Chemotherapy For HER2-negative Breast Cancer Research Articles

Maintenance Pembrolizumab Therapy in Patients with Metastatic HER2-negative Breast Cancer with Prior Response to Chemotherapy.

Accumulating toxicities hinder indefinite chemotherapy for many patients with metastatic/recurrent HER2-negative breast cancer. We conducted a phase II trial of pembrolizumab monotherapy following induction chemotherapy to determine the efficacy of maintenance immunotherapy in patients with metastatic HER2-negative inflammatory breast cancer (IBC) and non-IBC triple-negative breast cancer (TNBC) and a biomarker study. Patients with a complete response, partial response, or stable disease (SD) after at least three cycles of chemotherapy for HER2-negative breast cancer received pembrolizumab, regardless of programmed death-ligand 1 expression. Pembrolizumab (200 mg) was administered every 3 weeks until disease progression, intolerable toxicity, or 2 years of pembrolizumab exposure. The endpoints included the 4-month disease control rate (DCR), progression-free survival (PFS), overall survival, and response biomarkers in the blood. Of 43 treated patients, 11 had metastatic IBC and 32 non-IBC TNBC. The 4-month DCR was 58.1% [95% confidence interval (CI), 43.4-72.9]. For all patients, the median PFS was 4.8 months (95% CI, 3.0-7.1 months). The toxicity profile was similar to the previous pembrolizumab monotherapy study. Patients with high T-cell clonality at baseline had a longer PFS with pembrolizumab treatment than did those with low T-cell clonality (10.4 vs. 3.6 months, P = 0.04). Patients who achieved SD also demonstrated a significant increase in T-cell clonality during therapy compared with those who did not achieve SD (20% vs. 5.9% mean increase, respectively; P = 0.04). Pembrolizumab monotherapy achieved durable treatment responses. Patients with a high baseline T-cell clonality had prolonged disease control with pembrolizumab.

Comparison of the efficacy and safety of pegylated liposomal doxorubicin and epirubicin in neoadjuvant chemotherapy for HER2-negative breast cancer: a real-world case–control study

Purpose: The purpose of this study was to assess the effectiveness and side effects of pegylated liposomal doxorubicin (PLD) and epirubicin in neoadjuvant treatment for HER2-negative breast cancer. Patients and methods: The authors performed a retrospective analysis of 107 patients diagnosed with HER2-negative breast cancer who underwent TA (PLD 35 mg/m2, docetaxel 75 mg/m2) or TE (epirubicin 100 mg/m2, docetaxel 75 mg/m2) neoadjuvant chemotherapy (NAC) from January 2021 to December 2022. PLD was administered in 57 instances, while epirubicin was used in 50 cases. The clinicopathological features, chemotherapy effects, and adverse responses of these individuals were examined, and logistic regression was applied to determine the parameters defining the effectiveness of NAC. Results: The clinicopathological characteristics of the PLD and epirubicin groups were consistent, and there was no statistical difference. Also, there was no statistical difference in the efficacy of NAC between the two groups. Leukopenia, hair loss, digestive tract responses, and irregular electrocardiograms were dramatically decreased in the PLD group compared to the epirubicin group. However, hand-foot syndrome and hypersensitivity were significantly increased, with statistical relevance. Conclusion: PLD has the same efficacy as traditional epirubicin in NAC for HER2-negative breast cancer.

Efficacy and Safety of Albumin-Bound Paclitaxel Compared to Docetaxel as Neoadjuvant Chemotherapy for HER2-Negative Breast Cancer.

BackgroundNanoparticle albumin-bound paclitaxel (nab-paclitaxel) as neoadjuvant chemotherapy (NAC) for breast cancer remains controversial. We conducted a retrospective study to compare the efficacy and safety of nab-paclitaxel with those of docetaxel as neoadjuvant regimens for HER2-negative breast cancer.MethodsIn this retrospective analysis, a total of 159 HER2-negative breast cancer patients who had undergone operation after NAC were consecutively analyzed from May 2016 to April 2018. Patients were classified into the nab-paclitaxel group (n = 79, nab-paclitaxel 260 mg/m2, epirubicin 75 mg/m2, and cyclophosphamide 500 mg/m2) and the docetaxel group (n = 80, docetaxel 75 mg/m2, epirubicin 75 mg/m2, and cyclophosphamide 500 mg/m2) according to the drug they received for neoadjuvant treatment. The efficacy and adverse events were evaluated in the two groups.ResultsThe pathological complete response (pCR)(ypT0/isN0) rate was significantly higher in the nab-paclitaxel group than in the docetaxel group (36.71% vs 20.00%; P = 0.031). The multivariate analysis revealed that therapeutic drugs, lymph node status, and tumor subtype were the most significant factor influencing treatment outcome. At a median follow-up of 47 months, disease-free survival (DFS) was not significantly different in those assigned to nab-paclitaxel compared with docetaxel (82.28% vs 76.25%; P = 0.331). The incidence of peripheral sensory neuropathy in the nab-paclitaxel group was higher than that in the docetaxel group (60.76% vs 36.25%; P = 0.008), while the incidence of arthralgia was observed more frequently in the docetaxel group (57.50% vs 39.97%; P = 0.047).ConclusionsCompared with docetaxel, nab-paclitaxel achieved a higher pCR rate, especially those patients with triple-negative breast cancer or lymph node negative breast cancer. However, there was no significant difference in DFS between the two groups. This study provides a valuable reference for the management of patients with HER2-negative breast cancer.

Immunohistochemistry study of tumor vascular normalization and anti-angiogenic effects of sunitinib versus bevacizumab prior to dose-dense doxorubicin/cyclophosphamide chemotherapy in HER2-negative breast cancer

PurposeTumor angiogenesis controlled predominantly by vascular endothelial growth factor and its receptor (VEGF-VEGFR) interaction plays a key role in the growth and propagation of cancer cells. However, the newly formed network of blood vessels is disorganized and leaky. Pre-treatment with anti-angiogenic agents can “normalize” the tumor vasculature allowing effective intra-tumoral delivery of standard chemotherapy. Immunohistochemistry (IHC) analysis was applied to investigate and compare the vascular normalization and anti-angiogenic effects of two commonly used anti-angiogenic agents, Sunitinib and Bevacizumab, administered prior to chemotherapy in HER2-negative breast cancer patients.MethodsThis prospective clinical trial enrolled 38 patients into a sunitinib cohort and 24 into a bevacizumab cohort. All received 4 cycles of doxorubicin/cyclophosphamide chemotherapy and pre-treatment with either sunitinib or bevacizumab. Tumor biopsies were obtained at baseline, after cycle 1 (C1) and cycle 4 (C4) of chemotherapy. IHC was performed to assess the tumor vascular normalization index (VNI), lymphatic vessel density (LVD), Ki67 proliferation index and expression of tumor VEGFR2.ResultsIn comparison to Bevacizumab, Sunitinib led to a significant increase in VNI post-C1 and C4 (p < 0.001 and 0.001) along with decrease in LVD post-C1 (p = 0.017). Both drugs when combined with chemotherapy resulted in significant decline in tumor proliferation after C1 and C4 (baseline vs post-C4 Ki67 index p = 0.006 for Sunitinib vs p = 0.021 for Bevacizumab). Bevacizumab resulted in a significant decrease in VEGFR2 expression post-C1 (p = 0.004).ConclusionSunitinib, in comparison to Bevacizumab showed a greater effect on tumor vessel modulation and lymphangiogenesis suggesting that its administration prior to chemotherapy might result in improved drug delivery.Trial registryClinicalTrials.gov: NCT02790580 (first posted June 6, 2016).

Tumour-stroma ratio is associated with Miller-Payne grading system and pathological response to neoadjuvant chemotherapy in HER2-negative breast cancer

Background: In breast cancer, the tumour-stroma ratio (TSR) has shown to be a strong prognosticator, portraying that patients with stroma-low tumours have better survival outcomes than patients with stroma-high tumours. However, the precise role of the TSR as a predictive marker for neoadjuvant chemotherapy outcome is yet unknown. Therefore, we evaluated this association for HER2-negative breast cancer in the prospective, randomized, multicenter DIRECT and NEOZOTAC trials.

The history, present situation, and future directions of neoadjuvant chemotherapy for HER2-negative breast cancer.

Chemotherapy has played a significant role in breast cancer therapy and dramatically improved the outcome of breast cancer patients. Neoadjuvant chemotherapy (NAC) is defined as chemotherapy conducted before surgery. The rationale for NAC in operable breast cancer is that the benefit of systemic chemotherapy on the long-term prognosis does not change, regardless of whether chemotherapy is conducted before or after surgery. NAC is now widely used for early and advanced breast cancer patients since it has two significant advantages over conventional adjuvant chemotherapy after surgery. One is that the rate of the breast-conserving surgery increase resulted from tumor shrinkage during NAC, which can contribute to a minimal invasion from surgical therapy and good quality of life following therapy. Another is that a response to chemotherapy can be observed in in-vivo setting. Patients who achieve the pathological complete response (pCR) show a favorable prognosis. Thus, the response to NAC can be used as an indicator for personalized medicine. To date, novel agents for NAC have been explored in randomized trials, setting the pCR rate as an endpoint. Also, response- and residual disease-guided therapy have been ready for prime time in daily practice. The author describes the history, current situation, and future direction of NAC for HER2-negative breast cancer in the review article.

Abstract P1-10-01: Caveolin gene expression predicts for response and clinical outcomes of patients treated with preoperative paclitaxel-based chemotherapy regimens in early stage breast cancer

Abstract Background: Biomarkers are needed to prognosticate and predict efficacy of therapy for patients undergoing neoadjuvant chemotherapy for HER2-negative breast cancer (BC). Caveolin genes (CAV1, CAV2) are responsible for formation of caveolae, which are 50-100 nM membrane invaginations implicated in endocytosis and transcytosis of nutrients and substances, including albumin. Overexpression of caveolin family genes has been implicated in driving BC progression, but also in predicting response to nab-paclitaxel. We hypothesized that high CAV1/2 expression would correlate with poor clinical outcomes, but that patients with high CAV1/2 expression would have better outcomes with nab-paclitaxel based chemotherapy. Methods: We correlated tumor CAV1/2 RNA expression from available RNA-Seq data with pathologic complete response (pCR) and clinical outcomes (disease-free survival, DFS, and overall survival, OS) in the GeparSepto (G7) clinical trial, which randomized patients with early stage BC to preoperative paclitaxel versus nab-paclitaxel-based chemotherapy regimens. CAV1/2 log-transformed values were analyzed as a continuous variable and dichotomized about the mean for each gene. Multivariable logistic regression models were generated, and included age, T-stage, N-stage, tumor grade (G3 vs G1-2), Ki67 (continuous), and histology (non-ductal versus ductal). Results: There was RNA-Seq expression data available for 279 out of 810 HER2-negative patients, of whom 26.5% were hormone receptor (HR)-negative (triple negative). CAV1 and CAV2 expression values were directly correlated with each other (Pearson coefficient 0.452). There was no difference in CAV1 expression between HR-negative and HR-positive patients, but there was significant up-regulation of CAV2 expression (mean) in HR-negative patients (p=0.003). With regards to pCR, high CAV1/2 expression was associated with a strong benefit from nab-paclitaxel compared to paclitaxel (OR(CAV1)=4.92 (1.70-14.22) and OR(CAV2)=5.39 (1.76-16.47)) in contrast to low CAV1/2 expression (OR(CAV1)=0.94 (0.38-2.34) and OR(CAV2)=0.95 (0.39-2.29)) in multivariate modeling (tests for interaction p=0.023 and p=0.019). For CAV1 this effect continued beyond pCR with regards to survival: high CAV1 expression was associated with superior survival in the nab-paclitaxel arm (HR(DFS)=0.53 (0.27-1.05), HR(OS)=0.29 (0.11-0.77)) but not low CAV1 expression (HR(DFS)=1.37 (0.62-3.04), HR(OS)=2.47 (0.78-7.80)) in multivariate modeling (test for interaction p=0.077 (DFS) and p=0.005 (OS)). No significant interactions in hazard ratios for DFS and OS were detected for CAV2. With regard to prognostic effects, CAV2 expression was significantly associated with worse DFS and OS for all patients. In particular, high CAV2 expression was associated with poor prognosis for HR-negative patients in multivariate modeling (OR(DFS)=4.40 (1.44-13.46), OR(OS)=9.38 (1.13-77.75)), but not for HR-positive patients (OR(DFS)=1.60 (0.84-3.05), OR(OS)=2.05 (0.92-4.58)) (test for interaction p=0.125 and p=0.186). Conclusions: Higher CAV2 expression is associated with worse DFS and OS, in particular for HR-negative patients, confirming potential prognostic roles for CAV1/2. No significant differences in DFS and OS based on CAV1/2 expression were noted for patients who received nab-paclitaxel based treatment, but the odds of obtaining pCR were improved for patients with high CAV1/2 expression. Taken together, these findings suggest that CAV1/2 expression may offset the negative prognostic factor associated with higher CAV1/2 expression in patients treated with nab-paclitaxel regimens by enhancing the efficacy of treatment, perhaps through increased nab-paclitaxel endocytosis/transcytosis. Citation Format: Terence Williams, Andreas Schneeweiss, Christian Jackisch, Changxian Shen, Karsten Weber, Peter Fasching, Carsten Denkert, Jenny Furlanetto, Ernst Heinmoller, Sabine Schmatloch, Thomas Karn, Christopher Szeto, Marion van Mackelenbergh, Valentina Nekljudova, Elmar Stickeler, Patrick Soon-Shiong, Christian Schem, Barbara Fleige, Volkmar Muller, Frederik Marme, Michael Untch, Sibylle Loibl. Caveolin gene expression predicts for response and clinical outcomes of patients treated with preoperative paclitaxel-based chemotherapy regimens in early stage breast cancer [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P1-10-01.

Evaluation of Therapeutic Target Gene Expression Based on Residual Cancer Burden Classification After Neoadjuvant Chemotherapy for HER2-Negative Breast Cancer

IntroductionPatients with residual disease usually have a poor prognosis after neoadjuvant chemotherapy for breast cancer. The aim of this study was to explore therapeutic targets and potential additional adjuvant treatments for patients with residual disease after standard neoadjuvant chemotherapy. Patients and MethodsWe retrieved publicly available complementary DNA microarray data from 399 human epidermal growth factor receptor 2 (HER2)-negative primary breast cancer samples from patients who underwent standard neoadjuvant chemotherapy. We analyzed the messenger RNA (mRNA) expression levels of key breast cancer markers and therapeutic target genes according to residual cancer burden (RCB) classification: RCB-0/I, RCB-II, and RCB-III. ResultsAmong hormone receptor–positive samples, there were more luminal A tumors by PAM50 (Prediction Analysis of Microarray 50 [Prosigna], aka Prosigna Breast Cancer Prognostic Gene Signature Assay) in RCB-III than in RCB-0/I and RCB-II (P < .01). The mRNA expressions of ESR1 and PGR were significantly higher, and that of MKI67 was lower in RCB-II and RCB-III than in RCB-0/I. The mRNA expression of cyclin D1 was up-regulated in RCB-III and that of CDKN2A was down-regulated in RCB-III (P = .027 and < .01). Among triple-negative (TN) samples, RCB-III had higher clinical stage and more lymph node–positive samples than RCB-0/1 and RCB-II (P < .01). In both subtypes, VEGF-C expression was significantly higher in RCB-III than in RCB-0/I and RCB-II. ConclusionIn hormone receptor–positive breast cancer, biological features such as luminal A were associated with RCB; this trend was not observed in TN breast cancer. Further, some targeted therapies should be tested as new strategies after standard neoadjuvant chemotherapy in future clinical trials.

Abstract P1-15-20: DIetary REstriction as an adjunct to neoadjuvant ChemoTherapy for HER2-negative breast cancer: Final results from the DIRECT trial (BOOG 2013-04)

Abstract Background: Short term fasting (STF) protects from toxicity, while enhancing the efficacy of chemotherapy in cancer bearing mice and is a promising strategy to enhance the efficacy and tolerability of chemotherapy in humans. A specifically designed low calorie, low amino acid substitution diet (“Fasting Mimicking Diet”, FMD) has similar effects in vivo during chemotherapy as STF. The DIRECT trial evaluates the impact of FMD on toxicity and efficacy of neoadjuvant chemotherapy in women with HER2-negative early breast cancer. Patients and methods: Eligible patients had histologically confirmed, HER2-negative, stage II/III early breast cancer, adequate bone marrow, liver and renal function, BMI &amp;gt; 19kg/m2 and absence of diabetes mellitus. Women receiving 8 neo-adjuvant AC-T courses (adriamycin/cyclophosphamide - docetaxel) or 6 FEC-T courses (5-fluorouracil, epirubicin and cyclophosphamide - docetaxel); day 1, q 3 weeks, were randomized to receive FMD or regular diet for 3 days prior to and at the day of chemotherapy and 3 days prior to surgery. The FMD group received no dexamethasone during the AC or FEC courses. The primary endpoint of the phase II part was feasibility and grade III/IV toxicity and of the phase III pathological complete response (pCR) rate. Additionally, in a side study increase in DNA damage in lymphocytes before and three hours after chemotherapy was compared between the 2 arms. Results From February 2014 to January 2018 131 patients from 11 participating Dutch centers were randomized, whereof 100 received AC-T and 31 received FEC-T. Sixty-six of the patients received FMD. Compliance to the diet was low as 32% fasted at least half of the cycles and 24% of patients fasted during all of cycles. The main reasons of non-compliance were food aversion induced by chemotherapy and the taste of the diet. Intention to treat grade III/IV toxicity was not significantly different between the standard arm (67,2%) and in the FMD arm (79,4%), although the majority of the toxicities in the FMD arm were assessed in patients that did not complete the FMD diet preceding the measurements. The total overall pCR rate was 12,8%, lower than assumed in the sample size calculation and would therefore need minimally a doubling in patient numbers to be able to reach the expected pCR difference between both arms. Due to the poor compliance, slow accrual rate and low overall pCR rate the DIRECT study terminated after completion of the phase II part. Subgroup analysis will be presented at SABCS. In a side study, DNA damage after chemotherapy was significantly less increased in lymphocytes in the FMD group as compared to the control group (p=0.043). Conclusion The effect of STF on toxicity and efficacy of chemotherapy was not established due to poor compliance, however STF by FMD reduced a transient increase in chemotherapy induced DNA damage. Close monitoring of patients by nutritionists with expertise in low calorie diets as well as diets with a more variable taste are probably needed to successfully examine the impact on adverse effects and tumor biology. Citation Format: de Groot S, Lugtenberg RT, Welters MJ, Ehsan I, Vreeswijk MP, Smit VT, de Graaf H, Heijns JB, Portielje JE, van de Wouw AJ, Imholz AL, Kessels LW, Vrijaldenhoven S, Baars A, Meershoek-Klein Kranenbarg E, Duijm-de Carpentier M, van Leeuwen-Stok E, Putter H, Longo VD, van der Hoeven JJ, Nortier JW, Pijl H, Kroep JR. DIetary REstriction as an adjunct to neoadjuvant ChemoTherapy for HER2-negative breast cancer: Final results from the DIRECT trial (BOOG 2013-04) [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P1-15-20.

RETRACTED ARTICLE: Association of insulin-like growth factor 1 receptor and estrogen receptor with pathological complete response to neoadjuvant chemotherapy in HER2-negative breast cancer

RETRACTED ARTICLE: Association of insulin-like growth factor 1 receptor and estrogen receptor with pathological complete response to neoadjuvant chemotherapy in HER2-negative breast cancer

Efficacy and safety of nanoparticle albumin-bound paclitaxel as neoadjuvant chemotherapy in HER2-negative breast cancer.

Nanoparticle albumin-bound paclitaxel (Nab-PTX) is a form of paclitaxel bound to albumin nanoparticles and is used widely in a neoadjuvant setting for patients with breast cancer. We conducted a retrospective study to compare the efficacy and safety of Nab-PTX to PTX as neoadjuvant chemotherapy for patients with operable HER2-negative breast cancer. In total, 50 patients were enrolled. Nab-PTX was administered in the study group, and PTX was administered in the control group. The clinical response and safety profile were recorded. The expression of secreted protein acidic rich in cysteine (SPARC) in tumor tissue was examined. The efficacy and safety analyses were computed using SPSS statistical software. Multiple logistic regression analysis was performed to evaluate the exploratory variables (age, stage, estrogen receptor, partial response, and SPARC expression) for the pathological complete response (pCR), and Fisher's exact test was performed to evaluate the relationship between SPARC and pCR. Both groups of patients achieved a good clinical response. The pCR rate for the Nab-PTX regimen was significantly higher than that for the PTX regimen. The most common adverse events were neutropenia, peripheral sensory neuropathy, arthralgia, and myalgia. In 68% of cases in the Nab-PTX group, high SPARC expression was observed. As neoadjuvant therapy, the Nab-PTX regimen has advantages over conventional taxane regimen in patients with HER2-negative breast cancer. With this regimen, a high pCR rate was achieved with a good safety profile.

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.

Efficacy of neoadjuvant chemotherapy combined with bevacizumab versus neoadjuvant chemotherapy alone for Her2-negative breast cancer: a meta-analysis of randomized controlled clinical trials

Objective: To evaluate the efficacy and safety of neoadjuvant chemotherapy combined with bevacizumab versus neoadjuvant chemotherapy alone for Her2-negative breast cancer.Methods: We searched PubMed, the Cochrane Library, Web of Science, CNKI, Wanfang Database and the abstracts of major international conferences in recent 5 years to identify prospective randomized controlled clinical trials that met the inclusion and exclusion criteria. Study selection and analyses were undertaken according to the Cochrane Handbook. Meta-analysis was performed using RevMan 5.3 software.Results: Six trials were identified with 4440 eligible patients. The results of this meta-analysis showed that the rate of pathological complete response (pCR) was higher in Her-2 negative breast cancer patients receiving bevacizumab combined with neoadjuvant chemotherapy than that in patients with neoadjuvant chemotherapy alone (24.7% vs 20.1%, RR=1.23, 95%CI:1.10-1.37, P<0.01). In addition, the pCR rate rose up when bevacizumab was added to neoadjuvant chemotherapy both in hormone receptor-positive patients (13.1% vs 10.2%,RR=1.28, 95%CI:1.04-1.58,P<0.05) and in hormone receptor-negative patients (46.3% vs 37.1%, RR=1.25, 95%CI:1.12-1.39, P<0.01). Statistical differences were observed in the rate of relevant adverse events such as hypertention (3.2% vs 0.6%, RR=5.292, 95%CI:2.933-9.549, P<0.01) and mucositis (10.5% vs 2.0%, RR=5.340, 95%CI:3.743-7.617, P<0.01) between the combination group and the chemotherapy alone group. Differences in other toxicities such as febrile neutropenia, infection, surgical complications, neutropenia and hand-foot syndrome were also found to be statistically significant between the combination group and the chemotherapy alone group (all P<0.05), while such difference was not found in the occurrence of peripheral neuropathy (P>0.05). Conclusion: The addition of bevacizumab to neoadjuvant chemotherapy in Her2-negative breast cancer can significantly improve pathological complete response, but may bring more grade 3 and 4 toxicities.More neoadjuvant trials need to be done to define subgroups of Her2-negative breast cancer that would have clinically significant long-term benefit from bevacizumab treatment.

Role of vascular density and normalization in response to neoadjuvant bevacizumab and chemotherapy in breast cancer patients

Preoperative bevacizumab and chemotherapy may benefit a subset of breast cancer (BC) patients. To explore potential mechanisms of this benefit, we conducted a phase II study of neoadjuvant bevacizumab (single dose) followed by combined bevacizumab and adriamycin/cyclophosphamide/paclitaxel chemotherapy in HER2-negative BC. The regimen was well-tolerated and showed a higher rate of pathologic complete response (pCR) in triple-negative (TN)BC (11/21 patients or 52%, [95% confidence interval (CI): 30,74]) than in hormone receptor-positive (HR)BC [5/78 patients or 6% (95%CI: 2,14)]. Within the HRBCs, basal-like subtype was significantly associated with pCR (P = 0.007; Fisher exact test). We assessed interstitial fluid pressure (IFP) and tissue biopsies before and after bevacizumab monotherapy and circulating plasma biomarkers at baseline and before and after combination therapy. Bevacizumab alone lowered IFP, but to a smaller extent than previously observed in other tumor types. Pathologic response to therapy correlated with sVEGFR1 postbevacizumab alone in TNBC (Spearman correlation 0.610, P = 0.0033) and pretreatment microvascular density (MVD) in all patients (Spearman correlation 0.465, P = 0.0005). Moreover, increased pericyte-covered MVD, a marker of extent of vascular normalization, after bevacizumab monotherapy was associated with improved pathologic response to treatment, especially in patients with a high pretreatment MVD. These data suggest that bevacizumab prunes vessels while normalizing those remaining, and thus is beneficial only when sufficient numbers of vessels are initially present. This study implicates pretreatment MVD as a potential predictive biomarker of response to bevacizumab in BC and suggests that new therapies are needed to normalize vessels without pruning.

Randomized study of tailored neoadjuvant chemotherapy according to the expression of tau, topo II α, and ERCC1 versus standard chemotherapy in HER2-negative breast cancer.

1025 Background: We hypothesized that selecting chemotherapy (CT) agents according to the expressions of drug sensitivity predictive biomarkers from tumor sample may improve the treatment efficacy for breast cancer (BC). Methods: Patients (pts) with stage II/III HER2 negative BC were eligible. Tumor biopsy samples were tested with immunohistochemistry study for the expression of tau, topo II α, and ERCC1. Four cycles of neoadjuvant CT were given after randomization, followed by operation. For control arm, Docetaxel (T)/ epirubicin (E) was given. For tailored arm, 1 of the 7 different CT regimens that containing 2 drugs among T, E, cisplatin, vinorelbine, and weekly high dose 5FU/leucovorin were given according to the expression of tumor biomarkers. After operation, 2-4 cycles of adjuvant CT were given and the choice of regimens were at investigators discretion. The primary endpoint was the primary tumor (T) pathological complete response (pCR) rate, and 268 pts were planned to be recruited. In the pre-pla...

Accuracy of MRI for treatment response assessment after taxane- and anthracycline-based neoadjuvant chemotherapy in HER2-negative breast cancer

BackgroundStudies suggest that MRI is an accurate means for assessing tumor size after neoadjuvant chemotherapy (NAC). However, accuracy might be dependent on the receptor status of tumors. MRI accuracy for response assessment after homogenous NAC in a relative large group of patients with stage II/III HER2-negative breast cancer has not been reported before. Methods250 patients from 26 hospitals received NAC (docetaxel, adriamycin and cyclophosphamide) in the context of the NEOZOTAC trial. MRI was done after 3 cycles and post-NAC. Imaging (RECIST 1.1) and pathological (Miller and Payne) responses were recorded. Accuracy measures were calculated and MRI and pathologically assessed tumor sizes were correlated. Tumor size over- and underestimation were quantified. ResultsAccuracy of MRI for determining pathological complete response (pCR) was 76%. The ROC-curve of MRI response and pCR had an area under the curve value of 0.63 (95% C.I. 0.52–0.74). The correlation coefficient of MRI and histopathological tumor measurements was 0.46 (p < 0.001). Correlations were different for ER-positive (r = 0.40, p < 0.001) and ER-negative (r = 0.76, p < 0.001) breast tumors. MRI under- and overestimated the tumor size in 47% and 40% of all patients. In cases of substantial tumor size underestimation (>2 cm), surgical margins were more often tumor positive compared to the rest of the patients (33% vs.12%, p = 0.005). ConclusionMRI measurements correlated moderately with tumor size on the surgical specimen. Only in ER-negative breast tumors, MRI tumor sizes correlated sufficiently with residual tumor size on the pathological specimen. Therefore, post-NAC MRI should be interpreted with caution.

Abstract OT3-1-03: DIRECT: A phase II/III randomized trial with dietary restriction as an adjunct to neoadjuvant chemotherapy for HER2-negative breast cancer

Abstract Background: Preclinical evidence shows that short-term fasting protects normal cells, while cancer cells are sensitized to chemotherapy. Furthermore, a specifically designed very low calorie, low amino acid substitution diet (“Fasting Mimicking Diet”, FMD) has similar effects on chemotherapy as short-term fasting. This trial evaluates the impact of FMD on tolerance to and efficacy of neoadjuvant chemotherapy in women with HER2-negative early breast cancer. Trial design: DIRECT is a Dutch, randomized, open-label multicenter phase II/III trial. Women receiving neoadjuvant TAC courses (docetaxel/adriamycin/cyclophosphamide; day 1, q 3 weeks with G-CSF support at day 2) will be randomized with or without FMD for 3 days prior to and the day of chemotherapy and 3 days prior to surgery. Eligibility criteria: Eligible women are WHO 0-2, age ≥18 years, HER2-negative, stage II or III breast cancer and adequate bone marrow, liver and renal function, BMI &amp;gt; 19kg/m2 and absence of diabetes mellitus. Study endpoints: The primary endpoints are grade III/IV toxicity (phase II) and the pathologic complete response rate (pCR) (phase III). Secondary endpoints are grade I/II toxicity, metabolic and inflammatory response to chemotherapy, DNA damage, apoptosis, immunology and nutrient sensing pathways in the tumor, biomarkers as single nucleotide polymorphisms, Ki67 and tumor stroma/ratio, patient's quality of life and (disease free) survival. Optional side studies include chemotherapy-induced DNA damage and nutrient sensing pathways in leukocytes and proteomics. Statistical Methods: Using a 5% significance level based on the two-sided Fisher's exact test with a power of 80%, 128 patients (64/arm) will be enrolled to show a 50% decrease of grade III/IV adverse events in the experimental arm (phase II) and 250 patients (125/arm) are needed to show an improvement of the pCR rate from 18% to 36% (phase III). Target accrual: Recruitment will start in September 2013. The expected end of accrual of 250 patients from multiple centers in the Netherlands will be the last quarter of 2015. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr OT3-1-03.

Prospective Validation of Immunological Infiltrate for Prediction of Response to Neoadjuvant Chemotherapy in HER2-Negative Breast Cancer – A Substudy of the Neoadjuvant GeparQuinto Trial

IntroductionWe have recently described an increased lymphocytic infiltration rate in breast carcinoma tissue is a significant response predictor for anthracycline/taxane-based neoadjuvant chemotherapy (NACT). The aim of this study was to prospectively validate the tumor-associated lymphocyte infiltrate as predictive marker for response to anthracycline/taxane-based NACT.Patients and MethodsThe immunological infiltrate was prospectively evaluated in a total of 313 core biopsies from HER2 negative patients of the multicenter PREDICT study, a substudy of the neoadjuvant GeparQuinto study. Intratumoral lymphocytes (iTuLy), stromal lymphocytes (strLy) as well as lymphocyte-predominant breast cancer (LPBC) were evaluated by histopathological assessment. Pathological complete response (pCR) rates were analyzed and compared between the defined subgroups using the exact test of Fisher.ResultsPatients with lymphocyte-predominant breast cancer (LPBC) had a significantly increased pCR rate of 36.6%, compared to non-LPBC patients (14.3%, p<0.001). LPBC and stromal lymphocytes were significantly independent predictors for pCR in multivariate analysis (LPBC: OR 2.7, p = 0.003, strLy: OR 1.2, p = 0.01). The amount of intratumoral lymphocytes was significantly predictive for pCR in univariate (OR 1.2, p = 0.01) but not in multivariate logistic regression analysis (OR 1.2, p = 0.11).ConclusionConfirming previous investigations of our group, we have prospectively validated in an independent cohort that an increased immunological infiltrate in breast tumor tissue is predictive for response to anthracycline/taxane-based NACT. Patients with LPBC and increased stromal lymphocyte infiltration have significantly increased pCR rates. The lymphocytic infiltrate is a promising additional parameter for histopathological evaluation of breast cancer core biopsies.

Proteomics of Genetically Engineered Mouse Mammary Tumors Identifies Fatty Acid Metabolism Members as Potential Predictive Markers for Cisplatin Resistance

In contrast to various signatures that predict the prognosis of breast cancer patients, markers that predict chemotherapy response are still elusive. To detect such predictive biomarkers, we investigated early changes in protein expression using two mouse models for distinct breast cancer subtypes who have a differential knock-out status for the breast cancer 1, early onset (Brca1) gene. The proteome of cisplatin-sensitive BRCA1-deficient mammary tumors was compared with that of cisplatin-resistant mammary tumors resembling pleomorphic invasive lobular carcinoma. The analyses were performed 24 h after administration of the maximum tolerable dose of cisplatin. At this time point, drug-sensitive BRCA1-deficient tumors showed DNA damage, but cells were largely viable. By applying paired statistics and quantitative filtering, we identified highly discriminatory markers for the sensitive and resistant model. Proteins up-regulated in the sensitive model are involved in centrosome organization, chromosome condensation, homology-directed DNA repair, and nucleotide metabolism. Major discriminatory markers that were up-regulated in the resistant model were predominantly involved in fatty acid metabolism, such as fatty-acid synthase. Specific inhibition of fatty-acid synthase sensitized resistant cells to cisplatin. Our data suggest that exploring the functional link between the DNA damage response and cancer metabolism shortly after the initial treatment may be a useful strategy to predict the efficacy of cisplatin.

SERPINA6, BEX1, AGTR1, SLC26A3, and LAPTM4B are markers of resistance to neoadjuvant chemotherapy in HER2-negative breast cancer

Response rates to chemotherapy remain highly variable in breast cancer patients. We set out to identify genes associated with chemotherapy resistance. We analyzed what is currently the largest single-institute set of gene expression profiles derived from breast cancers prior to a single neoadjuvant chemotherapy regimen (dose-dense doxorubicin and cyclophosphamide). We collected, gene expression-profiled, and analyzed 178 HER2-negative breast tumor biopsies ("NKI dataset"). We employed a recently developed approach for detecting imbalanced differential signal (DIDS) to identify markers of resistance to treatment. In contrast to traditional methods, DIDS is able to identify markers that show aberrant expression in only a small subgroup of the non-responder samples. We found a number of markers of resistance to anthracycline-based chemotherapy. We validated our findings in three external datasets, totaling 456 HER2-negative samples. Since these external sets included patients who received differing treatment regimens, the validated markers represent markers of general chemotherapy resistance. There was a highly significant overlap in the markers identified in the NKI dataset and the other three datasets. Five resistance markers, SERPINA6, BEX1, AGTR1, SLC26A3, and LAPTM4B, were identified in three of the four datasets (p value overlap < 1 × 10(-6)). These five genes identified resistant tumors that could not have been identified by merely taking ER status or proliferation into account. The identification of these genes might lead to a better understanding of the mechanisms involved in (clinically) observed chemotherapy resistance and could possibly assist in the recognition of breast cancers in which chemotherapy does not contribute to response or survival.