Anthracycline And Cyclophosphamide Research Articles

Abstract LBO1-02: Pathologic complete response (pCR) of neoadjuvant therapy with or without atezolizumab in HER2-positive, early high-risk and locally advanced breast cancer: APTneo Michelangelo randomized trial

Abstract Background: Neoadjuvant dual targeting of HER2 with trastuzumab (H) and pertuzumab (P) plus chemotherapy is the standard of care for high-risk HER2-positive (HER2+) breast cancer (BC). Compelling data show the contribution of the immune system in prognosis and response/resistance to HER2 directed therapies, supporting combination of immune checkpoint inhibitors with anti HER2 antibodies. We designed APTneo to test the role of adding atezolizumab to neoadjuvant dual targeting of HER2 with chemotherapy, and the value of also using anthracyclines in this setting. Methods: In this multicenter open label phase III trial (NCT03595592), 661 patients (pts) with high-risk early and locally advanced (LA) centrally confirmed HER2+ BC were randomized to neoadjuvant HPCT (H and P d1, carboplatin and paclitaxel iv d1 and 8) given q3 wks for 6 cycles w/o (n=223, ARM A) or with atezolizumab 1200 mg iv d1 (n=438, ARM B). In Arm B pts were randomized to Arm B1 (n=218) to receive anthracycline and cyclophosphamide (AC) + atezolizumab iv d1 q3 wks for 3 cycles followed by HPCT + atezolizumab for 3 cycles, or to arm B2 (n=220) to receive HPCT + atezolizumab for 6 cycles. After surgery pts continued adjuvant HER2 directed therapies w/wo atezolizumab until completion of 1 year. Among intent-to-treat (ITT) pts, 44.8% were LABC, 35% hormonal receptor (HR) negative and 30.4% PD-L1 positive. Primary endpoint is event-free survival (EFS) of Arm B vs A. A key secondary endpoint is the rate of pCR (ypT0/Tis, ypN0) w/wo atezolizumab. Primary population for all efficacy endpoints is ITT. We also assessed baseline PD-L1 status (Ventana SP142) and stromal Tumor Infiltrating Lymphocytes (sTILs). Results: pCR rate in Arm B (57.8%) vs Arm A (52.0%) was not significantly increased (adjHR 1.33, 95% CI 0.95-1.86; p=0.091). Also, the difference in pCR rate in Arm B1 (61.9%) vs Arm B2 (53.6%) was not significant (adjHR 1.402, 95% CI 0.95-2.07; p=0.089). Compared to Arm A, Arm B1 had a 9.9% significantly higher pCR rate (multivariate analysis in Table). The different pCR rate in arms B1 and A was similar regardless of HR and PD-L1 status. High sTILs (≥30%) and PD-L1positive tumors had a higher likelihood of pCR in all arms. Serious adverse events (SAE) after start of therapy occurred in 6.8% pts in Arm A and 14.1% in Arm B (p=0.0064). SAE were numerically more frequent in Arm B1 than Arm B2 (16.7% and 11.6%, respectively), due to hematological toxicity with AC. Immune-related SAE were quite infrequent and similar in B1 (4.7%) and B2 (7.8%), respectively. No grade 5 AE did occur. Conclusions: Addition of atezolizumab to chemotherapy and HP did not significantly increase the rate of pCR in women with HER2+ BC. An exploratory analysis showed that adding atezolizumab to neoadjuvant AC followed by HPCT led to higher pCR rate compared to HPCT and atezolizumab. This could be because of anthracyclines themselves or to drug-drug enhancement of anthracyclines and immune modulation. Atezolizumab did not cause major tolerability issues. Molecular studies of collected biospecimens are ongoing. Patients will continue to be followed up for EFS and overall survival analyses. Table. Supported in part by unrestricted grant from Hoffman-La Roche, Ltd, Switzerland Citation Format: Luca Gianni, Elisabetta Munzone, Mauro Mansutti, Giampaolo Bianchini, Yann Izarzuzaga, Elena Rota Caremoli, Luc Dirix, Lucia Del Mastro, Santiago González-Santiago, Andreas Schneeweiss, Jose Ponce, Chiun-Shen Huang, Pauline Wimberger, Sevilay Altintas, Miguel Martín, Nicoleta Antone, Christian F. Singer, Ugo De Giorgi, Ana Godoy Ortiz, Hans-Joachim Lueck, Riccardo Spezia, Angelica Fasolo, Giuseppe Viale, Pinuccia Valagussa. Pathologic complete response (pCR) of neoadjuvant therapy with or without atezolizumab in HER2-positive, early high-risk and locally advanced breast cancer: APTneo Michelangelo randomized trial [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr LBO1-02.

Work loss and activity impairment due to extended nausea and vomiting in patients with breast cancer receiving CINV prophylaxis

PurposeChemotherapy-induced nausea and vomiting (CINV)’s impact on work loss remains poorly described. We evaluated associations between the duration of CINV episodes, CINV-related work loss (CINV-WL), and CINV-related activity impairment (CINV-AI) in patients with breast cancer receiving highly emetogenic chemotherapy.MethodsWe analyzed data from a prospective CINV prophylaxis trial of netupitant/palonestron and dexamethasone for patients receiving an anthracycline and cyclophosphamide (AC) for breast cancer (NCT0340371). Over the observed CINV duration (0–5 days), we analyzed patient-reported CINV-WL and CINV-AI for the first two chemotherapy cycles. We categorized patients as having either extended (≥ 3 days) or short (1–2 days) CINV duration and quantified its impact on work using the Work Productivity and Activity Impairment Questionnaire (WPAI).ResultsOverall, we captured data for 792 cycles in 402 women, including 136 (33.8%) employed patients with 35.3% reporting CINV. Of those with CINV, patients reported CINV-WL in 26 cycles and CINV-AI in 142 cycles. Of those with CINV, 55.3% of extended CINV cycles experienced CINV-WL compared to 16.7% of short CINV cycles (p < 0.001). The relative risk of CINV-WL between extended and short CINV was 3.32 (p < 0.01) for employed patients. The mean difference in CINV-AI scores (higher = worse) between extended and short duration CINV was 5.0 vs. 3.0 (p < 0.001).ConclusionExtended (≥ 3 days) CINV was associated with more than triple the risk of CINV-WL and higher CINV-AI compared with short CINV.

Abstract P4-07-40: Magnetic resonance imaging (MRI) and clinicopathological analysis of triple-negative breast cancer (TNBC) patients (pts) treated with primary anthracyclines(A)/taxanes(TX)-based chemotherapy

Abstract Background Radiological complete response (CR-MRI) to neoadjuvant chemotherapy (NAC) by MRI predicts pathologic complete response (pCR) rates in pts with TNBC treated preoperatively with A/TX-based regimens and in some studies, it correlates with disease-free survival (DFS). The main aim of this study was to assess the relevance of the MRI response to primary chemotherapy associated with clinical stage and HER2 expression (Zero vs Low), in a cohort of 143 TNBC pts treated with A and TX +/- carboplatin (CP) in the NAC setting. Methods Retrospective study of pts treated with NAC for TNBC between January 2002 and June 2021, who underwent MRI to assess tumour response before NAC, after 4 cycles of anthracycline and cyclophosphamide (AC) and after TX. Survival analysis was based on the Kaplan-Meier and survival curves were compared using the log-rank test. A p value of less than 0.05 was considered as statistically significant. Results A total of 143 TNBC pts with a median age of 52 years; 7, 63 and 73 pts had stage I, II and III disease, respectively. The NAC regimen consisted in 117 pts 4 cycles of AC followed by TX and in 24 pts the same adding CP (in 21 pts with non-CR-MRI, 2 with CR-MRI and 1 without MRI after AC). PCR was observed in 41%. Of 30 pts with CR-MRI after AC, 83% obtain a pCR (p&amp;lt; 0.001), and of 52 pts with CR-MRI at the end of NAC, 70.7% obtain a pCR (p&amp;lt; 0,001) of which 90% had a CR-MRI after AC. Adding CP increased pCR by 6% (p=0.564). According HER2-zero vs low expression, the pCR was 38% and 47% respectively, with no significant differences. With a median follow-up of 60 months, 34% recurred and 16% died of TNBC. In pts with pCR, the DFS at 5 years (y) was 96% and 47% for pts without pCR (p&amp;lt; 0.001), with a DFS of 91% if CR-MRI at the end of NAC and 48% if non-CR-MRI (p&amp;lt; 0.001). In HER2-Zero tumours the DFS at 5 y was 64% vs 66% in HER-2 low. Interestingly, overall survival (OS) at 5 y was 72% in HER2-Zero and 84% in HER2-low (p=0.080). Conclusions Performing serial MRI in the course of NAC in TNBC may be a reliable indicator of pCR, adding platinum to TX in pts with CR-MRI may increase pCR rate. HER2-Zero expression in TNBC, seems to confer worse OS rates. Citation Format: Marina Sierra Boada, Luis Antonio Fernandez, Elsa Dalmau, Gemma Llort, Maria Marin, Pablo Andreu, Natalia Lopez, Carla Climent, Marta Rodriguez, Sandra Soriano, Miquel Angel Segui. Magnetic resonance imaging (MRI) and clinicopathological analysis of triple-negative breast cancer (TNBC) patients (pts) treated with primary anthracyclines(A)/taxanes(TX)-based chemotherapy. [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P4-07-40.

Abstract 1684: Multi-omics profiling of breast cancers during neoadjuvant chemotherapy identified distinct molecular changes and biomarkers associated with clinical response

Abstract The molecular bases underlying neoadjuvant chemotherapy (NAC) response are poorly understood. To elucidate the effects of NAC on breast tumor biology and its association with clinical outcome, we have conducted WES and RNA-Seq profiling of a longitudinal breast cancer (BC) cohort consisting of 146 cases (281 tumors, 109 pairs), including 55 (38%) that achieved pathologic complete responses (pCR) and 91 (62%) that harbored residual diseases at time of surgery. Tumor biopsies were collected for each patient at three time points - pre-treatment, three weeks after the first cycle of anthracycline and cyclophosphamide (AC) and at the time of surgery, after 3 more cycles of AC followed by 4 cycles of taxane. In addition to somatic mutations and copy number alterations, we also derived a comprehensive set of genomic and molecular features for each tumor including chromosomal instability, loss-of-heterozygosity, mutation burden, mutation signatures and expression signatures for oncogenic signaling pathways and immune cell subsets. Virtual microdissection analysis inferred 14 factors that represent distinct tissue compartment including a tumor infiltrating lymphocyte (TIL) factor and revealed that initial NAC treatment increased stromal and adjacent normal tissue fractions while reducing tumor cellularity. NAC also induced dynamic changes in immune gene expressions over time, a pattern that was validated through detecting and quantifying the density of TILs from H&amp;E images. To investigate NAC induced changes in tumor intrinsic biology we classified tumors into five oncogenic cellular states on a reference Onco-GPS map defined by transcriptional signatures from breast cancer cell lines. We observed that, as a result of NAC treatment, tumors often change from one oncogenic state to another, transiently upregulating an EMT program that appears to mediate drug resistance and increase the likelihood of residual disease. Multiple regression and multivariate analyses were performed to identify predictive biomarkers of pCR status while adjusting for BC subtypes and tumor purity. We found that ER+ subtype and estrogen response signature but not Ki-67 were independently associated with NAC response. Within TNBC, the immunomodulatory subtype was enriched in responders while the basal-like subtype had the poorest response. Pretreatment TIL and changes in TIL level over time were independently associated with NAC response, implicating anti-tumor immunity in mediating the efficacy of chemotherapies. Through multi-omics characterization of longitudinally paired tumor biopsies, we have revealed dynamic changes in the tumor molecular states in BC patients undergoing NAC treatment, identified molecular markers of treatment outcome and derived insights into the mechanism of action as well as resistance to an important class of therapy. Citation Format: Samir Lal, Ying Ding, Jeong Eon Lee, Soo-Hyeon Lee, Se Kyung Lee, Jae-Yong Nam, Jong Han Yu, Yoon-la Choi, Seok Won Kim, Seok Jin Nam, Ji-Yeon Kim, Sripad Ram, Eric Powell, Keith A. Ching, Pablo Tamayo, William Kim, Huwate Yeerna, Soo Youn Cho, Vinicius Bonato, Shibing Deng, Jinho Kim, Hyuntae Shin, Woong-Yang Park, Paul A. Rejto, Jadwiga Bienkowska, Yeon-Hee Park, Zhengyan Kan. Multi-omics profiling of breast cancers during neoadjuvant chemotherapy identified distinct molecular changes and biomarkers associated with clinical response [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1684.

Abstract PD5-08: Neoadjuvant chemotherapy alters the genomic landscape and immune microenvironment of breast cancers

Abstract Understanding how standard-of-care drug treatments affect tumor intrinsic biology and microenvironment is critical for elucidating drug resistance mechanisms and developing better combination therapies as well as new therapies. To characterize the effects of neoadjuvant chemotherapy (NAC) on the genome, transcriptome and tumor infiltrating leukocytes (TILs), we have conducted whole exome and whole transcriptome sequencing of a large longitudinal breast cancer cohort consisting of 146 cases and 281 paired tumor samples. In total, 52 (38%) patients achieved pathologic complete response (pCR) while 85 patients (62%) had residual disease with standard chemotherapy regimen. Tumor biopsies were collected for each patient at three time points – pre-treatment, three weeks after the first cycle of anthracycline and cyclophosphamide (AC) and at the time of surgery after 3 more cycles of AC followed by 4 cycles of taxane or taxane plus Herceptin in case of HER2+ subtype. We detected 5,955 protein-altering somatic mutations affecting 4,414 genes in pretreatment samples and 502 acquired mutations in surgery samples affecting 477 genes including 19recurrently mutated genes such as TP53 and NOTCH1. Across all subtypes, 4,346 genes were differentially expressed (DE) following NAC treatment and significantly enriched in pathways such as cell cycle, ER signaling, PI3K/mTOR, immune and metabolism. Expression-based virtual microdissection analysis indicated that NAC treatment induced an increase in the fractions of stromal and adjacent normal tissue compartment, consistent with observed reduction in tumor cellularity. To assess the NAC induced changes in the molecular landscape of these tumors, we compared molecular features including gene expression signatures, mutation prevalence and copy number alteration between three time points while adjusting for confounding effects of molecular subtype and tumor cellularity. We found that NAC induced dynamic changes in gene expression signatures associated with proliferation and immunomodulatory treatment response. We further validated the observed pattern of change in TILs through histopathology and digital imaging analyses. In pretreatment tumors, 116 genes were DE between patients with pCR vs. those with residual disease with significant enrichment in immune/inflammatory pathways. Further, pre-treatment TIL levels were found to be significantly associated with pCR, echoing previous reports in breast cancers that implicated anti-tumor immunity in mediating the efficacy of chemotherapies. Our analyses also revealed associations between NAC response and baseline genomic attributes such as genomic alterations that affect DNA damage repair pathways. Taken together, these results suggest that NAC induced a multitude of changes on the genomic landscape and immune microenvironment of breast cancers, some of which point to combination strategies with immunomodulatory therapies and therapies that target DNA damage repair. Citation Format: Kan Z, Lal S, Ding Y, Lee JE, Lee S-H, Lee SK, Yu JH, Choi Y-l, Kim SW, Nam SJ, Kim J-Y, Ram S, Powell E, Ching K, Cho SY, Bonato V, Deng S, Park W-Y, Rejto P, Bienkowska J, Park Y-H. Neoadjuvant chemotherapy alters the genomic landscape and immune microenvironment of breast cancers [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 PD5-08.

Effects of anthracycline, cyclophosphamide and taxane chemotherapy on QTc measurements in patients with breast cancer.

AimAcute and subacute cardiotoxicity are characterized by prolongation of the corrected QT interval (QTc) and other measures derived from the QTc interval, such as QTc dispersion (QTdc) and transmural dispersion of repolarization (DTpTe). Although anthracyclines prolong the QTc interval, it is unclear whether breast cancer patients who undergo the ACT chemotherapy regimen of anthracycline (doxorubicin: A), cyclophosphamide (C) and taxane (T) may present with QTc, QTdc and DTpTe prolongation.MethodsTwenty-three consecutive patients with breast cancer were followed prospectively during ACT chemotherapy and were analyzed according to their QT measurements. QTc, QTdc and DTpTe measurements were determined by a 12-lead electrocardiogram (EKG) prior to chemotherapy (baseline), immediately after the first phase of anthracycline and cyclophosphamide (AC) treatment, and immediately after T treatment. Serum troponin and B-type natriuretic peptide (BNP) levels were also measured.ResultsCompared to baseline values, the QTc interval was significantly prolonged after the AC phase (439.7 ± 33.2 ms vs. 472.5 ± 36.3 ms, p = 0.001) and after T treatment (439.7 ± 33.2 ms vs. 467.9 ± 42.6 ms, p < 0.001). Troponin levels were elevated after the AC phase (23.0 pg/mL [min-max: 6.0–85.0] vs. 6.0 pg/mL [min-max: 6.0–22.0], p < 0.001) and after T treatment (25.0 pg/mL [min-max: 6.0–80.0] vs. 6.0 pg/mL [min-max: 6.0–22.0], p < 0.001) compared to baseline values.ConclusionIn this prospective study of patients with non-metastatic breast cancer who underwent ACT chemotherapy, significant QTc prolongation and an elevation in serum troponin levels were observed.

Abstract P6-11-11: Single-dose fosaprepitant for the prevention of chemotherapy-induced nausea and vomiting in patients with breast cancer receiving moderately emetogenic chemotherapy regimens

Abstract Background: Aprepitant has demonstrated efficacy in patients with breast cancer receiving anthracycline and cyclophosphamide (AC)-based chemotherapy, but the efficacy of single-day fosaprepitant in patients receiving moderately emetogenic chemotherapy (MEC) regimens not including AC has not been widely reported. In a post hoc analysis, we explored prevention of chemotherapy-induced nausea and vomiting (CINV) in a subgroup of patients with breast cancer using a single-day triple-antiemetic fosaprepitant (FA) regimen compared to a standard 3-day control regimen. Methods: This was a global, randomized, double-blind, parallel-group, phase 3 study in adult subjects who were scheduled to receive an intravenous (IV) dose of ≥1 MEC on the first day of treatment (NCT01594749). AC regimens were excluded as they are no longer considered MEC. Subjects were randomly assigned to a control or FA regimen (1:1). The control regimen consisted of oral ondansetron 8 mg, dexamethasone 20 mg, and IV saline as placebo before the first dose of MEC on day 1, and oral ondansetron 8 mg 8 hours after the first dose and every 12 hours on days 2 and 3. The FA regimen consisted of the same dose of oral ondansetron on day 1, along with dexamethasone 12 mg and a single dose of IV FA 150 mg before the first dose of MEC on day 1, with no additional prophylactic antiemetic beyond day 1. The primary end point was complete response (CR; no vomiting or rescue medication) in the delayed phase (25-120 hours after chemotherapy initiation). Results: Overall, 1000 subjects were included in the intention-to-treat population (FA: N = 502; control: N = 498), and the primary end point was met (P &amp;lt; 0.001; FA vs control). In a subset of 231 subjects with breast cancer, 110 received the FA regimen and 121 the control regimen. Subjects were female, with the exception of 1 male in the FA group, most were aged 50 years or older (67%), and 210 subjects (91%) received single-day MEC regimens on day 1. Among them, 17 subjects in the FA group (8.1%) and 27 in the control group (12.9%) received carboplatin-based chemotherapy, and the remaining 166 subjects received other MEC regimens. CR in the delayed phase was achieved by 76.4% of subjects in the FA group and 68.6% in the control group (difference, 7.8%). Approximately 79% in each group had no vomiting episodes in the overall phase (hours 0-120). Completion on study medication was high, at approximately 98% in each group. Adverse events (AEs) were similar between groups: overall AEs occurred in 79.1% and 73.6% of subjects in the FA and control groups, respectively. AEs considered treatment related by the investigator were also balanced by treatment arm, occurring in 14 (12.7%) and 13 (10.7%) subjects in the FA and control groups, respectively; there was 1 treatment-related serious AE (hypersensitivity) that occurred in the FA group. Conclusions: A single-day IV FA regimen is effective for preventing CINV in breast cancer patients receiving MEC. Citation Format: Weinstein C, Jordan K, Green S, Khanani S, Beckford-Brathwaite E, Vallejos W, Pong A, Noga SJ, Rapoport BL. Single-dose fosaprepitant for the prevention of chemotherapy-induced nausea and vomiting in patients with breast cancer receiving moderately emetogenic chemotherapy regimens [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P6-11-11.

Control of Nausea and Vomiting in Patients Receiving Anthracycline/Cyclophosphamide Chemotherapy for Breast Cancer.

Chemotherapy-induced nausea and vomiting (CINV) is one of most distressing adverse events during cancer chemotherapy. In breast cancer patients receiving anthracycline and cyclophosphamide (AC) chemotherapy, CINV is poorly controlled. The prevalence of guideline-consistent antiemetic medication and control of CINV were investigated retrospectively in breast cancer patients receiving the first cycle of AC chemotherapy. Risks for CINV were analyzed by the multivariate logistic regression analysis. The effect of olanzapine added to the standard antiemetic medication on the incidence of CINV was subsequently evaluated in separate patients who received the first cycle of AC chemotherapy. Although the guideline-consistent antiemetic medication was performed in all subjects, the control rate of nausea (32%), but not vomiting (78%) was low. Risk analysis indicated that age younger than 55-year-old was a significant factor that reduces the control of both nausea and vomiting. Olanzapine (5 mg/day for 5 days), when added to the standard three-drug antiemetic medication, significantly improved the control of nausea and complete response. CINV was poorly controlled in breast cancer patients receiving AC chemotherapy, in which age younger than 55-year-old was a significant risk for both nausea and vomiting. Olanzapine was effective for improvement of the control of CINV associated with AC chemotherapy. Therefore, care should be taken to prevent CINV in young patients receiving AC chemotherapy by adding olanzapine to the standard three-drug antiemetic medication.

2016 Updated MASCC/ESMO consensus recommendations: Emetic risk classification and evaluation of the emetogenicity of antineoplastic agents.

Employing the same framework as in previous guideline updates, antineoplastic agents were classified into four emetic risk categories. The classification of the emetogenic level of new antineoplastic agents, especially for the oral drugs, represents an increasing challenge. Accurate reporting of emetogenicity of new antineoplastic agents in the absence of preventive antiemetic treatment is rarely available. A systematic search was conducted for drugs approved after 2009 until June 2015 using EMBASE and PubMed. The search term was "drug name." The restrictions were language (English records only), date (2009 to 2015), and level of evidence ("clinical trial"). From January 2009 to June 2015, 42 new antineoplastic agents were identified and a systematic search was conducted to identify relevant studies to help define emetic risk levels. The reported incidence of vomiting varied across studies for many agents, but there was adequate evidence to allow 41 of the 42 new antineoplastic agents to be classified according to emetogenic risk. No highly emetogenic agents were identified. Seven moderately emetogenic agents, 26 low emetogenic, agents and eight minimal emetogenic agents were identified and classified accordingly. The MASCC/ESMO update committee also recommended reclassification of the combination of an anthracycline and cyclophosphamide (AC) as highly emetogenic. Despite several limitations, we have attempted to provide a reasonable approximation of the emetic risk associated with new antineoplastic agents through a comprehensive search of the available literature. Hopefully by the next update, more precise information on emetic risk will have been collected during new agent development process.

2016 Updated MASCC/ESMO Consensus Recommendations: Prevention of Nausea and Vomiting Following High Emetic Risk Chemotherapy.

This review summarizes the recommendations for the prophylaxis of nausea and vomiting in adults receiving highly emetogenic chemotherapy (HEC) which includes cisplatin, mechlorethamine, streptozocin, cyclophosphamide >1500mg/m2, carmustine, dacarbazine, and the combination of an anthracycline and cyclophosphamide (AC) administered to women with breast cancer, as agreed at the MASCC/ESMO Antiemetic Guidelines Update meeting in Copenhagen in June 2015. A systematic review of the literature using PubMed and the Cochrane Database from 2009 to June 2015 was performed. The NK1-receptor antagonists netupitant (300mg given in combination with palonosetron 0.5mg as NEPA) and rolapitant have both completed phase II and III programs and were approved by FDA (both) and EMA (NEPA) in 2014-2015. Addition of one of these agents (or of (fos)aprepitant) to a combination of a serotonin (5-HT)3-receptor antagonist and dexamethasone improved the number of patients with a complete response (no emesis and no rescue medication) days 1-5 after AC HEC with 8-9% and after non-AC HEC by 8-20%. Olanzapine has improved control of delayed nausea as compared to aprepitant in a randomized open designed study. In the prophylaxis of delayed nausea and vomiting, metoclopramide is an option instead of aprepitant in patients receiving cisplatin-based chemotherapy and dexamethasone is an option instead of aprepitant in patients receiving AC chemotherapy. Two new NK1-receptor antagonists (netupitant and rolapitant) have been included in the updated recommendations as additional options to aprepitant or fosaprepitant. Addition of one of these NK1-receptor antagonists to a combination of a 5-HT3-receptor antagonist and dexamethasone is recommended in both non-AC HEC and AC HEC. Olanzapine is included as an option in HEC in particular if nausea is the main symptom.

Serial MRI scans help in assessing early response to neoadjuvant chemotherapy and tailoring breast cancer treatment

BackgroundTailoring neoadjuvant chemotherapy (NAC) during breast cancer treatment is performed to improve overall tumour response, with increasing evidence to support its role. This study evaluates our breast unit's experience in MRI assessment of tumour response as an aid in tailoring NAC. Materials and methodsThis is a retrospective study of patients treated with NAC for breast cancer between 2005 and 2009 who underwent MRI to assess tumour response. Response to NAC was monitored before NAC and after 2 and/or 4 cycles of anthracycline and cyclophosphamide (AC) chemotherapy. Taxane was substituted for AC if MRI response was deemed inadequate. Tumour response on last MRI was correlated with final pathology against different tumour subtypes and in inflammatory tumours. Strength of agreement was measured using Kappa analysis. Potential predictive factors for MRI response were assessed for significance. Results166 tumours were assessed with serial MRI scans. MRI showed high sensitivity rate (93.1%) in predicting response to NAC particularly for tumours showing partial (PR) or complete (CR) response on pathology (p < 0.001) with fair agreement on Kappa analysis (K = 0.31). MRI seems more accurate in triple negative, HR+/HER2+ and high-grade tumours. Early identification of non-responders on MRI resulted in early tailoring of NAC, with improved rates of tumour response seen in 74.2% following switching NAC. Logistic regression showed that PR or CR observed on MRI after 2 NAC cycles significantly predicted pCR (p < 0.001). ConclusionSerial MRI can be used to assess patterns of tumour response to NAC. This study shows that tailoring NAC according to pattern of response can improve overall tumour response rates.

Abstract P1-15-04: Irriversible chemotherapy-induced alopecia in breast cancer patient

Abstract Introduction Patients with breast cancer who received chemotherapy have distressing side effects such as mucositis, alopecia, gastritis, and BM suppression. Chemotherapy-induced alopecia(CIA) is one of considerable psychological events in self-esteem in patients with breast cancer, but the possibility of irreversible alopecia is often overlooked by physician. We investigated clinical characteristics of CIA and prevalence of irreversible severe hair loss in patient with breast cancer who received chemotherapy. Methods We conducted a survey to collect demographic information about CIA with 150 breast cancer patients who had passed at least 6 months since their last day of chemotherapy from February 2015 to May 2015 in Yonsei Cancer Center. We obtained clinical information as age, elapsed time from end of chemotherapy, chemotherapy regimen, and other adjuvant therapy using their electrical medical records. We compared irreversible CIA characters between anthracycline and cyclophosphamide (AC) and taxane based regimen groups. The severe alopecia was defined as the hair density loss over 50% compared to the hair density before chemotherapy. Results The mean age at chemotherapy was 48 years old (±17.3) and the mean elapsed time after chemotherapy was 37 months (±9.5) in total patients. Remnant alopecia was reported in 71 patients (47.3%). Wig or hat were used in 39 patients (26.0%). The mean satisfaction score with a five-point scale was 4 in patients without alopecia or hair character change and 2.2 in patients with irreversible alopecia (p&amp;lt;0.001). The severe irreversible hair loss was complained by the 12 (8.2%) patients. AC and taxane based chemotherapy were carried out in 65 and 85 patients, respectively. In AC group, remnant alopecia was shown in 18 patients (27.7%), and more than a half of patients in taxane group, 53 patients (62.4%), showed remnant alopecia (p&amp;lt;0.001). While only five patients (7.8%) in AC group suffered for severe hair loss, 26 patients (31.3%) in taxane group were affected by severe hair loss (p=0.001). The mean satisfaction level of hair status in patients in taxane group was 2.5 as compared to 3.6 in those in AC group (p&amp;lt;0.001). Conclusion Contrary to general expectation, About a half of breast cancer patients who received chemotherapy complained of irreversible hair loss even though at least 6 months has elapsed since the end of chemotherpy. In particular, patients with taxane based chemotherapy had more irreversible and severe alopecia than those with AC chemotherapy. Citation Format: Kim S, Park HS, Kim JY, Nam S, Kim GM, Sohn JH, Kim SI. Irriversible chemotherapy-induced alopecia in breast cancer patient. [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 P1-15-04.

Palonosetron in the prevention of chemotherapy-induced nausea and vomiting: an evidence-based review of safety, efficacy, and place in therapy.

Introduction: The second-generation 5-hydroxytryptamine-3 (5-HT3) receptor antagonist palonosetron is effective in the prevention of chemotherapy-induced nausea and vomiting (CINV) associated with highly and moderately emetogenic chemotherapy (HEC and MEC, respectively). In addition, palonosetron has been the first and, at present, the only 5-HT3 receptor antagonist to have a specific indication for the prevention of delayed CINV associated with MEC. The unique pharmacology of this antagonist is thought to partly explain its improved efficacy against delayed symptoms.Aims: To review the evidence underlying the use of palonosetron in preventing CINV.Evidence review: A recent meta-analysis consistently showed that palonosetron significantly increases the control of both emesis and nausea during the acute and delayed phases after single-day HEC or MEC. Consistent with these findings from trials that did not include an neurokinin-1 (NK-1) receptor antagonist, randomized controlled trials recently showed that a triple combination with palonosetron achieves significantly better control of delayed CINV, particularly delayed nausea, in patients undergoing HEC or the high-risk combination of an anthracycline and cyclophosphamide (AC). Evidence from randomized studies also supports palonosetron as a valuable option to reduce the total corticosteroid dose administered in patients undergoing multiple cycles of MEC or AC chemotherapy. Additional benefits of palonosetron include the lack of a warning on cardiac safety and no known clinically significant drug–drug interactions.Place in therapy and conclusion: Evidence currently available indicates that palonosetron significantly adds to the clinician’s ability to effectively control CINV in patients undergoing HEC or MEC. It is recommended in the international guidelines for the prevention of CINV caused by MEC. The high safety profile and the opportunity to reduce the total corticosteroid dose with no loss in efficacy against delayed CINV should also contribute to a wider use of palonosetron in clinical practice.

Abstract P6-08-16: NSAS BC02 substudy of chemo-induced amenorrhea (CIA) in premenopausal women who received either taxane alone or AC followed by taxane as a postoperative chemotherapy

Abstract Background: Chemotherapy has a direct cytotoxic effect to breast cancer cells as well as ovarian suppression. In NSABP-B30 study, Swain, et al demonstrated that CIA contributed to reduce recurrence and prolong overall survival in premenopausal women with ER positive breast cancer. Thus far, incidence of CIA by anthracycline and cyclophosphamide (AC), or CMF has been reported. However, there has been no report on CIA by taxane alone therapy. Therefore, it is critically important to evaluate the incidence of the CIA in NSAS-BC02 (Watanabe T, ASCO2009) which compared taxane alone (q3w Docetaxel 75mg/m2 x8: DTX:, q3w Paclitaxel 175mg/m2 x8: PTX? to AC -&amp;gt; taxane (q3wAC 60/600mg/m2 x4 -&amp;gt; DTX x4: ACD, q3wAC x4 -&amp;gt; PTX x4: ACP) in postoperative patients with node-positive breast cancer. In addition, we examined the relationship between CIA and prognosis in this substudy. Methods: Menstrual status of all women participating in NSAS BC02 was assessed at study entry, every cycle during chemotherapy, at 2 months after protocol treatment, and then at every 6 months until 5 years. After 5 years, menstrual status was assessed annually. Women who were having regular menstrual cycles (premenopause) or irregular menstrual cycle (perimenopause) at study entry were included in this CIA substudy. We defined CIA as having no menstrual cycle for at least 6 months after chemotherapy. Results: Of the 1049 women enrolled in NSAS BC02, 395 were analyzed, including 315 with premenopause and 80 with perimenopause. Median age was 44.2 years old (42-62). Mean body mass index was 22.7 (15.4-38.4). Tumor characteristics were pathological stage I/IIA/IIB/IIIA 12.7%/39.0%/37.0%/11.4%, ER positivity 56.0% and PgR positivity 54.4%. Of 395 women, 287 (72.7%) was CIA due to protocol treatment. Regarding the type of protocol regimen, proportion of the CIA was 76.9% in ACP, 75.2% in ACD, 62.8% in PTX and 75.2% in DTX. There was no significant difference of CIA frequency between AC followed by taxane and taxane alone ?76.0?vs 69.4%, respectively; p=0.14?. Predictive factors of CIA were ACD against PTX (odds ratio (OR): 2.15), age increase by 5 years (OR: 1.50), and ER negativity (OR: 2.08) according to logistic regression analysis. In terms of effect to prognosis, CIA was an independent prognostic factor for disease-free survival (DFS) and overall survival in overall population of substudy according to multivariate Cox analysis. To eliminate guarantee time bias (GTB) (Giobbie-Hurder et al. JCO 2013), we used time-dependent Cox model. As a result, CIA was not statistically significant prognostic factor of DFS, even in the subgroup analysis of both ER positive and ER negative patients (Table 1). DFS in time-dependent Cox modelSubjectsHazard ratio95% Confidence intervalp valueOverall0.770.52-1.160.21ER positive0.600.31-1.160.13ER negative0.820.47-1.430.49 Conclusion: Although there has been no data on CIA by taxation alone regimen, eight cycles of taxation treatment caused a high frequency of CIA in premenopausal women with breast cancer (PTX62.8% and DTX75.2%). It would be cautious to conclude that CIA was statistically significant association with prognosis, because it might be due to GTB. Table 1: The effect of CIA on DFS by time-dependent Cox model Citation Format: Fumikata Hara, Hirofumi Mukai, Toru Watanabe, Yukari Uemura, Yasuo Ohashi. NSAS BC02 substudy of chemo-induced amenorrhea (CIA) in premenopausal women who received either taxane alone or AC followed by taxane as a postoperative chemotherapy [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 P6-08-16.

Evaluation of the Survival Benefit of Different Chemotherapy Regimens in Patients with T1-2N0 Triple-Negative Breast Cancer.

PurposeThis study aimed to evaluate the survival benefit of different adjuvant chemotherapy regimens in patients with T1-2N0 triple-negative breast cancer.MethodsOf 67,321 patients who were registered in the Korean Breast Cancer Society nationwide database between January 1999 and December 2008, 4,033 patients with T1-2N0 triple-negative breast cancer were included. The overall survival of patients who did not receive adjuvant chemotherapy was compared with those treated with adjuvant anthracycline and cyclophosphamide (AC), 5-fluorouracil, anthracycline, and cyclophosphamide (FAC), or cyclophosphamide, methotrexate, and 5-fluorouracil (CMF).ResultsThe median follow-up was 52.5 months. Chemotherapy was used in 87.4% of patients; it was used more commonly in patients with T2 tumors, those who were younger, had a higher histologic grade, and who showed lymphovascular invasion. The 5-year cumulative overall survival rate was 95.4%. Younger age, breast-conserving surgery, and adjuvant chemotherapy were significantly associated with improved overall survival. The 5-year cumulative overall survival rate of patients who did not receive adjuvant chemotherapy and those treated with AC, FAC, and CMF were 92.5%, 95.9%, 95.3%, and 95.9%, respectively. On multivariate analysis, the administration of any adjuvant chemotherapy regimen was significantly associated with improved overall survival (p=0.038). No significant difference in survival benefit was observed among the three different treatment groups.ConclusionA standard adjuvant chemotherapy regimen with the least drug-related toxicity might be a reasonable treatment for patients with T1-2N0 triple-negative breast cancer.

Efficacy of a triple antiemetic regimen with aprepitant for the prevention of chemotherapy-induced nausea and vomiting: effects of gender, age, and region

Objective:To determine the variability in treatment responses to antiemetic therapy (ondansetron and dexamethasone vs ondansetron and dexamethasone plus aprepitant) given with moderately emetogenic chemotherapy.Research design and methods:Post hoc subgroup analysis of data from a phase III, randomized, double-blind clinical trial evaluated whether the efficacy of aprepitant triple therapy (ondansetron and dexamethasone plus aprepitant) versus control (ondansetron and dexamethasone) varies by gender, age, or region in 848 men and women ≥18 years old with histologically confirmed malignancies and who were naïve to moderately or highly emetogenic chemotherapeutic agents. Endpoints compared were the incidences of no vomiting, complete response, and no use of rescue therapy, all during the overall period (0–120 h).Main outcome measures:Regardless of age, gender, or region, the aprepitant regimen provided better control for the no-vomiting and complete-response (no vomiting, no rescue therapy) endpoints.Results:The aprepitant regimen provided better control for the no-vomiting and complete-response (no vomiting, no rescue therapy) endpoints. Overall response rates were higher in men and in older (≥55 y) patients, but treatment differences were greater among women and younger patients, known to be at increased chemotherapy-induced nausea and vomiting (CINV) risk. Aprepitant showed a benefit versus control across regions, although the between-treatment difference appeared to be smaller for patients in Central/South America versus North America or international regions.Conclusions:Although we acknowledge that subset numbers in this post hoc analysis may be too small to allow definitive conclusions, the data suggest that aprepitant triple therapy provides a benefit over control therapy for the prevention of CINV in patients receiving anthracycline and cyclophosphamide (AC)- or non-AC-based moderately emetogenic chemotherapy across age, gender, and region. (Original trial results available at ClinicalTrials.gov: NCT00337727.)Trial registration: ClinicalTrials.gov identifier: NCT00337727.

NON-INVASIVE MEASUREMENT OF DEEP TISSUE TEMPERATURE CHANGES CAUSED BY APOPTOSIS DURING BREAST CANCER NEOADJUVANT CHEMOTHERAPY: A CASE STUDY

Treatment-induced apoptosis of cancer cells is one goal of cancer therapy. Interestingly, more heat is generated by mitochondria during apoptosis, especially the uncoupled apoptotic state,(1,2) compared to the resting state. In this case study, we explore these thermal effects by longitudinally measuring temperature variations in a breast lesion of a pathological complete responder during neadjuvant chemotherapy (NAC). Diffuse Optical Spectroscopic Imaging (DOSI) was employed to derive absolute deep tissue temperature using subtle spectral features of the water peak at 975 nm.3 A significant temperature increase was observed in time windows during the anthracycline and cyclophosphamide (AC) regimen but in not paclitaxel and bevacizumab regimen. Hemoglobin concentration changes generally did not follow temperature, suggesting that the measured temperature increases were likely due to mitochondrial uncoupling rather than a direct vascular effect. A simultaneous increase of tissue oxygen saturation with temperature was also observed, suggesting that oxidative stress also contributes to apoptosis. Although preliminary, this study indicates that longitudinal DOSI tissue temperature monitoring provides information that can improve our understanding of the mechanisms of tissue response during NAC.

Abstract 304: Predictive factors of pathological complete response by neoadjuvant chemotherapy for operable breast cancer

Abstract Background: Nonanthracycline regimens with taxanes have become to be used more frequently than before. Thus, it has become important to consider sensitivities to these two drugs in individual patients. Aim: To examine the association between the pathological response of each regimen and several pathological factors and whether individualized treatment based on HER2 may improve the overall pathological effects. Patients and methods: 1) Retrospective study: 170 patients treated with standard regimens consisted of anthracycline and/or taxan prior to surgery. 2) Prospective study: 18 patients with HER2 overexpression received 4 cycles of anthracycline and cyclophosphamide (AC), while 45 pathients without HER2 expression received 4 cycles of docetaxel and cyclophosphamide (TC). For these 2 studies, the overall pCR rates were examined. The association of pCR with pathological factors including estrogen- and progesterone-receptor (ER and PgR), HER2, nuclear grade, Ki-67, P-53 and Topoisomerase IIα (TopoIIα) etc. were also examined. Results: 1) The overall pCR rate was 24.2 % (41/170). Multivariate analysis with factors revealed that ER and nuclear grade were significantly associated with pCR. 2) The overall pCR rate was 36.5% (23/63), with pCR rates of 27.8% (5/18) and 40.0% (18/45) for the AC and TC regimens, respectively. TC regimen induced a pCR in most triple-negative cancer cases (15/19). Only low expression of ER maintained statistical significance as a predictor of pCR for the TC regimen. Conclusions: Individualized HER2-based treatment improved the efficacy of neoadjuvant chemotherapy, probably because HER2 is, at least at present, the most promising predictor for the efficacy of anthracyclines. Further studies with predictive factors including TopoIIα by FISH are now under investigation. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 304. doi:10.1158/1538-7445.AM2011-304

Phase III Trial of Casopitant, a Novel Neurokinin-1 Receptor Antagonist, for the Prevention of Nausea and Vomiting in Patients Receiving Moderately Emetogenic Chemotherapy

The purpose of this phase III trial was to evaluate the efficacy and safety of regimens containing casopitant, a novel neurokinin-1 receptor antagonist, for the prevention of chemotherapy-induced nausea and vomiting during the first cycle in patients receiving moderately emetogenic chemotherapy (MEC). Predominantly female patients (98%) diagnosed with breast cancer (96%) who were chemotherapy-naïve and scheduled to receive an anthracycline and cyclophosphamide (AC) -based regimen were enrolled onto this multinational, randomized, double-blind, parallel-group, placebo-controlled clinical trial. All patients received dexamethasone 8 mg intravenously (IV) on day 1 and oral ondansetron 8 mg twice daily on days 1 to 3. Patients were randomly assigned to a control arm (placebo), a single oral dose casopitant arm (150 mg orally [PO] on day 1), a 3-day oral casopitant arm (150 mg PO on day 1 plus 50 mg PO on days 2 to 3), or a 3-day IV/oral casopitant arm (90 mg IV on day 1 plus 50 mg PO on days 2 to 3). The primary end point was the proportion of patients achieving complete response (no vomiting/retching or rescue medications) in the first 120 hours after the initiation of MEC. A significantly greater proportion of patients in the single-dose oral casopitant arm, 3-day oral casopitant arm, and 3-day IV/oral casopitant arm achieved complete response (73%, 73%, and 74%, respectively) versus control (59%; P < .0001). The study did not demonstrate a reduced proportion of patients with nausea or significant nausea in those receiving casopitant. Adverse events were balanced among study arms. All casopitant regimens studied were more effective than the control regimen. Casopitant was generally well tolerated.

Aprepitant for the prevention of chemotherapy-induced nausea and vomiting associated with a broad range of moderately emetogenic chemotherapies and tumor types: a randomized, double-blind study

Aprepitant was shown previously to be effective for prevention of chemotherapy-induced nausea and vomiting (CINV) with moderately emetogenic chemotherapy (MEC) in breast cancer patients receiving an anthracycline and cyclophosphamide (AC)-based regimen. This study assessed aprepitant in patients receiving a broad range of MEC regimens with a variety of tumor types. This phase III, randomized, gender-stratified, double-blind trial enrolled patients with confirmed malignancies, naïve to MEC or highly emetogenic chemotherapy, who were scheduled to receive a single dose of at least one MEC agent. Patients received an aprepitant triple-therapy regimen (aprepitant, ondansetron, and dexamethasone) or a control regimen (ondansetron and dexamethasone) administered orally. Primary and key secondary efficacy endpoints were proportions of patients with no vomiting and complete response (no vomiting and no rescue medication), respectively, during the 120 h post-chemotherapy. Of 848 randomized patients, 77% were female, and 52% received non-AC-based antineoplastic regimens. Significantly, more patients in the aprepitant group achieved no vomiting and complete response, regardless of whether they received AC or non-AC regimens, in the 120 h after chemotherapy. Overall, the incidences of adverse events were generally similar in the aprepitant (62.8%) and control groups (67.2%). The aprepitant regimen provided superior efficacy in the treatment of CINV in a broad range of patients receiving MEC (non-AC or AC) in both no vomiting and complete response endpoints. Aprepitant was generally well tolerated. These results show the benefit of including aprepitant as part of the standard antiemetic regimen for cancer patients receiving MEC.