneficial in the metastatic setting rather than in the adjuvant setting for the treatment of HER2-negative breast cancer—a commentary on the E5103 randomized phase III clinical study

The randomized phase III, double-blind, clinical trial (E5103) enrolled 4,995 patients with human epidermal growth factor receptor 2-negative (HER2-negative) breast cancer and evaluated the efficacy and the safety of humanized monoclonal antibody bevacizumab targeting vascular endothelial growth factor (VEGF) in adjuvant chemotherapeutic setting (1).

Abstract P2-16-01: Discovery of fully human monoclonal antibodies as therapeutic candidates for the treatment of HER2-negative breast cancer

Abstract Unlike HER2-positive breast cancer, there are limited treatment options for patients diagnosed with triple negative and endocrine resistant HER2-negative breast cancer, and as such HER2-negative breast cancer represents a significant unmet medical need. The goal of this work is to use Theraclone’s proprietary I-STAR platform to mine the memory B cell immune repertoire of breast cancer patients for the discovery of therapeutically relevant monoclonal antibodies (mAbs) and targets that may be exploited as candidates for treatment of HER2-negative breast cancer. Matched serum and PBMC samples were collected from breast cancer patients at multiple clinical sites. The selected patient populations included, but were not limited to, patients who were treatment naïve, those who had received immunotherapy or adjuvant chemotherapy, and patients who had an exceptional clinical response to treatment and/or disease. Serum antibody binding to a diverse panel of 5 well characterized breast cancer-derived cell lines of luminal and basal sub-types was determined. Utilizing this approach, patients with a robust serological profile across multiple breast cancer cell lines were identified and prioritized for memory B cell repertoire analysis via the I-STAR platform. Using a high throughput and miniaturized, multiplex flow cytometry assay, the secreted IgG antibodies from over 85,000 individually enriched and expanded B cell clones were screened for binding to the tumor cell line panel and a large number of positive B cell clones were identified. The screening hits can be binned into several unique binding profiles, many of which were confirmed to be shared across multiple patient samples. Deep sequence analysis of the variable regions of the antibodies produced by the B cell clones demonstrated that several of the screening hits were derived from clonally related B cells; the majority of the screening hits represented antibodies derived from unique B cell clones. A representative set of these antibodies was expressed recombinantly for further in vitro characterization. Citation Format: Christy Boozer, Paul Algate, Aurelio Bonavia, Mark Branum, Po-Ying Chan-Hui, Alison Fitch, Brad Greenfield, Claire Sutherland, Kristine Swiderek. Discovery of fully human monoclonal antibodies as therapeutic candidates for the treatment of HER2-negative breast cancer [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P2-16-01.

Antiangiogenic Agents in the Treatment of HER2-Negative Metastatic breast Cancer: A Brief Review

Angiogenesis is an important step in breast cancer (BC) growth and progression. Targeting angiogenesis was the most interesting by developed strategy in the treatment of HER2-negative BC. Bevacizumab is a monoclonal humanized antibody targeting the vascular endothelial growth factor (VEGF) the most potent factor implicated in tumor angiogenesis. It is the most developed targeted agent in HER2-negative MBC and showed the most interesting results in combination with chemotherapy. Currently, bevacizumab is the only approved targeted therapy (in Europe only) in the first line treatment of HER2-negative metastatic BC in combination with weekly paclitaxel. The aim of the present paper is to review the role of anti-angiogenic agents (targeted agents only) in the treatment of HER2-negative metastatic BC. Keywords: Anti-angiogenic agents, bevacizumab, breast cancer, VEGF, VEGFR.

Abstract 896: Serum-vascular endothelial growth factors (sVEGF) A and C have a potential as predictive tests for neoadjuvant bevacizumab in primary breast cancer

Abstract Background: Vascular endothelial growth factor (VEGF) is the major angiogenic factor in human cancer; VEGF-A is the most studied cytokine; VEGF-C is also involved in lymphatic development and both can act through binding to VEGFR2. Bevacizumab (Bev) is a humanized antibody directed towards VEGF with a modest effect in unselected HER2-negative breast cancer (BC). Patients & Methods: These VEGFs were determined in the randomized GeparQuinto trial investigating Bev as neoadjuvant treatment for HER2-negative BC (von Minckwitz et al N Eng J Med 2012). Patients were randomized to neoadjuvant chemotherapy with ECx4 and docetaxelx4 with or without concomitant Bev. VEGF-A, VEGF-C and VEGFR2 (VEGFs) were determined in serum samples prior to any treatment by use of commercial enzyme-linked immuno assays (Quantikine, R & D Systems, Minneapolis, USA). Serum levels of VEGF-A; -C and R2 were analyzed as dichotomized variables and correlated with pathological complete response (pCR, ypT0 ypN0) at surgery. Results: The VEGFs were determined in 830 (43%) trial participants of which 289 had triple negative (TN) and 541 hormone receptor positive (HR+) BC. The median age was 48 years (range 42-56), 81% had a ductal cancer and 44% were grade III. Median levels were 295.0 range 160-497 pg/mL for VEGF-A; 2102 range 1576-2588 pg/mL for VEGF-C; and 2328 range 1887-2913 pg/mL for VEGFR2, respectively. STEPP (subpopulation treatment effect pattern plot) analyses revealed a potential predictive value for all 3 VEGF's. In dichotomized analyses, TNBC patients with high VEGF-C had a higher chance of pCR with Bev in univariate analysis [interaction OR=4.4; p= 0.010] and multivariate analysis (interaction OR=6.5; p= 0.005) adjusted for age (≥ 50y vs. < 50y), histological type (ductal vs. lobular vs. others), grade (III vs. I-II), tumor stage (stage 4 vs. 1-3) and nodal status (node-negative vs. node positive). High VEGFR2 was correlated with pCR in univariate analysis [interaction OR=7.9; p= 0.017] whilst no effect was seen in multivariate analysis. HR+BC patients with high VEGF-A had an increased chance of pCR in univariate analysis [interaction OR=25.7; p< 0.001] and multivariate analysis [OR=29.4; p< 0.001]. A total 37.7% of the TNBC were classified as having high VEGFC and 31.2% obtained a pCR; 44.8% with Bev vs. 15.7% without Bev. A total of 89.3% of the TN patients were classified as “high VEGFR2” with a pCR rate of 31.4%; 39.5% with Bev vs. 23.9% without Bev. In the HR+ group, 41.6% were classified as having high VEGFA with a pCR rate of 6.7%; 11% with Bev vs. 2.6% without Bev. Conclusions: Results from the prospective GeparQuinto study demonstrate that VEGFs determined in serum can function as predictive tests for chemotherapy+/-Bev in the neoadjuvant setting. Prominent findings were a predictive value for bevacizumab for VEGF-C in TNBC and for VEGF-A in HR+BC. Citation Format: Barbro K. Linderholm, Gϋnter von Minckwitz, Stefano Caramuta, Fabrice André, Christos Sotiriou, Maria A. Cerone, Matthias Schwenkglenks, Patricia Blank, Carsten Denkert, Stephan Gade, Sibylle Loibl, on behalf of the GBG neoadjuvant board and the RESPONSIFY consortium. Serum-vascular endothelial growth factors (sVEGF) A and C have a potential as predictive tests for neoadjuvant bevacizumab in primary breast cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 896. doi:10.1158/1538-7445.AM2014-896

Bevacizumab (Bv) in the adjuvant treatment of HER2-negative breast cancer: Final results from Eastern Cooperative Oncology Group E5103.

500 Background: Bv improves progression-free survival (PFS) but not overall survival (OS) in MBC. E5103 added Bv to adjuvant therapy in patients (pts) with HER2- disease. Methods: Pts were assigned...

Bevacizumab: where do we go from here in breast cancer?

Bevacizumab is a monoclonal antibody against circulating vascular endothelial growth factor A, which received accelerated FDA approval in 2008 for first line treatment of HER2-negative metastatic breast cancer. The initial approval was based on studies suggesting a progression-free survival and not overall survival. This observation served as the basis for looking into the use of bevacizumab as an adjunct to neoadjuvant chemotherapy in the treatment of HER2-negative breast cancer.

Ixabepilone and cyclophosphamide as neoadjuvant therapy in HER2-negative breast cancer with exploratory Oncotype DX assessments: A Sarah Cannon Research Institute phase II trial.

1066 Background: Ixabepilone (Ixa) is active in taxane-refractory metastatic breast cancer as well as in the neoadjuvant setting where Ixa yielded a pathologic complete response (pCR) rate of 18%. In this study, we evaluated Ixa in combination with cyclophosphamide (Cyc) as neoadjuvant treatment for HER2-negative breast cancer. The primary endpoint was pathologic complete response (pCR) rate, defined as no residual cancer in breast or lymph nodes. Responses were correlated with Oncotype DX recurrence scores. Methods: Eligible women were HER2-negative (IHC 0-1+ or FISH negative), node positive or T > 2 cm with inflammatory and T1N0 tumors excluded. Patients (pts) received Ixa 40mg/m2 with Cyc 600 mg/m2 day 1 of each 21-day cycle. Following 6 cycles, pts went to surgery. Postoperative radiation and hormonal treatments were at discretion of the treating MD. Core biopsies (pretreatment and at surgery) were analyzed using the Oncotype DX RT-PCR assay; the associations between recurrence scores and clinical responses were investigated in an interim analysis. Results: 156 women have been enrolled. Baseline characteristics for the first 78 pts are reported (median age 52 years; 86% invasive ductal; 50%/33% T2/T3; 41% triple negative). 50 pts have undergone surgery. 14 pts discontinued treatment early (disease progression – 6; pt/MD request – 5; toxicity – 3).Grade 3/4 toxicity included: neutropenia (69%), leukopenia (51%), neuropathy (9%), and febrile neutropenia (6%). The pCR rate was 18%. Higher pretreatment recurrence scores (>31) were associated with higher pCR rate (p=0.025) in 38 patients with available data. Non-significant trends were observed for ER and PR by RT-PCR, but not for HER2. None of these measures were predictive of clinical tumor responses after 3 or 6 cycles of therapy, although assessment methods varied across timepoints. Conclusions: Ixabepilone with cyclophosphamide as neaodjuvant therapy is feasible and active. Tumors with higher Oncotype DX recurrence scores at baseline were more likely to achieve pCR.

Bevacizumab in the treatment of HER2-negative breast cancer.

Angiogenesis has a clear and definite role in the breast cancer progression process, making antivascular endothelial growth factor (VEGF) therapies an attractive option for the treatment of metastatic breast cancer (MBC). Bevacizumab is a potent humanized monoclonal antibody to VEGF, which has shown regression of breast cancer in preclinical and clinical setting, either alone or in combination with cytotoxic treatment. Additionally, bevacizumab potentially increases the effectiveness of other anticancer therapies through the normalization of tumor vasculature, reduction of intratumoral pressure and improved tumor oxygenation. Phase 1/2 trials showed significant antitumor effects of bevacizumab in MBC, in particular in tumors not expressing HER2 receptor. A first phase 3 trial in pre-treated MBC patients showed better response rates but no survival benefit from the addition of bevacizumab to capecitabine. However, in two phase 2 trial in first-line setting in patients with MBC, bevacizumab improved progression-free survival in combination with weekly paclitaxel in comparison to paclitaxel alone or in combination with 3-weekly docetaxel in comparison with docetaxel alone, respectively. Bevacizumab in combination with taxanes seems to be a highly effective first-line treatment for MBC patients. Future research will investigate bevacizumab in the neoadjuvant or adjuvant setting, where even more potential may exist for these patients.