HER2-negative Operable Breast Cancer Research Articles

Anthracycline-free or short-term regimen as adjuvant chemotherapy for operable breast cancer: A phase III randomized non-inferiority trial

BackgroundDe-escalating anthracycline is gaining popularity for breast cancer patients. We aim to evaluate the non-inferiority of an anthracycline-free or short-term regimen to the standard anthracycline-based regimen for operable patients with human epidermal growth factor receptor 2 (HER2)-negative breast cancer. MethodsIt is a prospective, open-label, phase 3, randomized non-inferiority trial from June 1, 2010 to June 1, 2017. Follow-up had been kept until July 2019. This trial was conducted at Fudan University Shanghai Cancer Center. Patients with pT1–3N+ or pT2–3N0 but high-risk (grade II/III, lymphovascular invasion, ≤35 years of age or hormone-receptor negative) HER2-negative operable breast cancer were eligible and stratified by age, pathological tumour stage, pathological node status and hormone-receptor status. Patients were randomized to 6 cycles of docetaxel and cyclophosphamide (TC, n = 524), 3 cycles of cyclophosphamide/epirubicin/fluorouracil followed by 3 cycles of docetaxel (CEF-T, n = 523) or epirubicin and cyclophosphamide for 4 cycles followed by paclitaxel for 12 weeks (EC-P, n = 524) as the intention-to-treat population. Of these patients, 94% completed allocated therapy. Difference in disease-free survival (DFS) compared to EC-P. The prespecified non-inferiority margin was 4.5%, corresponding to the hazard ratio (HR) of 1.44 (one-sided α = 0.05), with an assumed 5-year DFS of 89% for EC-P. FindingsIncluded in the intention-to-treat population were 1571 patients (median [IQR] age, 50 [45–57] years; 92% estrogen receptor [ER]-positive; 59% pN+). Through a median follow-up of 5.5 years, HR for TC versus EC-P was 1.05 (5-year DFS: 85.0% vs. 85.9%; 90% confidence interval [CI]: 0.79–1.39, non-inferior P = 0.048) and for CEF-T versus EC-P, 0.99 (5-year DFS: 85.1% vs. 85.9%; 90% CI: 0.75–1.30, non-inferior P = 0.045). Grade 3 or 4 adverse events for TC included rash (3.9%) and peripheral neuropathy (2.8%) and for CEF-T and EC-P diarrhea and nausea/vomiting were predominant. Results of per-protocol analyses were similar. InterpretationBoth TC and CEF-T are non-inferior adjuvant regimen to EC-P mainly in patients with ER+HER2- breast cancer. TC is a safe regimen that avoids anthracycline-related side effects. FundingThis work was supported by grants from the National Natural Science Foundation of China (Grants 81672600, 81722032, 82072916, and 91959207), the 2018 Shanghai Youth Excellent Academic Leader, the Fudan ZHUOSHI Project, the Municipal Project for Developing Emerging and Frontier Technology in Shanghai Hospitals (grant SHDC12010116), the Cooperation Project of Conquering Major Diseases in the Shanghai Municipality Health System (grant 2013ZYJB0302), the Innovation Team of the Ministry of Education (grant IRT1223), and the Shanghai Key Laboratory of Breast Cancer (grant 12DZ2260100) and the National Cancer Institute (grant P30 CA16058).

Comparative Effectiveness of Adjuvant Chemotherapy in Early-Stage Breast Cancer: A Network Meta-analysis

BackgroundThere are several regimens recommended by the National Comprehensive Cancer Network (NCCN) for HER2-negative operable breast cancer. To our knowledge, no trials have yet been performed comparing these regimens head to head. We performed a network meta-analysis comparing the efficacy of NCCN-recommended chemotherapy regimens. MethodsWe searched Medline, Embase, Web of Science, the Cochrane Central Register of Controlled Trials, and World Health Organization (WHO) International Clinical Trials Registry Platform from inception to February 2020. We included randomized clinical trials comparing adjuvant regimens in predominantly node-positive operable breast cancer patients. We compared (1) DDACT, (2) TCx4 cycles, (3) TAC, and (4) ACWKT. Common comparators were (5) AC, (6) ACT, and (7) ACD. Preferred Reporting Items for Systematic Reviews and Meta-analysis (PRISMA) guidelines were followed. The Cochrane risk of bias tool assessed quality of the studies. Odds ratios (ORs) were calculated as measures of treatment effects with AC as reference. We used Bayesian hierarchical random-effects models with noninformative priors for mixed multiple treatment comparisons. Effectiveness was estimated by disease-free and overall survival using ORs. Sensitivity analyses were performed. Safety outcomes included febrile neutropenia. ResultsWe identified 7 randomized controlled trials with 16,332 patients. TC (odds ratio [95% confidence interval], 0.71 [0.36-1.40]), TAC (0.77 [0.37-1.57]), ACWKT (0.68 [0.34-1.38]), and DDACT (0.72 [0.35-1.42]) were similar for overall survival. TC (0.64 [0.36-1.14]), TAC (0.67 [0.39-1.15]), ACWKT (0.63 [0.37-1.07]), and DDACT (0.59 [0.35-1.01]) had similar disease-free survival benefit. With regard to toxicity, TAC (2.67 [0.30-21.04]) had the highest odds of febrile neutropenia. ConclusionThe current generation of regimens are similar in efficacy. Given the lower toxicity of TCx4 comparatively, it is an acceptable alternative for lower-risk early-stage HER2-negative breast cancers.

SOLTI-1503 PROMETEO TRIAL: combination of talimogene laherparepvec with atezolizumab in early breast cancer.

New treatment strategies such as immune checkpoint inhibitors and oncolytic viruses are opening new possibilities in cancer therapy. Preliminary results in melanoma and other tumors showed that the combination of talimogene laherparepvec with an anti-PD-1/PD-L1 or anti-CTLA4 has greater efficacy than either therapy alone, without additional safety concerns beyond those expected for each agent. The presence of residual cancer after neoadjuvant chemotherapy in early breast cancer patients is an unmet medical need. SOLTI-1503 PROMETEO is a window of opportunity trial, which evaluates the combination of talimogene laherparepvec in combination with atezolizumab in women with operable HER2-negative breast cancer who present residual disease after neoadjuvant chemotherapy. The primary end point is the rate of residual cancer burden 0/1. Clinical Trial Registration: NCT03802604.

Neoadjuvant letrozole for postmenopausal estrogen receptor-positive, HER2-negative breast cancer patients, a study from the Danish Breast Cancer Cooperative Group (DBCG)

Introduction: Neoadjuvant endocrine treatment (NET) is a low-toxicity approach to achieve operability in locally advanced breast cancer, and to facilitate breast conservation in early breast cancer, particular in patients with highly estrogen receptor (ER) positive and HER2-negative disease. Here, we report the results obtained by neoadjuvant letrozole in patients with early breast cancer in a phase-II design.Material and methods: A total of 119 postmenopausal women with ER-positive, HER2-negative operable breast cancer were assigned to four months of neoadjuvant letrozole before definitive surgery. Sentinel node or diagnostic fine needle aspiration cytology procedure was performed prior to treatment and the women were assessed prior, at two months, and before surgery with clinical examination, mammography and ultrasonography. Surgical specimens were examined for pathological response. Primary outcome was pathological and clinical response.Results: The per protocol population consisted of 112 patients. Clinical response was evaluated in 109 patients and pathological response in 108. Overall a mean decrease in tumor size was 15% (p ≤ .0001). One patient had complete pathological response and 55% of patients had partial pathological response. ER at 100%, ductal subtype, tumor size below 2 cm and lymph node–negative status was significantly associated with a better response to NET and malignancy grade 3 with a poorer response to NET. One patient progressed during treatment and received neoadjuvant chemotherapy. Eight patients received adjuvant chemotherapy due to lack of response.Conclusion: Neoadjuvant aromatase inhibitor therapy is an acceptable strategy in selected postmenopausal patients with ER-rich and HER2-negative early breast cancer with ductal histology and should be considered when chemotherapy either isn’t indicated or feasible.

Phase II study of neoadjuvant anthracycline combined with nanoparticle albumin‑bound paclitaxel for human epidermal growth factor receptor 2‑negative breast cancer

Neoadjuvant chemotherapy (NAC) with anthracyclines followed by taxane chemotherapy has become the standard treatment for patients with locally advanced, operable breast cancer. Recently, the efficacy of nanoparticle albumin-bound paclitaxel (nab-PTX) for metastatic breast cancer was reported. However, there are still few studies of a neoadjuvant regimen including nab-PTX. Thus, the present phase II study evaluated the efficacy and safety of 5-fluorouracil, epirubicin and cyclophosphamide (FEC regimen) followed by nab-PTX as neoadjuvant treatment for operable human epidermal growth factor receptor 2 (HER2)-negative breast cancer. Women with operable HER2-negative breast cancer (clinical stage T1a-4N1-3) received 4 cycles of FEC (5-fluorouracil 500 mg/m2, epirubicin 100 mg/m2 and cyclophosphamide 500 mg/m2 every 21 days), followed by 4 cycles of nab-PTX at 260 mg/m2 every 21 days. The patients then underwent mastectomy or breast-conserving surgery (BCS). The primary endpoint was pathological complete response (pCR) rate. The secondary endpoints included clinical response rate, pathological response rate, BCS rate and safety. A total of 16 patients were evaluated and 3 patients (18%) achieved pCR (1 patient with estrogen receptor-positive cancer and 2 with estrogen receptor-negative cancer). The pCR rate was 12 and 25% in patients with estrogen receptor-positive and -negative cancers, respectively. The clinical response rate was 100% (clinical complete and partial response in 6 and 10 patients, respectively). The BCS rate was 31.25%. Three patients experienced grade 3 neutropenia during FEC therapy, and no grade 3/4 events occurred during nab-PTX therapy. Thus, neoadjuvant therapy with FEC followed by nab-PTX for operable HER2-negative breast cancer was found to be a safe and effective option.

Abstract P1-09-15: Tumor and serum DNA methylation in women receiving preoperative chemotherapy (PST) with or without vorinostat in primary operable HER2-negative breast cancer in TBCRC008

Abstract Background: DNA methylation is a promising prognostic and predictive biomarker of response to treatment in advanced breast cancer (Fackler MJ. Can Res 2014). We evaluated whether baseline and change in tissue and serum methylation would predict pathological complete response (pCR) in patients with HER2-negative early breast cancer treated with PST. Methods: TBCRC008 was a multicenter placebo-controlled trial that investigated pCR (no invasive cancer in breast/axilla) following 12 weeks of preoperative carboplatin and albumin-bound paclitaxel with or without the histone deacetylase (HDAC) inhibitor vorinostat in 62 patients with HER2-negative breast cancer. We performed an exploratory planned biomarker study correlating baseline and change (D15) in tumor tissue and serum methylation with pCR. Methylation was measured using cumulative methylation index (CMI) in quantitative multiplexed methylation-specific polymerase chain reaction (QM-MSP) assays; cMethDNA assay for serum (Fackler MJ. Can Res 2014) and QM-MSP for tissue (Fackler MJ. Can Res 2004). The analysis population included all patients with available methylation and pCR data. Association between CMI level (log transformed baseline, D15, change) and pCR was evaluated using univariate as well as multivariable logistic regression models controlling for treatment arm and estrogen receptor (ER) status. Additional subgroup analyses assessed association of CMI level with pCR stratified by ER status and treatment arms, respectively. Spearman's correlation coefficient was performed to evaluate the correlation between tissue and serum CMI. Results: pCR data were available for 61 of 62 patients. One patient with unknown response was treated as a non-responder. The pCR rate was similar in both arms (vorinostat 25.8%, placebo 29%). Both tissue and serum CMI data were available in 55 (baseline), 50 (D15) and 46 (change) patients. Elevated serum methylation based on a predefined threshold (6.9 units) was identified in 23/59 (39%) patients. In univariate analysis, one log unit increase in tissue CMI levels at D15 was associated with a 40% lower chance of obtaining a pCR (odds ratio, OR=0.60, 95% CI 0.37-0.97; p=0.037). The multivariable analysis did not show a statistically significant association of tissue or serum CMI with pCR, although a similar trend in magnitude towards association with pCR was observed for D15 and change in tumor tissue CMI (OR 0.67 and 0.57, p=0.129 and 0.147 respectively). Subgroup analyses suggested a significant association between tissue CMI levels at D15 and pCR in the group treated with vorinostat [tissue OR: 0.44 (0.20, 0.93), p=0.03; serum OR 0.37 (0.13, 1.07), p=0.07] but not in the placebo group. No significant correlation was observed between tissue and serum CMI. Conclusion: This is the first study to evaluate the predictive role of tissue and serum methylation (CMI) in patients with early breast cancer treated with PST ± an HDAC inhibitor. Methylation was detected more frequently in tissue than serum. Tissue CMI levels at D15 may predict poor response to this regimen. Further evaluation of the predictive role of methylation in early breast cancer is warranted. Citation Format: Connolly RM, Fackler MJ, Zhang Z, Zhou XC, Goetz MP, Boughey JC, Walsh B, Carpenter J, Storniolo AM, Watkins S, Barielson E, Sukumar S, Stearns V. Tumor and serum DNA methylation in women receiving preoperative chemotherapy (PST) with or without vorinostat in primary operable HER2-negative breast cancer in TBCRC008 [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P1-09-15.

The Effect on Surgical Complications of Bevacizumab Added to Neoadjuvant Chemotherapy for Breast Cancer: NRG Oncology/NSABP Protocol B-40.

NRG Oncology/NSABP trial B-40 tested the impact of adding bevacizumab (bev) to neoadjuvant chemotherapy for operable breast cancer. Secondary endpoints included rates of surgical complications after surgery in patients who did or did not receive bev. A total of 1206 women with HER2-negative operable breast cancer were randomly assigned to receive one of three different docetaxel-plus-anthracycline-based regimens, without or with bev (15mg/kg every 3weeks) for the first 6 of 8 cycles and for 10 doses postoperatively. Surgical complications were assessed from date of surgery through 24months following study entry. Early surgical complications were significantly more frequent in the bev group (25.4 vs. 18.9%; trend test p = 0.008), but most were grade 1-2. Early noninfectious wound dehiscences were infrequent and not significantly different (5.4 vs. 3.1%; trend test p = 0.15). Long-term noninfectious wound complications were significantly higher for patients receiving bev (11.8 vs. 5.1%; trend test p = 0.0007), but the incidence of grade ≥3 wound dehiscence was low in both groups (<1%). Among 193 patients undergoing expander or implant reconstructions, 19 (19.6%) of 97 in the bev-receiving group versus 10 (10.4%) of 96 in the non-bev group had grade ≥3 complications (Pearson, p = 0.11). Overall, adding bev increased surgical complications, but most serious complications were not significantly increased. In particular, the need for surgical intervention in patients undergoing breast reconstruction with prosthetic implants was higher with bev but was not statistically significantly different. With precautions, bev can be used safely perioperatively in patients undergoing surgery for breast cancer.

206P - Bevacizumab plus dose-dense neoadjuvant FEC followed by docetaxel chemotherapy in patients with HER2-negative breast cancer: a multicentre, phase 2 study by the Hellenic Oncology Research Group

Addition of bevacizumab to standard chemotherapy in the neoadjuvant setting improves the proportion of patients with HER2-negative breast cancer who achieve pathological complete response. We aimed to assess the addition of bevacizumab to dose-dense neoadjuvant chemotherapy. We enrolled women with operable HER2-negative breast cancer (T1c-T4 and N0-3). Patients underwent treatment every 2 weeks (with pegfilgrastim support) of fluorouracil (500 mg/m2), epirubicin (75 mg/m2), cyclophosphamide (500 mg/m2), and bevacizumab (10 mg/kg) for 4 cycles followed by docetaxel (75 mg/m2) and bevacizumab for 4 cycles. After surgery, patients received adjuvant radiotherapy, and hormone therapy (if indicated). The primary endpoint was pathological complete response in breast and the axilla, and safety of the combination. A two-stage trial design was planned with 15 and 33 patients to enroll, respectively. The trial was terminated early due to slow accrual and follow-up is ongoing. Between Oct, 2011, and Apr, 2015, we enrolled 34 patients, of whom 3 didn't undergo surgery, leaving 31 patients in the primary endpoint analysis. After neoadjuvant therapy, 5 (16.1%) of 31 patients achieved a pathological complete response according to centralized review. No patient discontinued treatment due to adverse events. The most frequent grade 3–4 toxicities were neutropenia (23.5%), nausea and vomiting (5,8%), and febrile neutropenia (2,9%). Only one patient developed grade III bevacizumab-related toxicity (hypertention). One patient died of pneumonia after cycle 8 and before surgery, which was thought to be unrelated to bevacizumab. After 25,2 months of median follow-up (range: 2,3-43,3) five patients experienced a disease relapse (16,1%). Our results seem to indicate that the addition of bevacizumab to dose-dense neoadjuvant chemotherapy with FEC and docetaxel, although safe and feasible, does not provide clinical benefit to patients with non-metastatic HER2-negative breast cancer. Translational research to identify patients who might benefit from bevacizumab is needed.

Abstract CT057: A single-arm, preoperative, pilot study to evaluate the safety and biological effects of orally administered reparixin in early breast cancer patients who are candidates for surgery

Abstract Background. Experimental models and retrospective clinical observations point to Cancer Stem Cells (CSC) as responsible for tumor initiation, treatment resistance, disease recurrence and metastasis. CXCR1, one of the receptors for CXCL8, was identified on breast cancer (BC) CSC. Reparixin, an investigational allosteric inhibitor of CXCR1, administered as monotherapy reduced the metastatic spread of human BC cells and the CSC content of human BC xenograft in mice (Ginestier C et al., JCI 2010).Methods. In this single arm, monotherapy trial (NCT01861054) patients were female aged ? 18 years with HER-2 negative operable BC with a clinical diameter of &amp;gt;1 cm not eligible for neoadjuvant treatment. It was planned to enrol 20 patients with ER+ and/or PgR+ and 20 patients with ER-/PgR- BC (i.e., Triple-Negative BC, TNBC). Patients received reparixin oral tablets 1000 mg 3 times daily (t.i.d.) for 21 days prior to surgery. Patients underwent core biopsies at baseline and at the completion of therapy. Primary objectives were evaluation of the effects of reparixin on CSC and tumor microenvironment and the safety of reparixin. The secondary objective was to define the pharmacokinetic (PK) profile of orally administered reparixin. Signal of Activity (SoA) was defined as a reduction by at least 20% in ALDH-1+ or CD24-/CD44+ CSC by flow cytometry (FC), with consistent reduction by immunohistochemistry (IHC).Results. 18 patients with ER+ and/or PgR+ BC and 2 with TNBC were enrolled. The trial was terminated due to slow enrolment in TNBC cohort. Safety: adverse reaction of grade ?2 (none serious) were experienced by 10/20 patients. All patients completed study treatment. PK: reparixin was rapidly absorbed (median Tmax 1h) and metabolized with median t1/2 of about 1.5 hr on both day 1 and 21. Efficacy: 12/18 and 2/2 patients in the ER+ and/or PgR+ BC group and TNBC group, respectively, had a sizeable ALDH+ and/or CD24-/CD44+ cell population at baseline and a second biopsy evaluated by FC. 11 evaluable patients achieved SoA (9/12 ER+ and/or PgR+ and 2/2 TNBC). The possibility to confirm FC results in tissue sections was hindered by very low numbers of CSC. A reduction in total CXCR1+ cells was found by FC in 7/13 evaluable patients and a reduction in p62 by IHC in 8/13 evaluable patients, suggesting target engagement and induction of autophagy.Conclusions. Enrolment of patients with TNBC in preoperative trials with single non cytotoxic agents is limited by the widespread use of neoadjuvant treatment. Reparixin 1000 mg t.i.d. for 21 consecutive days appeared to be well tolerated. SoA was achieved in 11/14 evaluable patients. The clinical relevance of a ?20% reduction of CSC following a single 21-day course of reparixin in this patient population is unknown. A randomized phase 2 study of reparixin plus paclitaxel versus paclitaxel in frontline treatment of metastatic TNBC is ongoing (NCT02370238). Citation Format: Lori J. Goldstein, Raymond P. Perez, Denise A. Yardley, Linda K. Han, James M. Reuben, Susan McCanna, Beth Butler, Pier Adelchi Ruffini, Jenny C. Chang. A single-arm, preoperative, pilot study to evaluate the safety and biological effects of orally administered reparixin in early breast cancer patients who are candidates for surgery. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr CT057.

Primary analysis of a randomized phase II, multicenter trial: Neoadjuvant weekly nab-paclitaxel 100mg/m2 followed by FE100C compared with docetaxel 75mg/m2 followed by FE100C for early breast cancer in Japan.

136 Background: Nanoparticle Albumin-Bound Paclitaxel (nab-PTX) is a new solvent free taxane-based anticancer drug. According to CA024 trial, nab-PTX 100mg/m2 demonstrated superior response to docetaxel (DTX) in patients with metastatic breast cancer. Besides, nab-PTX 100mg/m2 was less toxicity. In operable breast cancer, GeparSepto study was reported that the pCR rate were significantly higher with nab-PTX 125/150 mg/m2 compared to paclitaxel. We planned the randomized parallel design phase II trial to evaluate nab-PTX 100mg/m2in early breast cancer. Methods: Stage II-III HER2-negative breast cancer patients were included in this trial and received either 4 cycles of DTX (75 mg/m2 day1) q 3 w or 4 cycles of nab-PTX (100 mg/m2 day1/8/15) q4w followed by 4 cycles of FE100C. The primary end point is pCR (ypT0/is ypN0) rate, and the secondary end points are response rate, histological effect of treatment, breast conservation rate, and toxicity. Results: Between March 2011 to March 2014, 152 eligible patients were enrolled at 6 centers (75 pts were allocated for nab-PTX). Baseline characteristics were well balanced; median age was 51/49 years (DTX/nab-PTX), 61/61% of the patients with ER positive, 38/36% triple negative breast cancer, 57/65% Ki67 &gt; 20%. Clinically response rate was similar to each drug. (53/57%) The pCR rate was 12/17% (p = 0.323). In TNBC group, the pCR rate was 28/30% (p = 0.866). In Ki67 &gt; 20% group, the pCR rate was significantly higher, 16/48% (p = 0.021) with nab-PTX arm. The most common grade3-4 adverse event was neutropenia, which was observed in 40/36% of cases. Non-hematological adverse events of any grade were; 34/32% myalgia (DTX/nab-PTX), 42/35% arthralgia, 55/65% peripheral sensory neuropathy. No Grade3-4 peripheral sensory neuropathy was observed in nab-PTX arm. Infusion reaction of DTX occurred in 1 patient. Conclusions: In this initial effectively analysis, neoadjuvant weekly nab-paclitaxel 100mg/m2 were promising drug in HER2-negative operable breast cancer patients. Larger studies will be needed to evaluate neoadjuvant weekly nab-paclitaxel compared with DTX. Clinical trial information: 000005388.

Abstract S2-03: Preoperative window of opportunity study of the PI3K inhibitor pictilisib (GDC-0941) plus anastrozole vs anastrozole alone in patients with ER+, HER2-negative operable breast cancer (OPPORTUNE study)

Abstract Background: Preclinical and clinical data support a key role for the PI3K pathway in resistance to endocrine therapy in patients with ER+ breast cancer and suggest that combining PI3K inhibitors with endocrine therapy may overcome resistance. Short-term preoperative window of opportunity (WOO) studies are a validated strategy for novel treatments to provide proof-of-concept and define the most appropriate patient population by directly assessing treatment effects in tumour tissue before and after treatment. This is the first WOO study with the PI3K inhibitor pictilisib (GDC-0941) in combination with anastrozole (ANA). Methods: 73 postmenopausal patients (pts) have been randomized (2:1 in favour of the combination) to receive 2-week preoperative treatment with ANA plus pictilisib (n=50, "ANA+PIC" arm) or ANA alone (n=23, "ANA" arm). Pts had newly diagnosed, operable, ER+, HER2-negative breast cancer of ≥1 cm size. Pts receiving HRT were excluded. Treatment effects and correlative studies were assessed using FFPE and frozen tumour biopsies taken before and after 14 days of study treatment. The primary endpoint was inhibition of tumour-cell proliferation, as measured by change in Ki67 expression, determined centrally by 2 investigators. Secondary endpoints include induction of apoptosis (Caspase3) and safety. Comprehensive biomarkers analyses include targeted NGS of a comprehensive cancer panel of &amp;gt;400 genes, copy number analyses, and pre- and post-treatment reverse-phase protein arrays (RPPA) and RNA profiling. Results: Baseline (BL) disease characteristics were similar between both study arms. PAM50 analysis showed that 53% and 47% of tumors were Luminal (Lum) A and B, respectively. 65% of tumors had &amp;gt;14% Ki67-positive cells. Observed treatment-emergent AEs were consistent with those previously described for single-agent pictilisib and anastrozole. Mean post-treatment percentage reduction of Ki67 was 84% (95% CI, 75%-89%) for ANA+PIC and 72% (54%-87%) for ANA. Ki67-response (≥50% drop in % of Ki67+ cells) was 86% for ANA+PIC and 60% for ANA. By using the definition that pts with a natural logarithm of %Ki67+ cells of ≤1 or 1-2 have a day 15 anti-proliferative response, 93% [ln(ki67): &amp;lt;1, 46%; 1-2, 46%] of ANA+PIC were responders compared with 60% [&amp;lt;1, 47%; 1-2, 13%] of ANA-treated pts (p = 0.01). Preplanned subgroup analyses showed a significant interaction of response to ANA+PIC with molecular subtype and Ki67 levels. Patients with LumB tumors or high BL Ki67 (&amp;gt;14%) had a higher Ki67 response with ANA+PIC compared to ANA (LumB, 83% vs 38%; Ki67&amp;gt;14%, 94% vs 55%), whereas Ki67 response was similar for both treatments for LumA tumors (ANA, 75%; ANA+PIC, 73%) or tumors with low BL Ki67. Mean post-treatment % reduction of Ki67 in LumB tumors was 87% (95% CI, 49%-96%) for ANA+PIC and 56% (16%-77%) for ANA (p=0.03). Additional data on apoptosis and comprehensive pre- and post-treatment biomarkers analyses will be presented. Conclusions: This first report of a preoperative WOO study evaluating a PI3K inhibitor in early breast cancer demonstrated addition of pictilisib to ANA was associated with increased anti-proliferative response over single-agent ANA. Citation Format: Peter Schmid, Sarah E Pinder, Duncan Wheatley, Jane Macaskill, Charles Zammit, Jennifer Hu, Robert Price, Nigel Bundred, Sirwan Hadad, Alice Shia, Louise Lim, Shah-Jalal Sarker, Patrycja Gazinska, Natalie Woodman, Darren Korbie, Matt Trau, Paul Mainwaring, Peter Parker, Arnie Purushotham, Alastair M Thompson. Preoperative window of opportunity study of the PI3K inhibitor pictilisib (GDC-0941) plus anastrozole vs anastrozole alone in patients with ER+, HER2-negative operable breast cancer (OPPORTUNE study) [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 S2-03.

A phase II study of preoperative capecitabine in women with operable hormone receptor positive breast cancer

Conventional preoperative chemotherapy regimens have only limited efficacy in hormone receptor positive (HR+) breast cancer and new approaches are needed. We hypothesized that capecitabine, which is effective in metastatic breast cancer, may be an active preoperative treatment for HR+ breast cancer. Women with HR+, HER2-negative operable breast cancer received capecitabine, 2000 mg/m2 daily in divided doses for 14 days, followed by a 7-day rest period. Treatment was repeated every 21 days for a total of four cycles. The primary endpoint of the study was to determine the rate of pathological complete response (pCR). Because of slow accrual, the study was closed after 24 patients were enrolled. Three patients had a complete clinical response, and eight patients had a partial clinical response, for an overall clinical response rate of 45.8%. There were no cases of pCR. Of the 22 patients who had pathological response assessment by the Miller–Payne grading system, there were six grade 3 responses, and no grade 4 or 5 responses. Toxicity was manageable: the only grade 3 toxicities observed were one case each of diarrhea, palmar plantar erythrodysesthesia, hypokalemia, and mucositis. There was no association between baseline levels, or change in level from baseline to cycle 1, or from baseline to time of surgery, of thymidine phosphorylase (TYMP), thymidylate synthase (TYMS), dihydropyrimidine dehydrogenase (DPYD), or Ki67 and pathological, clinical, or radiographic response. Preoperative capecitabine is a well-tolerated regimen, but appears not lead to pCR when used as monotherapy in HR+ breast cancer.

Preoperative letrozole plus lapatinib/placebo for HR+/HER2 negative operable breast cancer: Biomarker analyses of the randomized phase II LET-LOB study.

530 Background: This is a randomized, double-blind, placebo controlled study aimed to evaluate the clinical and biological effects of letrozole + lapatinib or placebo as neoadjuvant therapy in previously untreated hormone receptor positive/HER2 negative operable breast cancer. Methods: 92 postmenopausal patients with stage II-IIIA breast cancer were randomly assigned to 6 months letrozole-lapatinib (Arm A, n=43) or letrozole-placebo (Arm B, n= 49). Clinical response was evaluated according to RECIST. The following biomarkers were centrally evaluated by IHC on diagnostic core biopsy and on surgical specimens: HER2, Ki-67, EGFR, pAKT, PTEN. PIK3CA mutations were evaluated by pyrosequencing. Results: 81 patients were evaluable by USG, 8 were assessed with mammography and/or palpation. Three patients who discontinued therapy and withdrew consent were counted as non-responders according to the ITT analysis. No differences in terms of objective response rate (partial+complete response) were observed between the two arms (70% vs 63%). The percentage of patients achieving disease progression, disease stabilization, partial response and complete response were 2%, 23%, 58%, 12% respectively in the letrozole-lapatinib arm, and 6%, 29%, 61%, 2% respectively in the letrozole-placebo arm. No patients achieved pCR. All the patients were centrally confirmed as having HER2 negative disease. A significant decrease in Ki67 and pAKT expression from baseline to surgery was observed in both arms. A trend for a greater Ki67 suppression was observed in responding patients (mean Ki67 suppression -8.8 in responders vs -3.6 in non responders, p= 0.06). A mutation in PIK3CA exon 9 or 20 was observed in 37% of the patients. Overall, no differences in response were observed according to PIK3CA mutations, however, in the letrozole-lapatinib arm, the probability of achieving a clinical response was significantly higher in the PIK3CA mutation subgroup (ORR 93% vs 63% in PIK3CA WT, Pearson’s chi2 p=0.040). Conclusions: This is the first trial showing a significant correlation between PIK3CA mutation and response to letrozole-lapatinib in Hormone Receptor +/HER2- disease. Clinical trial information: NCT00422903.

A phase II clinical trial of neoadjuvant therapy with zoledronic acid for operable breast cancer.

e22027 Background: The neoadjuvant use of bisphosphonates has been reported to increase rates of pathological response in patients with operable breast cancer. We conducted a study to determine whether treatment with zoledronic acid (ZOL) would improve outcomes in such patients when it was added to standard neoadjuvant chemotherapy (NAC). Methods: From April 2010 to June 2012, 30 patients with HER2-negative operable breast cancer were eligible for the study. The patients received NAC (4 cycles of CEF: intravenous epirubicin 100mg/m2, cyclophosphamide 500mg/m2, and fluorouracil 500mg/m2 on day 1, then 12 cycles of weekly paclitaxel 80mg/m2) with ZOL. The ZOL was administered after each cycle of NAC in a 4-mg dose by intravenous infusion every 3 to 4 weeks. The primary end point of the study was pathological response (pPR) rate. The secondary end points were pathological complete response (pCR) rate, adverse effects (AEs) and the changes in the numbers of disseminated tumor cells (DTC), circulating tumor cells (CTC), and circulating endothelial cells (CEC). We evaluated the efficacy and safety of ZOL in the NAC in patients by use of Fisher’s exact test. Results: 29 patients completed surgery after NAC, and pathological analyses and the numbers of CTC and CEC were assessed. Two patients had progressive disease during NAC, with brain metastasis and bone metastasis, respectively. The pPR rate, pCR rate, was 31.0%, 10.4%, respectively. CTC were detected in 3 patients at baseline, and CTC had changed to positive in one patient in D15 of the first cycle, then after NAC, all four patients changed to negative. CTC were negative in two patients at baseline, but after NAC, changed to positive. There were no factors associated with the change rates of CTC. CEC after NAC increased from baseline significantly (p&lt;0.001). The increase rates of CEC were not significantly different among premenopausal and postmenopausal, PR and non-PR, and luminal and triple negative patients. There were no severe AEs associated with ZOL to discontinue treatment. Conclusions: These data suggested ZOL in combination with NAC might not have a significant direct anti-tumor effect. Change of CEC would be a biomarker for NAC, but further analyses would be necessary. Clinical trial information: 000003498.

Abstract LB-76: Tissue biomarkers and interstitial fluid pressure in a phase II study of preoperative (preop) bevacizumab (bev) followed by dose-dense doxorubicin (A)/cyclophosphamide (C)/paclitaxel (T) in combination with bev in HER2-negative operable breast cancer (BC)

Abstract Purpose: Recent studies evaluating the efficacy of bev in BC have shown conflicting results, particularly in hormone receptor (HR)+ BC. Identification of predictive biomarkers and their relationship to the pharmacodynamic effects of bev would facilitate the identification of BC patients (pts) most likely to benefit from bev. To examine this, we conducted a unique preop phase II trial with a run-in of single agent bev followed by dose-dense AC-T with bev in two cohorts, one with HR+HER2- BC pts, and a smaller triple negative (TN) BC pts. Methods: Pts with HR+, HER2- or TNBC were eligible. Treatment consisted of a single dose of bev 10 mg/kg, followed two wks later by A 60 mg/m2 and C 600 mg/m2 with bev 10 mg/kg q2 wks x 4, followed by T 175 mg/m2 with bev 10 mg/kg q2 wks x 3, followed by T 175 mg/m2 x1. Core biopsies and interstitial fluid pressure (IFP) were assessed pre- and post- bev alone. Pathologic response was confirmed centrally and Miller-Payne (MP) was assessed. Results: The study enrolled 84 pts with HR+ and 20 pts with TN BC. Amongst HR+ pts, 79 had surgical tissue centrally reviewed, and 6 (8%) had a pCR. Amongst TN BC pts, 19 pts had tissue centrally reviewed and 9 (47%) had a pCR. Grade was found to predict MP response in both HR+ and TN pts (p=0.001). Tissue biomarkers and IFP were evaluated as predictors of response to bev. Single-agent bev reduced the mean IFP in the overall cohort and HR+ patients by 20 (p=0.020) and 24.5% (p=0.001), respectively. The IFP decreased &amp;gt; 50% in 24/65 pts and did not change in others. Bev reduced the mean vascular density (MVD) by 33.0% (p&amp;lt;0.05) in TN BC pts, but did not affect the vessel area fraction covered by perivascular cells (PCs). Bev did not modify the fraction of tumor tissue positive for the hypoxia marker CAIX. In TN BC pts, pre- and post-bev, the MVD was inversely correlated with the CAIX fraction (p&amp;lt;0.01). In addition, a drop in MVD associated with increased CAIX+ fraction post-BEV (p=0.05). MP score was more favorable for TN BC pts with lower CAIX+ fraction at baseline (p=0.058) and post-BEV (p&amp;lt;0.05), and higher MVD at baseline (p&amp;lt;0.05) and post-BEV (p&amp;lt;0.05). In contrast, in HR+ BC, BEV reduced MVD non-significantly by 15% (p=0.25) and increased the vessel area fraction covered by PCs (p&amp;lt;0.05). There was no significant correlation between MVD and CAIX+ fraction in HR+ BCs. In contrast to TN BC, in HR+ BCs the fraction of CAIX+ tumor was directly correlated with MP score (p&amp;lt;0.01). Discussion: Collectively, these results indicate that vascular pruning post-BEV may reduce vascular function and increase hypoxia, which is associated with less favorable pathologic response after BEV with chemotherapy in TN BC. In conclusion, our exploratory study suggests that elevated hypoxia and reduced MVD in TN BC reduces the effectiveness of chemotherapy. Citation Format: Yves Boucher, John D. Martin, Sara M. Tolaney, Giogio Seano, Shom Goel, Marek Ancukiewicz, Steven J. Isakoff, Eric P. Winer, Ian E. Krop, Rakesh K. Jain. Tissue biomarkers and interstitial fluid pressure in a phase II study of preoperative (preop) bevacizumab (bev) followed by dose-dense doxorubicin (A)/cyclophosphamide (C)/paclitaxel (T) in combination with bev in HER2-negative operable breast cancer (BC) [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr LB-76. doi:10.1158/1538-7445.AM2013-LB-76

Bevacizumab plus preoperative chemotherapy in operable HER2 negative breast cancer: biomarkers and pathologic response

PurposeThe primary aim of this trial was to assess the rate of pathologic complete responses (pCR) of doxorubicin/cyclophosphamide (AC) followed by bevacizumab/docetaxel (BT), as neoadjuvant therapy for breast cancer (BC). Furthermore, the association between biomarkers and the pCR was explored.MethodsPatients with HER-negative operable stage II–III BC ≥2 cm were enrolled. Four cycles of AC (A 60 mg/m2 and C 600 mg/m2, every 3 weeks) followed by 4 cycles of BT (B 15 mg/kg and T 75 mg/m2, every 3 weeks), were planned. A core-biopsy was performed for biological markers assessment.ResultsSeventy-two women were included. Forty-three (63 %) patients were hormone receptor-positive. Sixty-four (89 %) completed the planned treatment, and 66 evaluable patients underwent surgery (92 %): a pCR was achieved in 16 of them (24, 95 % CI 15–36 %). pCR was significantly higher in tumors hormone receptor-negative, and in those with Angiotensin II type 1 receptor (AGTR1) protein overexpression. The overall clinical response rate was 86 % (95 % CI 76–93 %), including 42 complete responses. No unexpected toxicities or treatment-related deaths were observed.ConclusionThis regimen showed a remarkable clinical and pathological activity: the suggested relation between pCR and AGTR1 overexpression should be confirmed in larger trials.

A phase II study of preoperative (preop) bevacizumab (bev) followed by dose-dense (dd) doxorubicin (A)/cyclophosphamide (C)/paclitaxel (T) in combination with bev in HER2-negative operable breast cancer (BC).

1026 Background: Two recent preop studies evaluating bev showed conflicting results, particularly in hormone receptor (HR)+ BC. Identification of predictive markers and their relationship to the pharmacodynamic effects of bev would facilitate the identification of BCs most likely to benefit from bev. To accomplish these goals, we conducted a unique preop trial with a run-in of single agent bev followed by ddACT with bev in two cohorts, one with HR+HER2– BC, and a smaller triple negative (TN) cohort. Methods: Pts with HR+, HER2– or TN BC were eligible if their tumor (T) was ≥1.5 cm and high grade, or had axillary LN involvement; or if T≥2.5cm and was low/intermediate grade. Treatment consisted of a single dose of bev 10 mg/kg, followed two wks later by A 60 mg/m2 and C 600 mg/m2 with bev 10 mg/kg q2 wks x 4, followed by T 175 mg/m2 with bev 10 mg/kg q2 wks x 3, followed by T 175 mg/m2 x1. Research core biopsies and interstitial fluid pressure (IFP) were assessed pre- and post- bev alone. Pathologic response was confirmed centrally and Miller-Payne (MP) was assessed. Results: 84 pts with HR+ and 20 pts with TN breast cancer were enrolled. Amongst HR+ pts, 74 had surgical tissue centrally reviewed, and 6 (8%) had a pCR. Amongst TN pts, 18 pts had tissue centrally reviewed and 8 (44%) had a pCR. Grade was found to predict MP response in both HR+ and TN pts (p=0.001). Several biomarkers were evaluated as predictors of response to bev. Baseline sVEGFR1 correlated with MP response to treatment among TN pts (p=0.015). Single-agent bev reduced the mean vascular density by 18.5% (p=0.049) in HR+ patients and the mean IFP in the overall cohort and HR+ patients by 20 (p=0.020) and 24.5% (p=0.001), respectively. The reductions in IFP correlated with higher levels of sVEGFR2 (p=0.003). The IFP decreased &gt; 50% in 24/65 pts and did not change in others. Gene expression profiling by PAM50 is underway. Conclusions: The addition of bev to preop chemotherapy is well tolerated. Tumor grade appears to predict MP response in HR+ and TN tumors, and sVEGFR1 may be a predictor of MP response to bev in TN tumors. Further work for biomarker predictors of response to bev is ongoing.

Predictive significance of the proportion of ER-positive or PgR-positive tumor cells in response to neoadjuvant chemotherapy for operable HER2-negative breast cancer

Estrogen receptor (ER) and progesterone receptor (PgR) status are predictive factors for the clinical and pathological response to neoadjuvant chemotherapy for operable breast cancer. However, it remains unclear as to how the proportion of ER-positive or PgR-positive tumor cells affects the response to neoadjuvant chemotherapy. We examined the correlation of the proportion of ER-positive or PgR-positive tumor cells with the clinical and pathological response to neoadjuvant chemotherapy for operable human epidermal growth factor receptor 2 (HER2)-negative breast cancer. From April 2002 to October 2010, 103 patients received neoadjuvant chemotherapy containing epirubicin and taxane in our clinic. A clinical response was observed in 86 (83%) patients, and a pathological complete response (pCR) was observed in 16 (16%) patients. Fourteen (30%) of 46 patients with ER-negative tumors achieved pCR and 15 (26%) of 57 patients with PgR-negative tumors achieved pCR. Patients with more than 30% ER-positive tumor cells or more than 1% PgR-positive tumor cells did not achieve pCR. No significant correlation was observed between pCR and the menopausal status, tumor size, grade and Ki-67 expression. In univariate analysis, pCR was associated with the ER status (p=0.001), PgR status (p=0.0001) and chemotherapy regimens (p=0.03). Multivariate analysis revealed that ER and PgR status were significant factors for pCR, and patients with ER-negative tumors were 18.6 times more likely to achieve pCR than those with greater than or equal to 30% ER-positive tumor cells (p=0.006; 95% confidence interval 2.3-149.9). We demonstrated a predictive significance of the proportion of ER-positive or PgR-positive tumor cells in the response to neoadjuvant chemotherapy for operable HER2-negative breast cancer. ER-negativity (<1%) was a significant predictive factor for achieving pCR in multivariate analysis. Conversely, patients with more than 30% ER-positive tumor cells or more than 1% PgR-positive tumor cells may not achieve pCR.

5159 POSTER A Randomized Study Comparing Standard to Response-adapted Sequence in HER2 Negative Operable Breast Cancer

5159 POSTER A Randomized Study Comparing Standard to Response-adapted Sequence in HER2 Negative Operable Breast Cancer

Abstract P2-09-22: Predictive Significance of the Proportion of ER-or PgR-Positive Tumor Cells in Neoadjuvant Chemotherapy for Operable HER2-Negative Breast Cancer

Abstract Background Estrogen receptor (ER) and progesterone receptor (PgR) status are predictive for clinical and pathological response in neoadjuvant chemotherapy for operable breast cancer. However, it remains unclear how the proportion of ER-or PgR-positive staining tumor cells affect responses to neoadjuvant chemotherapy. The purpose of this study was to examine the correlation of the proportion of ER-or PgR-positive staining tumor cells with the clinical and pathological responses to neoadjuvant chemotherapy for operable HER2-negative breast cancer. Patients and Methods From April 2002 to May 2010, 101 patients received neoadjuvant chemotherapy containing epirubicin and taxane in our clinic. We assessed menopausal status, tumor size, lymph node status, histological grade, ER, PgR, p53 and Ki-67. In this study, we defined the positivity of ER and PgR as more than or equal to 1% of the positive staining tumor cells according to ASCO/CAP announcement in April 2010. Furthermore, patients with ER-positive tumor were divided into two groups at 30% of ER positive staining tumor cells. Results A clinical response was seen in 82% of all patients and a pathological complete response (pCR) was seen in 17%. Of the 101 patients, 60 (59%) had ER-positive tumors and 38 (63%) of the patients had tumors with more than 90% of ER-positive staining cells. Also, 52 (51%) had PgR-positive tumors. Fourteen (34%) of the 41 patients with ER-negative tumors achieved a pCR and 15 (31%) of the 49 patients with PgR-negative tumors achieved a pCR. Patients with more than 30% of ER-or more than 1% of PgR-positive staining tumor cells did not achieve a pCR. There was no significant correlation of pCR with menopausal status, tumor size, grade and Ki-67. In univariate analysis, a pCR was associated with ER status (p=0.0001), PgR status (p=0.0001), and chemotherapy regimens (p=0.014). Multivariate analysis revealed that ER status was a significant factor for pCR, and patients with ER-negative tumors were 20.1 times more likely to achieve a pCR than those with more than or equal to 30% tumors staining tumor cells (p=0.005; 95% confidential interval, 2.5-16.5). Conclusion We demonstrated a predictive significance of the proportion of ER-or PgR-positive tumor cells in neoadjuvant chemotherapy for operable HER2- negative breast cancer. ER-negativity (&amp;lt;1%) is significantly predictive to achieve a pCR in multivariate analysis. Conversely, it seems very possible that patients with more than 30% ER-or more than 1% PgR-positive staining tumor cells do not achieve a pCR. It is important to take the proportion of ER-and PgR-positive staining tumor cells into consideration in the treatment of breast cancer. Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P2-09-22.