Therapy In HER2-negative Breast Cancer Research Articles

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.

Multicenter phase II study of apatinib single or combination therapy in HER2-negative breast cancer involving chest wall metastasis.

ObjectiveBreast cancer (BC) with chest wall metastasis (CWM) usually shows rich neovascularization. This trial explored the clinical effect of apatinib on human epidermal growth factor receptor 2 (HER2)-negative advanced BC involving CWM.MethodsThis trial involved four centers in China and was conducted from September 2016 to March 2020. Patients received apatinib 500 mg/d [either alone or with endocrine therapy if hormone receptor-positive (HR+)] until disease progression or unacceptable toxicity. Progression-free survival (PFS) was the primary endpoint.ResultsWe evaluated 26 patients for efficacy. The median PFS (mPFS) and median overall survival (mOS) were 4.9 [range: 2.0−28.5; 95% confidence interval (95% CI): 2.1−8.3] months and 18 (range: 3−55; 95% CI: 12.9−23.1) months, respectively. The objective response rate (ORR) was 42.3% (11/26), and the disease-control rate was 76.9% (20/26). In the subgroup analysis, HR+ patients compared with HR-negative patients had significantly improved mPFS of 7.0 (95% CI: 2.2−11.8) monthsvs. 2.3 (95% CI: 1.2−3.4) months, respectively (P=0.001); and mPFS in patients without or with chest wall radiotherapy was 6.4 (95% CI: 1.6−19.5) monthsvs. 3.0 (95% CI: 1.3−4.6) months, respectively (P=0.041). In the multivariate analysis, HR+ status was the only independent predictive factor for favorable PFS (P=0.014). ConclusionsApatinib was highly effective for BC patients with CWM, especially when combined with endocrine therapy. PFS improved significantly in patients with HR+ status who did not receive chest wall radiotherapy. However, adverse events were serious and should be carefully monitored from the beginning of apatinib treatment.

Abstract 2009: Breast cancer stem cells are associated with HER2-mediated radioresistance and the molecular subtype conversion of HER2-negative breast cancer

Abstract Although it has been proposed that the benefits of HER2-targeted therapy in HER2-negative breast cancer are associated with molecular subtype conversion, the underlying mechanism and the clinical biomarkers are unclear. Herein, we showed that breast cancer stem cells (BCSCs) mediate HER2 subtype conversion and radioresistance in HER2-negative breast cancer cells and evaluated serum HER2 as a clinical biomarker for HER2 subtype conversion. We found that the CD44+/CD24-/low BCSCs from HER2-negative breast cancer cells overexpressed HER2/EGFR and showed the radioresistant phenotype. In addition, we showed that trastuzumab treatment sensitized the radioresistant phenotype of the CD44+/CD24-/low cells with decreased levels of HER2/EGFR, which suggested that HER2-targeted therapy in HER2-negative breast cancer may be effective by targeting BCSCs that overexpress HER2/EGFR. Importantly, our clinical data showed that serum HER2 could be a clinical biomarker for the evaluation of HER2 subtype conversion in recurrent HER2-negative breast cancer patients. Therefore, our data provide in vitro and in vivo evidence for the molecular subtype conversion of HER2-negative breast cancer. Citation Format: Jae-Sung Kim. Breast cancer stem cells are associated with HER2-mediated radioresistance and the molecular subtype conversion of HER2-negative breast cancer [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 2009.

Breast cancer stem cells in HER2-negative breast cancer cells contribute to HER2-mediated radioresistance and molecular subtype conversion: clinical implications for serum HER2 in recurrent HER2-negative breast cancer.

Although it has been proposed that the beneficial effect of HER2-targeted therapy in HER2-negative breast cancer is associated with the molecular subtype conversion, the underlying mechanism and the clinical biomarkers are unclear. Our study showed that breast cancer stem cells (BCSCs) mediated HER2 subtype conversion and radioresistance in HER2-negative breast cancer cells and evaluated serum HER2 as a clinical biomarker for HER2 subtype conversion. We found that the CD44+/CD24–/low BCSCs from HER2-negative breast cancer MCF7 cells overexpressed HER2 and EGFR and showed the radioresistant phenotype. In addition, we showed that trastuzumab treatment sensitized the radioresistant phenotype of the CD44+/CD24–/low cells with decreased levels of HER2 and EGFR, which suggested that HER2-targeted therapy in HER2-negative breast cancer could be useful for targeting BCSCs that overexpress HER2/EGFR. Importantly, our clinical data showed that serial serum HER2 measurement synchronously reflected the disease relapse and the change in tumor burden in some patients who were initially diagnosed as HER2-negative breast cancer, which indicated that serum HER2 could be a clinical biomarker for the evaluation of HER2 subtype conversion in patients with recurrent HER2-negative breast cancer. Therefore, our data have provided in vitro and in vivo evidence for the molecular subtype conversion of HER2-negative breast cancer.

Efficacy of taxanes followed by anthracyclines as neoadjuvant therapy in HER2-negative breast cancer (BC): Analysis of everyday clinical practice.

e12112 Background: Pathological complete response (pCR) after neoadjuvant chemotherapy for BC has been related with survival, and the sequence of anthracyclines followed by taxanes (AT) has been the strategy to achieve this response. Some studies suggest that the reverse sequence (TA) might improve cancer outcomes. The aim of our study was to compare clinical response, toxicity and efficacy in terms of pCR rate (ypT0/pTis, ypN0) between both sequences Methods: A retrospective cohort study was designed. TA cohort received Docetaxel (100 mg/m2) x 4, followed by AC (60/600 mg/m2) x 4. AT cohort received the reverse sequence at the same doses. To be included, it was necessary to have received at least one cycle in the planned sequence. Logistic regression analysis was performed to obtain a model adjusted by age, menopausal status, tumor size, nodal status, grade, estrogen receptor (ER), progesterone receptor, and Ki67 Results: From June 2008 to December 2015, 135 consecutive patients with stage II – III HER2 negative BC were treated: TA (n = 48) and AT (n = 87). No significant differences in patient characteristics between groups were found, except for histological grade 3 (63.2% to AT vs. 35.4% to TA), and ER negative (41.4% to AT vs. 22.9% to TA). The pCR rate for TA was 16.7% (8 of 40) vs. 14.9% (13 of 74) for AT. Multivariate logistic regression analysis found OR = 3.65 to achieve pCR for TA (95%CI 1.03 – 12.94; p = .045). We also performed the same analysis for two clinical parameters of response: Neoadjuvant response index (NRI) with cut-off > 0.5 (OR 3.96, 95%CI 1.42-11.08; p = .009) and Clinical response (CR) > 50% (OR 3.65, 95%CI 1.03 – 12.94; p = .045). These parameters were correlated in our series with DFS (p = .011 to NRI and p = .00023 to CR) and OS (p = .034 to NRI and p = .0014 to CR) using the Kaplan-Meier method. No significant differences between rates of either, hospitalizations, neutropenia or dose intensity were found Conclusions: Sequence of T followed by A was slightly significantly more effective to achieve pCR as well as better clinical outcomes in our series of HER2 negative BC than classical sequence of A followed by T, and support the design of large prospective studies to confirm these results

Abstract P1-14-06: A phase II randomized study with eribulin/cyclophosphamide (ErC) and docetaxel/cyclophosphamide (TC) as neoadjuvant therapy in HER2-negative breast cancer- Final analysis of primary endpoint and correlative analysis results

Abstract Background: Eribulin mesylate (Er) is a non-taxane inhibitor of microtubule growth that results in G2-M cell cycle arrest, disruption of normal mitotic spindles and apoptosis. Er demonstrated an overall survival (OS) but not progression free survival (PFS) advantage in anthracycline and taxane refractory breast cancer pts. This OS rather than PFS benefit has been attributed to Er's potential to suppress new metastases through its effects on the epithelial mesenchymal transition (EMT) pathway, even in the absence of an effect on the primary tumor or established metastases. In this study ErC was compared to TC, a standard regimen for (neo) adjuvant treatment. A companion exploratory analysis examined the EMT markers E-cadherin and vimentin, as well as the endothelial marker CD-31 assessing tumor vasculature. Final assessments of the primary endpoint of pathological complete response (pCR) and results of the correlative studies will be presented. Methods: Women with histologically confirmed invasive HER2-negative (IHC 0-1+ or FISH/SISH negative), cT1-3, cN0-2, M0 (pN3a disease allowed) adenocarcinoma of the breast were eligible. Following a 10 pt lead-in to confirm the safety/feasibility of ErC, pts were randomized 2:1. Arm 1, Er 1.4 mg/m2 IV (Days 1 & 8) and C 600 mg/m2 IV (Day 1); Arm 2, T 75 mg/m2 IV and C 600 mg/m2 IV on Day 1, both regimens administered q 21 days x 6 cycles followed by surgery. Tumor samples were collected at baseline and from residual breast cancer at the time of surgery. Samples were assayed for E-cadherin, vimentin, and CD-31 expression by immunohistochemistry. Results: Enrollment was completed 4/2014 (76 pts); 10 pts in lead-in phase, 66 pts were randomized (Arm 1, 44; Arm 2, 22). In the randomized population, 77% had invasive ductal adenocarcinoma; median tumor size 3.1 cm (range, 0.4-10cm; 29.5% were T3); axillary nodes clinically positive in 52%. 34% of pts were triple negative (TN). 59 pts (89%) underwent surgery after receiving neoadjuvant chemotherapy (NAC) on study. pCR rates were 9% and 18% on the TC and ErC arms respectively. 4/7 pts with pCR on the ErC arm were TN. tumor samples were analyzed from 69 pts (including lead-in pts) for expression of the EMT biomarkers. Of these, 40 pts had paired pre- and post-treatment samples, and 29 pts had either a pre- or post-treatment sample (including 8 pre-treatment samples from pts who achieved pCR). In pre-treatment tumor specimens (61 samples), E-cadherin levels were modest-high in 80%, vimentin expression was seen in 39%, and CD-31 expression observed in 21% of the samples. Analysis of pre- and post-treatment paired specimens and differential effects according to treatment regimen will be presented. Conclusion: The observed pCR rate of 18% with ErC in this HER2- pt population was comparable with other NAC regimens. Correlative evaluation of EMT markers and tumor vascular density with response is ongoing and will be presented. Citation Format: Yardley DA, Chandra P, Hart L, Wright GS, Ward P, Mani A, Shastry M, Finney L, Guo S, DeBusk LM, Hainsworth JD, Burris III HA. A phase II randomized study with eribulin/cyclophosphamide (ErC) and docetaxel/cyclophosphamide (TC) as neoadjuvant therapy in HER2-negative breast cancer- Final analysis of primary endpoint and correlative analysis results. [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 P1-14-06.

Abstract P3-11-08: Eribulin/cyclophosphamide (ErC) versus docetaxel/cyclophosphamide (TC) as neoadjuvant therapy in locally advanced HER2-negative breast cancer: A randomized phase II trial of the Sarah Cannon Research Institute

Abstract Background: Pathologic complete response (pCR) following neoadjuvant chemotherapy for locally advanced breast cancer strongly correlates with improved disease-free survival, rates of breast-conserving surgery, and provides an early indicator of treatment efficacy. Standard taxane-containing neoadjuvant combinations result in pCR rates of 18% in unselected patient (pt) populations. Eribulin (Er) is a novel inhibitor of microtubule dynamics. In the EMBRACE trial, Er demonstrated a survival advantage in anthracycline and taxane pretreated breast cancer. This study evaluated non-anthracycline regimens of Er in combination with cyclophosphamide (ErC) and docetaxel/cyclophosphamide (TC) as neoadjuvant therapy in HER2-negative breast cancer. Methods: Adult women with histologically confirmed invasive HER2-negative (defined as IHC 0-1+ or FISH/SISH negative), clinical stage T1-3, N0-2, M0 (pN3a disease allowed) adenocarcinoma of the breast were eligible. Additional eligibility criteria included: ECOG PS 0,1 or 2; normal cardiac function, known hormone receptor status for stratification; adequate hematologic, liver, and renal function. Following a 10 pt lead-in to confirm the safety and feasibility of ErC, pts were randomized in a 2:1 ratio: Arm 1, Er 1.4 mg/m2 IV (Days 1 & 8) and C 600 mg/m2 IV (Day 1); Arm 2, T 75 mg/m2 IV and C 600 mg/m2 IV on Day 1, both regimens administered q 21 days x 6 cycles followed by surgery. Locoregional radiation and/or antiestrogen therapy were prescribed postoperatively according to standard guidelines. Tumor samples were collected at baseline and from residual disease noted at the time of surgery. A pCR rate ≥18% in pts treated with ErC warranted further evaluation. Results: Enrollment was completed April 2014 (76 pts); 66 pts were randomized (Arm 1, 44; Arm 2, 22). Median age was 52 years (range, 23-77); 88% ECOG 0; 79% invasive ductal adenocarcinoma; median baseline primary tumor size 3cm (range, 0.4-10cm; 30% were T3); axillary nodes clinically positive in 51%. Thirty-three percent were triple negative. 55 pts (72%) received neoadjuvant therapy and underwent surgery. 16 pts continue to receive study treatment. At this time, pts who underwent surgery have similar pCR rates with ErC and TC (14%, 5/37 vs. 11%, 2/18 respectively). 3 of 51 hormone receptor positive pts (6%) and 4 of 25 triple negative pts (16%) had pCR. Neutropenia (40%) was the most common grade 3/4 toxicity. Common treatment-related toxicities included: fatigue (66%), alopecia (57%), and nausea (54%). Peripheral neuropathy incidence is currently lower with ErC than with TC (30% vs 45%) with 3 grade 3 events on TC. Prophylactic growth factor use was higher in TC than with ErC (77% vs 24%). Conclusions: Eribulin in combination with cyclophosphamide was well tolerated with no unexpected toxicities. At present, pCR rates with both regimens are within the range previously reported with docetaxel/cyclophosphamide and other standard taxane-containing neoadjuvant regimens. Final efficacy and toxicity data will be presented. A planned exploratory correlative tissue analysis may identify tumors more likely to derive benefit from eribulin-based therapies. Citation Format: Denise Yardley, Karyn Dyehouse, Aruna Mani, Carmen Calfa, David Drosick, Kathleen Yost, Diana Shipley, Raven Quinn, Robyn Young, Lindsey Finney, Chris Earwood, Mythili Shastry, John Hainsworth. Eribulin/cyclophosphamide (ErC) versus docetaxel/cyclophosphamide (TC) as neoadjuvant therapy in locally advanced HER2-negative breast cancer: A randomized phase II trial of the Sarah Cannon Research Institute [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 P3-11-08.

Phase II Randomized Study of Ixabepilone Versus Observation in Patients With Significant Residual Disease After Neoadjuvant Systemic Therapy for HER2-Negative Breast Cancer

BackgroundResidual disease (RD) after neoadjuvant chemotherapy carries an increased risk for recurrence. Ixabepilone has activity in anthracycline/taxanes-resistant breast cancer. We explored adjuvant ixabepilone in patients with significant RD HER2-negative breast cancer. MethodsA phase II study in patients with residual cancer burden II or III randomized to ixabepilone versus observation was conducted. Circulating tumor cells (CTCs) were measured at baseline and at 9 and 18 weeks. Survival probabilities were estimated by Kaplan–Meier product limit. Toxicities were reported as proportions in the ixabepilone arm. ResultsAccrual was stopped because of ixabepilone toxicity. Sixty-seven patients were registered; 43 were randomized, 19 received ixabepilone, and 24 went to observation. One patient (9.1%) in the observation arm versus 2 patients (18.2%) in the ixabepilone arm had CTCs at 18 weeks (P = 1.0). Three-year recurrence-free survival and overall survival were 94% and 82%, and 100% and 79% in the observation and ixabepilone arms (P = .35 and .18), respectively. Most common adverse events (AEs) included fatigue, pain, neuropathy, constipation, nausea, rash, anorexia, and diarrhea. Serious AEs included pain (63.2%), fatigue (31.6%), and neuropathy (31.6%). ConclusionsAdjuvant ixabepilone in patients with significant RD after neoadjuvant chemotherapy was difficult to administer because of AEs and did not change the presence of CTC or affect survival outcomes. NCT00877500.

Feasibility study of cationic liposome-encapsulated paclitaxel in combination with paclitaxel followed by FEC as induction therapy in HER2-negative breast cancer.

e12008 Background: Cationic liposome-encapsulated paclitaxel , a tumor endothelial targeting agent (composition of paclitaxel combined with neutral and cationic lipids) has shown activity in metastatic triple-negative breast cancer (BC) in combination with paclitaxel (Awada et al. ESMO2010). No data exist in the non-metastatic setting. Methods: HER2-negative BC candidates for neoadjuvant chemotherapy were scheduled to receive 12 cycles of weeklycationic liposome-encapsulated paclitaxel 22mg/m2 plus paclitaxel 70mg/m2 followed by 3 cycles of FEC (Fluorouracil 500mg/m2, Epirubicin 100mg/m2, Cyclophosphamide 500mg/m2) every 3 weeks followed by surgery. Primary endpoint was percent (%) reduction in Magnetic Resonance Imaging (MRI) estimated tumor volume at the end of cationic liposome-encapsulated paclitaxel plus paclitaxel administration as compared to baseline. Safety, pathological complete response (pCR) defined as no residual tumor in breast and axillary nodes at surgery and correlation between % reduction in MRI estimated tumor volume and pCR were also evaluated. Results: Six patients with estrogen receptor (ER)-negative/HER2-negative and 9 with ER-positive/HER2-negative BC were included. Nine patients completed treatment as per protocol. Despite premedication and slow infusion rates, grade 3 hypersensitivity reactions to cationic liposome-encapsulated paclitaxel were observed during the 1st, 2nd, 3rd and 6th weekly infusion in 4 patients, respectively and required permanent discontinuation of the cationic liposome-encapsulated paclitaxel . Two patients stopped cationic liposome-encapsulated paclitaxel plus paclitaxel after 8 and 9 weeks due to clinical disease progression, two patients had grade 3 increase in transaminases and 1 patient grade 4 neutropenia. PCR was observed in 5 of the 6 ER-/HER2- and in none of the 8 ER+/HER2- BC patients. The median % reduction in MRI estimated tumor volume at the end of cationic liposome-encapsulated paclitaxel plus paclitaxel treatment was 90% (95% Confidence Interval: 69-99%), (p<0.001, sign test) for the 14 patients that underwent surgery; 99% (CI:87-100%) for patients with pCR and 84% (CI:50-95%) for patients with no pCR. Conclusions: The cationic liposome-encapsulated paclitaxel and paclitaxel combination showed promising preliminary activity as preoperative treatment, especially in ER-/HER2- patients. Further studies are warranted with need of premedication optimization. Clinical trial information: NCT01537536.

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.

Comparison of T-FEC therapy for HER2-negative breast cancer with TC6 cycle therapy

e11513 Background: TC4 cycle therapy was more useful than AC4 cycle therapy. In this study, we compared the treatment completion rate and safety of a regimen involving anthracycline, T-FEC (docetaxel followed by FEC) therapy, with those of TC6 cycle therapy in patients with HER2-negative breast cancer in whom there may be no topoisomerase IIa amplification. Methods: We administered T-FEC q3w or TC q3w to HER2-negative breast cancer patients with axillary lymph node metastasis, or high-risk breast cancer patients without metastasis. As a primary endpoint, the treatment completion rate was evaluated. As secondary endpoints, the safety such as short- and long-term toxicity including cardiac toxicity, as well as the administration state, were assessed. Results: The T-FEC group consisted of 21 patients. The TC6 group consisted of 22 patients. There were no significant differences in the patient background between the two groups. In the T-FEC group, the treatment completion rate and relative dose intensity were 95.2 and 98.90%, respectively. In the TC6 group, the values were 86.4 and 93.2%, respectively. Concerning hemotoxicity, Grade 3 or higher adverse reactions included neutropenia (T-FEC group: 33%, TC6 group: 41%) and febrile neutropenia (TC6 group: 14%). As non-hemotoxicity adverse reactions, general malaise, nausea/vomiting, anorexia, and stomatitis were noted in 52, 38, 48, and 33% of the patients in the T-FEC group, respectively. The incidence of nausea/vomiting was significantly higher in this group. In the TC6 group, general malaise, nausea/vomiting, anorexia, and stomatitis were observed in 46, 9, 37, and 18% of the patients, respectively. In addition, exanthema and peripheral neuropathy were noted in 23 and 50%, respectively. These percentages were significantly higher. Conclusions: With respect to adverse reactions, exanthema and peripheral neuropathy were characteristic of TC6 cycle therapy, and T-FEC therapy frequently caused nausea/vomiting. These results suggest that TC6 cycle therapy is tolerable, and that this regimen can also be performed at outpatient clinics. However, in the TC6 group, the treatment completion rate was slightly lower than in the T-FEC group; appropriate supportive therapy may be necessary.