Cycles Of Anthracycline-based Chemotherapy Research Articles

The PARTNER trial of neoadjuvant olaparib with chemotherapy in triple-negative breast cancer

PARTNER is a prospective, phase II–III, randomized controlled clinical trial that recruited patients with triple-negative breast cancer1,2, who were germline BRCA1 and BRCA2 wild type3. Here we report the results of the trial. Patients (n = 559) were randomized on a 1:1 basis to receive neoadjuvant carboplatin–paclitaxel with or without 150 mg olaparib twice daily, on days 3 to 14, of each of four cycles (gap schedule olaparib, research arm) followed by three cycles of anthracycline-based chemotherapy before surgery. The primary end point was pathologic complete response (pCR)4, and secondary end points included event-free survival (EFS) and overall survival (OS)5. pCR was achieved in 51% of patients in the research arm and 52% in the control arm (P = 0.753). Estimated EFS at 36 months in the research and control arms was 80% and 79% (log-rank P > 0.9), respectively; OS was 90% and 87.2% (log-rank P = 0.8), respectively. In patients with pCR, estimated EFS at 36 months was 90%, and in those with non-pCR it was 70% (log-rank P < 0.001), and OS was 96% and 83% (log-rank P < 0.001), respectively. Neoadjuvant olaparib did not improve pCR rates, EFS or OS when added to carboplatin–paclitaxel and anthracycline-based chemotherapy in patients with triple-negative breast cancer who were germline BRCA1 and BRCA2 wild type. ClinicalTrials.gov ID: NCT03150576.

0855 Patient-reported sleep symptoms across four cycles of chemotherapy among adults with lymphoma: A pilot study

Abstract Introduction Sleep disturbance is one of the primary symptoms reported by cancer survivors before, during, and after treatment. To better understand trajectories of sleep disturbance over the course of chemotherapy, we evaluated patient-reported symptoms among adults being treated for lymphoma. Methods Participants were 18-74 years old, English-speaking, and scheduled to be treated with a full course of anthracycline-based chemotherapy. Among other assessments, participants completed a battery of patient-reported outcome measures prior to the first cycle of chemotherapy (T1) and on the final days of the second (T2) and fourth (T3) cycles. Sleep symptoms were assessed with the Insomnia Severity Index (ISI), PROMIS Sleep Disturbance (PROMIS-SD), and PROMIS Sleep-Related Impairment (PROMIS-SRI) measures. Given the small sample size, descriptives and effect sizes were calculated rather than conducting inferential analyses. Results Participants were 9 adults with Hodgkin’s (n=5) or Non-Hodgkin’s (n=4) lymphoma, mean age 41 years (SD=13.9), mostly male (89%), White (78%), and non-Hispanic (89%). The majority had higher scores on the ISI (85.7%), PROMIS-SD (71.4%), and PROMIS-SRI (71.4%) at T2 than T1, demonstrating more sleep disturbance mid-chemotherapy than prior to chemotherapy. Conversely, the majority had lower scores at T3 than T2 (ISI: 80.0%, PROMIS-SD: 80.0%, PROMIS-SRI: 100.0%), demonstrating less sleep disturbance at late-chemotherapy than mid-chemotherapy. For most participants scores remained higher at T3 than T1 (all 3 measures: 75.0%), indicating more sleep disturbance at late-chemotherapy than pre-chemotherapy. Averaged across participants, differences in scores from T1 to T2 were small-to-medium (ISI: Hedges’ g=0.42, PROMIS-SD: g=0.44, PROMIS-SRI: g=0.62), from T1 to T3 were small (ISI: g=0.26, PROMIS-SD: g=0.26, PROMIS-SRI: g=0.23), and from T2 to T3 were medium-to-large (ISI: g=0.98, PROMIS-SD: g=0.73, PROMIS-SRI: g=0.53). Conclusion Patient-reported sleep symptoms worsened over the first two cycles of anthracycline-based chemotherapy. Symptoms improved over the subsequent two cycles; however, for most participants they remained worse than baseline levels. Pending replication in a larger sample, intervening before initiating chemotherapy or during the early cycles thereof may be beneficial to diminish sleep disturbance among patients with lymphoma. Support (if any) The project described was supported by the Robert H. Lurie Comprehensive Cancer Center. RSF was supported by NCI grant #K08CA247973. EH was supported by NHLBI grant #K01HL152009.

Abstract P2-26-23: Transcriptomic modification induced by the first cycle of neoadjuvant chemotherapy impacts response to treatment in triple negative breast cancer (TNBC)

Abstract Background Despite adequate neoadjuvant chemotherapy, TNBC remains poor prognosis. Non-responding patient have 25-40% risk of relapse at 5 years. pCR is therefore currently considered as a major goal in TNBC and new tools of early prediction of residual disease should be identified. TransTep is a phase 2 monocentric clinical trial which aims to identify transcriptomic profile of triple-negative cancer cells associated with early tumor chemoresistance, as identified by FDG PET after the first course of neoadjuvant chemotherapy. Twenty patients were included between January 2015 and October 2017, with stage II or III of the UICC classification (except stage T4d). All patients received neoadjuvant chemotherapy with anthracyclines and taxanes sequentially, none of them had a dose-dense chemotherapy. Six patients obtained metabolic response (Delta SUV &amp;lt; -30%) after one cycle of anthracycline. Methods Total RNA was extracted from biopsies (HES &amp;gt; 30%) and used to prepare libraries thanks to TruSeq RNA library Prep kit (Illumina) and sequenced on NextSeq500 device. Results Transcriptomic expression analysis between tumors before chemotherapy and tumors after one course of chemotherapy showed that tumors showing a significant decrease of their Delta SUV (←30%) had a much higher gene expression variation than tumors with a Delta SUV &amp;gt;-30%. These tumors presented, after one course of chemotherapy, a decrease of cell cycle, DNA replication and Fanconi anemia pathway related genes, while they harbored an increase of genes belonging to immunity related pathways such as natural killer cell mediated toxicity, TH17 cell differentiation, or chemokine signaling pathway. As patients had a surgery after neoadjuvant chemotherapy, we had Chevalier tumor response. As observed with FDG PET data, patients with a good response according to Chevalier (class 1) criteria presented a much higher transcriptomic modification after one course of chemotherapy. Patients with a little gene expression modification were classified as Chevalier 3. When we focused on pathways impacted by chemotherapy in tumors classified as Chevalier 1, we observed a significant decrease of cell cycle, DNA replication and DNA repair pathways related gene after one course of chemotherapy, whereas a high number of genes belonging to immunity related genes (NK cells, antigen processing and presentation, or chemokine signaling pathway) were increased. Conclusion Our results tend to indicate that transcriptomic tumor response after one course of chemotherapy could forecast final response to treatment. Moreover, it seems that one cycle of anthracycline-based chemotherapy is able to get hot some breast tumors, and that this tumor warming could be a marker of good response to the full treatment. In the following months, we will test whether transcriptomic could predict progression free survival and/or overall survival of patients. We will also look for the best early marker of response between PET FDG and tumor transcriptomic modifications. Based on these results, a new trial will be organized. A therapeutic adaptation depending on the transcriptomic or metabolic data will be proposed to increase pCR rate and prognosis of patients. Moreover, with years and therapeutic innovations, patient managment obviously evolves. This was recently the case with a new standard of care in triple negative breast cancer with combination of platinum salt and immunotherapy. Therefore, a new trial, similar to TRANSTEP, will be carried out with this new standard of care. Citation Format: Isabelle Desmoulins, David Chardin, Corentin Richard, Laurent Arnould, ALEXANDRE COCHET, Olivier Humbert, Romain Boidot. Transcriptomic modification induced by the first cycle of neoadjuvant chemotherapy impacts response to treatment in triple negative breast cancer (TNBC) [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 P2-26-23.

Mid-treatment Ultrasound Descriptors as Qualitative Imaging Biomarkers of Pathologic Complete Response in Patients with Triple-Negative Breast Cancer.

This study aimed to investigate mid-treatment breast tumor ultrasound characteristics that may predict eventual pathologic complete response (pCR) in triple-negative breast cancer; specifically, we examined associations between pCR and two parameters: tumor response pattern and tumor appearance. Ultrasound was performed at mid-treatment, defined as the completion of four cycles of anthracycline-based chemotherapy and before receiving taxane-based chemotherapy. Consensus imaging review was performed while blinded to pathology results (i.e., pCR/non-pCR) from surgery. Tumor response pattern was described as "complete," "concentric," "fragmented," "stable" or "progression." Tumor appearance was designated as "mass," "architectural distortion," "flat tumor bed" or "clip only." Univariate and multivariate regression analyses of 144 participants showed significant associations between mid-treatment response pattern and pCR (p=0.0348 and p=0.0173, respectively), with complete and concentric response patterns more likely to achieve pCR than other patterns. Univariate and multivariate regression analyses further showed significant associations between mid-treatment tumor appearance and pCR (p < 0.0001 for both), with persistent appearance of mass less likely than other appearances to achieve pCR. To conclude, our study demonstrated strong associations between pCR and both tumor response pattern and tumor appearance, thereby suggesting that these parameters have potential as qualitative imaging biomarkers of pCR in triple-negative breast cancer.

Abstract PD6-06: Radiomic phenotypes from dynamic contrast-enhanced MRI (DCE-MRI) parametric maps for early prediction of response to neoadjuvant systemic therapy (NAST) in triple negative breast cancer (TNBC) patients

Abstract Background and Purpose:Early and accurate assessment ofbreast cancer response to NAST is important for patient management. In this study, we investigated the value of radiomic phenotypes derived from semi-quantitative and quantitative DCE-MRI parametric maps for early prediction of NASTresponse in TNBC patients. MATERIALS AND METHODS:This IRB approved study included 74 patients with stage I-III TNBC who were enrolled in the prospective ARTEMIS trial (NCT02276443). Pathologic complete response (pCR) and non-pCR were assessed by surgical histopathology after NAST (pCR=34; non-pCR=40).MRI scans were obtained at 3 time points during the NAST treatment with every 2-week anthracycline-based chemotherapy (AC): at baseline (BSL=74), post-2 cycles of AC (C2= 27) and post-4 cycles of AC (C4= 27). Patients went on to receive taxane-based chemotherapy prior to surgery. Tumor regions of interest (ROIs) were segmented by a breast radiologist at the early-phase subtractions of DCE-MRI scans using in-house developed software, followed by co-registration of the ROIs with quantitative (Ktrans, Veand Kep), and semi-quantitative DCE parametric maps (Maximum Slope Increase (MSI), Positive Enhancement Integral (PEI) and Peak Signal Enhancement Ratio (SER)).A total of 93 first order radiomic features were extracted from the tumor ROIs of each time point semi-quantitative DCE parametric map, while a total of 390 extracted radiomic features (first order-histogram features and second order grey-level-co-occurrence matrix) were extracted from each quantitative DCE parametric map using an in-house developed Matlab software.Radiomic features at each time point and changes between the 3 time points were compared between pCR and non-pCR using Wilcoxon Rank Sum test and Fisher’s exact test. Area under the receiver operating characteristics curve (AUC) was used to determine which features predicted pCR.Logistic regression was performed for feature selection, and used to build the radiomic phenotype model. The model performance was assessed by leave-one-out cross validation and 3-fold cross validation. RESULTS:Thirty-three radiomic features from PEI map were significantly different between pCR and non-pCR. The PEI most significant features were changesbetween BSL and C4 in skewness, mean and median (AUC=0.87, 0.85 and 0.87, p=&amp;lt;0.001, 0.001 and 0.002 respectively). Additionally, 31 MSI features were significantly different between pCR and non-pCR. The top 2 features were the interscan-change in skewness between BSL and C2 (AUC=0.80, P=0.007) and C4 standard deviation (AUC=0.80, P=0.006). Four BSL Veradiomic features were statistically significant between pCR and non-pCR with the best being range of difference variance (AUC=0.64, P=0.03). One BSL Kepfeature (Angular-Variance of Information measure of correlation-2) was able to differentiate pCR from non-pCR (AUC=0.64, P=0.04). Five C4-Ktrans features were able to differentiate pCR and non-pCR, with the most significant being mean value (AUC=0.86, P=0.001). BSL-Kepradiomic model built from 24 features (AUC=0.80, p=0.003) and combined (Ktrans, Veand Kep)C2-radiomic model consisting of 20 features (AUC=0.97, p=0.01) showed the best performance for prediction of pCR. CONCLUSIONS:Radiomic phenotypes form DCE-MRI parametric maps were useful for differentiation between pCR and non-pCR and showed promise as noninvasive imaging biomarkers for early prediction of NAST response in TNBC. Potentially, DCE-MRI radiomic features may be used for development of diagnostic predictive model for early noninvasive assessment of NAST treatment response in TNBC patients. Citation Format: Nabil Elshafeey, Beatriz E Adrada, Rosalind P Candelaria, Abeer H Abdelhafez, Benjamin C Musall, Jia Sun, Medine Boge, Rania M.M Mohamed, Hagar S Mahmoud, Jong Bum Son, Aikaterini Kotrosou, Shu Zhang, Jessica Leung, Deanna Lane, Marion Scoggins, David Spak, Elsa Arribas, Lumarie Santiago, Gary J. Whitman, Huong T Le-Petross, Tanya W Moseley, Jason B White, Elizabeth Ravenberg, Ken-Pin Hwang, Peng Wei, Jennifer K Litton, Lei Huo, Debu Tripathy, Vicente Valero, Alastair M Thompson, Stacy Moulder, Wei T Yang, Mark D Pagel, Jingfei Ma, Gaiane M Rauch. Radiomic phenotypes from dynamic contrast-enhanced MRI (DCE-MRI) parametric maps for early prediction of response to neoadjuvant systemic therapy (NAST) in triple negative breast cancer (TNBC) patients [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PD6-06.

Primary analysis of KAITLIN: A phase III study of trastuzumab emtansine (T-DM1) + pertuzumab versus trastuzumab + pertuzumab + taxane, after anthracyclines as adjuvant therapy for high-risk HER2-positive early breast cancer (EBC).

500 Background: The standard of care for HER2-positive EBC is chemotherapy plus one year of HER2-directed therapy. However, recurrence—particularly in high-risk populations—remains a problem, as does systemic chemotherapy-associated toxicity. In KAITLIN, we aimed to improve efficacy and reduce toxicity by replacing taxanes and trastuzumab with T-DM1. Methods: KAITLIN (NCT01966471) is a phase 3, randomized, open-label study that enrolled 1846 patients with adequately excised, centrally confirmed HER2-positive EBC either node-positive (LN+); or node-negative, HR-negative, and tumor size &gt; 2.0 cm. Within 9 weeks of surgery, patients were randomized 1:1 to 3-4 cycles of anthracycline-based chemotherapy followed by 18 cycles of T-DM1 3.6 mg/kg + pertuzumab 420 mg q3w (loading dose [LD] 840 mg) (AC-KP) or taxane (3-4 cycles) + concurrent trastuzumab 6 mg/kg (LD 8 mg/kg) + pertuzumab 420 mg q3w (LD 840 mg) (AC-THP). Patients were stratified by world region, nodal status, HR status, and anthracycline type. Adjuvant radiotherapy and/or endocrine therapy was administered after 4 cycles of HER2-targeted therapy when indicated. The co-primary endpoints were invasive disease-free survival (IDFS) in the LN+ and in the ITT populations applying a hierarchical testing procedure. Secondary endpoints included overall survival (OS), patient-reported outcomes (PROs), and safety. Results: KAITLIN did not meet its co-primary endpoints. In LN+ patients (n = 1658), there was no significant difference between arms in IDFS event risk (stratified hazard ratio = 0.97; 95%CI 0.71–1.32). Three-year IDFS was 94.1% with AC-THP and 92.7% with AC-KP. Results were similar in the ITT population (stratified hazard ratio = 0.98; 95%CI 0.72–1.32; 3-year IDFS: 94.2% vs 93.1%). OS data are immature with an event rate of ~4%–5% in each arm. During the study overall, there was a similar incidence of grade ≥3 AEs (55.4% vs 51.8%) and SAEs (23.3% vs 21.4%) with AC-THP and AC-KP, respectively. More patients receiving AC-KP than AC-THP discontinued T-DM1 or trastuzumab, respectively, because of AEs (26.8% vs 4.0%). PRO data will be presented. Conclusions: Replacing adjuvant taxane and trastuzumab with T-DM1 did not result in significantly improved efficacy or overall safety. Nonetheless, in this high-risk population, a favorable IDFS outcome was achieved in both study arms. HP + chemotherapy remains the standard of care for patients with high-risk HER2-positive EBC. Clinical trial information: NCT01966471 .

The paradox of the first cycle of chemotherapy-transient improvement of contractility and diastolic function after the first cycle of anthracycline-based chemotherapy: a prospective clinical trial.

AimsBreast cancer is the most common cancer among women, and anthracyclines are the most commonly administered drugs for these patients. Cardiotoxicity is one of the complications, which limits the success of this therapy. Very few studies have evaluated anthracycline toxicities within the first few hours after the first infusion, and the majority of published studies were performed in animal models. The present study aimed to evaluate changes in echocardiographic parameters in women with breast cancer 24 hours after receiving the first dose of an anthracycline.Materials and Methods and ResultsThe present study included 75 chemotherapy-naive female patients without heart failure, who were diagnosed with breast cancer and were scheduled to undergo anthracycline-based chemotherapy (epirubicin and doxorubicin). During their visits to the Heart Center, the patients underwent detail echocardiographic examination, including assessment of systolic and diastolic function and longitudinal strain. There were no differences in baseline echocardiographic parameters between patients with and those without cardiotoxicity. Cardiotoxicity was observed during follow-up in 14 patients (18.7%). Improvements in left ventricular ejection fraction and global longitudinal strain were observed at 24 hours after administration of the cytotoxic agent in the subgroup of patients without further cardiotoxicity. The changes were transient and the assessment of left ventricular ejection fraction after completion of chemotherapy revealed similar values to those before the treatment.ConclusionsThe findings of our study suggest that transient improvement in contractility and systolic and diastolic function might occur 24 hours after anthracycline administration, especially in patients who do not develop cardiotoxicity.

Computed Tomography Assessment of Hepatic Metastases of Breast Cancer with Revised Response Evaluation Criteria in Solid Tumors (RECIST) Criteria (Version 1.1): Inter-Observer Agreement.

SummaryBackgroundTo assess inter-observer agreement of revised RECIST criteria (version 1.1) for computed tomography assessment of hepatic metastases of breast cancer.Material/MethodsA prospective study was conducted in 28 female patients with breast cancer and with at least one measurable metastatic lesion in the liver that was treated with 3 cycles of anthracycline-based chemotherapy. All patients underwent computed tomography of the abdomen with 64-row multi- detector CT at baseline and after 3 cycles of chemotherapy for response assessment. Image analysis was performed by 2 observers, based on the RECIST criteria (version 1.1).ResultsComputed tomography revealed partial response of hepatic metastases in 7 patients (25%) by one observer and in 10 patients (35.7%) by the other observer, with good inter-observer agreement (k=0.75, percent agreement of 89.29%). Stable disease was detected in 19 patients (67.8%) by one observer and in 16 patients (57.1%) by the other observer, with good agreement (k=0.774, percent agreement of 89.29%). Progressive disease was detected in 2 patients (7.2%) by both observers, with perfect agreement (k=1, percent agreement of 100%). The overall inter-observer agreement in the CT-based response assessment of hepatic metastasis between the two observers was good (k=0.793, percent agreement of 89.29%).ConclusionsWe concluded that computed tomography is a reliable and reproducible imaging modality for response assessment of hepatic metastases of breast cancer according to the RECIST criteria (version 1.1).

Chemosensitization strategies for the treatment of lung cancer.

In spite of major research efforts, the treatment of advanced non-small cell lung cancer is still largely inefficient. Indeed, this cancer type has a poor prognosis, and no curative therapies are available. Over the last years, it has been become increasingly clear that (relatively) successful chemotherapies such as the anthracycline-based neoadjuvant treatment of locally advanced breast cancer are largely influenced by the immunosurveillance system. Thus, the pre-treatment composition of the immune infiltrate of mammary carcinomas determined by microarray analyses clearly affects the probability of successful therapy. A CXCL13-centered metagene signature reflecting the intratumoral presence of interferon-γ-producing T cells has a positive predictive impact, indicating that the pre-existing anticancer immune response influences therapeutic outcome [1]. In addition, changes in the immune infiltrate induced by chemotherapy have a prognostic impact. Complete pathological responses observed after six cycles of anthracycline-based chemotherapy are associated with an improvement of the ratio between CD8+ cytotoxic T lymphocytes (CTL) and immunosuppressive FOXP3+ regulatory T cells [2]. Thus, it appears that chemotherapy can indeed elicit anticancer immune responses. One important mechanism through which chemotherapy stimulates anticancer immunosurveillance consists in the induction of immunogenic cell death (ICD)[3]. ICD is a cell death modality that is preceded by cellular stress responses (in particular autophagy, endoplasmic reticulum stress, as well a type 1 interferon production) that affect the perception of dying cells and their corpses by the immune system. Premortem autophagy is required for the optimal release of ATP, and extracellular ATP is (one of) the major chemotactic factor(s) that attracts myeloid cells into the proximity of dying cancer cells. Endoplasmic reticulum (ER) stress facilitates the exposure of ER luminal proteins such as calreticulin on the surface of the plasma membrane, and surface-exposed calreticulin serves as a potent ‘eat-me’ signal facilitating the transfer of dead-cell antigens into immature dendritic cells. HMGB1, which leaks out from the nuclei of dead cells, stimulates the maturation of immature dendritic cells, which then can present tumor-associated antigens to CTL. Type 1 interferon is required for conditioning the tumor microenvironment to optimize the recruitment and action of CTL [3-5]. It is important to note that anthracyclines and oxaliplatin are efficient ICD inducers, perhaps explaining that these drugs can be successfully used for the adjuvant or neoadjuvant treatment of mammary and colorectal carcinomas, respectively. In contrast, cisplatin, which is widely used as the first-line treatment of lung cancer, is a relatively poor ICD inducer, presumably because it fails to stimulate an efficient ER stress response [3]. Many non-small cell lung cancers (NSCLC) are primarily resistant against cisplatin, a feature that can be explained by their metabolic characteristics. Thus, the levels of expression of pyridoxine kinase (PDXK) by NSCLC cells have a major prognostic impact on the survival of patients treated with cisplatin[6]. PDXK is the enzyme that converts cell-permeable pyridoxine (also called vitamin B6) into pyridoxine phosphate, the active metabolite that is trapped in cells and can serve as prosthetic group for multiple enzymes. Pyridoxine sensitizes NSCLC cells to the induction of apoptosis by cisplatin, but only if PDXK is expressed, meaning that it is indeed the intracellular level of pyridoxine phosphate that modulates the cisplatin response [6]. Importantly, pyridoxine does not only shift the dose response to cisplatin to lower levels with regard to apoptosis. Pyridoxine also enhances the efficacy of cisplatin with regard to the induction of the ER stress response, thereby improving the potential of the drug to trigger ICD (Figure ​(Figure1).1). As a result, cisplatin and pyridoxine can be advantageously combined for the treatment of mice with lung cancers. The synergistic interaction between cisplatin and pyridoxine is largely dependent on an adaptive anticancer immune response. Cisplatin plus pyridoxine can cure immunocompetent mice bearing orthotopic lung cancers, yet fail to achieve complete responses in nude mice, which lack T lymphocytes [7, 8]. Moreover, mice that have been cured from NSCLC by the combination therapy develop an effective immune response, making them resistant against re-challenge with NSCLC cells. Figure 1 An optimal strategy for chemosensitization Altogether, these findings support the notion that optimal chemosensitization strategies should pursue two parallel goals, namely (i) to render the cancer cells more susceptible to lethal responses and (ii) to seek maximum efficacy in the induction of ICD (Figure ​(Figure1).1). In other words, ICD should be routinely monitored for the development of novel combination therapies. Only those combinations that facilitate optimal stimulation of ICD and are compatible with the induction of an anticancer immune response will be clinically successful.

Abstract P5-15-01: Evaluation of sustained antiemetic efficacy over repeated cycles of anthracycline-cyclophosphamide (AC)-based chemotherapy: A phase 3 study of NEPA, a fixed-dose combination of netupitant and palonosetron for prevention of chemotherapy-induced nausea and

Abstract Background: International antiemetic guidelines recommend co-administration of an NK1 receptor antagonist (RA) and a 5-HT3 RA in breast cancer (BC) patients receiving anthracycline cyclophosphamide (AC) chemotherapy as this population is at increased risk of developing CINV. NEPA, a novel, oral fixed-dose combination of a new NK1 receptor antagonist (RA), netupitant (NETU 300 mg), and the 5-HT3 RA, palonosetron (PALO 0.50 mg), was previously reported to be superior to oral PALO after a single cycle (Aapro et al, Annals of Oncology 2014) and multiple cycles (Aapro et al, ASCO 2014) of chemotherapy. This posthoc analysis evaluates sustained efficacy over multiple cycles when censoring patients who experienced CINV in the previous cycle. Methods: This was a multinational, randomized, double-blind, parallel group study evaluating the efficacy/safety of single oral doses of NEPA versus oral PALO in chemotherapy-naïve patients receiving multiple cycles of anthracycline-based chemotherapy. All patients also received oral dexamethasone (DEX) 12 mg (NEPA) or 20 mg (PALO), only on Day 1. Overall (0-120 h) complete response (CR: no emesis, no rescue medication) was the efficacy endpoint evaluated. The analysis of sustained CR evaluates the probability that patients would remain complete responders over 4 cycles by censoring continuing patients who failed to have a CR in the prior cycle. A Kaplan Meier method and log-rank test comparing NEPA with oral PALO were utilized. Results: 1455 patients were randomized; 1286 participated in the multiple cycle extension after cycle 1. Treatment groups were comparable with 98% females and 97% with BC; the mean age was 54. The percentage of patients who experienced a CR in cycle 1 and who sustained a CR over cycles 2-4 was greater for NEPA than for oral PALO (p &amp;lt;0.0001, log rank test). The table shows the percent of patients with continuing CR over time; N = the number of patients at risk. Time since first chemotherapyNEPA + DEXOral PALO + DEXCycle 174.3% (N = 724)66.6% (N = 725)Cycle 268.5% (N = 485)57.1% (N = 434)Cycle 365.7% (N = 423)52.7% (N = 348)Cycle 463.6% (N = 375)50.6% (N = 300) Conclusions: This multiple cycle analysis indicates that NEPA, a novel, fixed-dose antiemetic combination, more effectively demonstrates sustained control of CINV over multiple cycles than oral PALO. As females with breast cancer represent a particularly challenging population in terms of emesis control, it is especially crucial that antiemetic recommendations are followed to allow these patients to maintain their quality of life and continue their treatment plan over multiple cycles of chemotherapy. NEPA offers effective guideline-recommended prophylaxis in a convenient single dose. Citation Format: Matti Aapro, Hope Rugo, Giada Rizzi. Evaluation of sustained antiemetic efficacy over repeated cycles of anthracycline-cyclophosphamide (AC)-based chemotherapy: A phase 3 study of NEPA, a fixed-dose combination of netupitant and palonosetron for prevention of chemotherapy-induced nausea and [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 P5-15-01.

Tumour size is the only predictive factor of distant recurrence after pathological complete response to neoadjuvant chemotherapy in patients with large operable or locally advanced breast cancers: A sub-study of EORTC 10994/BIG 1-00 phase III trial

PurposeAlthough achieving a pathological complete response (pCR) after neoadjuvant chemotherapy (NACT) in breast cancer predicts a better outcome, some patients still relapse. The objectives of this study were to describe the types of events in this group of patients and to identify predictive factors for relapse. MethodsPatients with large operable or locally advanced breast cancers (T4d tumours were excluded) were randomised to receive either six cycles of anthracycline-based chemotherapy or three cycles of docetaxel followed by three cycles of eprirubicin/docetaxel. pCR was defined as no evidence of residual invasive cancer (or very few scattered tumour cells) in the primary tumour and axillary lymph nodes at surgery. Two Cox regression analyses were performed to identify predictive factors of relapse: one for recurrence-free interval (RFI) and one for distant recurrence-free interval (DRFI). ResultsOut of 283 eligible patients who achieved a pCR, 40 (14.1%) and 28 (9.9%) presented an event of interest for the RFI and DRFI analyses, respectively. Five-year RFI, DRFI and overall survival (OS) were 85.3% (95% confidence interval (CI), 80.1–89.3), 89.6% (95% CI, 85.0–92.9) and 91.9% (95% CI, 87.2–94.9), respectively. No predictors for RFI after pCR were identified. For DRFI, tumour size was the only predictor: Hazard ratio (HR) T3 versus T1–2=3.62 (95% CI, 1.66–7.89); HR T4 versus T1–2: HR, 2.80 (95% CI, 0.62–12.64) p=0.0048. ConclusionIn this study, clinical tumour size emerged as the only predictor for DRFI after pCR, with T3 and T4 tumours having an increased risk for distant recurrence compared to T1–2 tumours.

Changes in aldehyde dehydrogenase-1 expression during neoadjuvant chemotherapy predict outcome in locally advanced breast cancer.

IntroductionAlthough neoadjuvant chemotherapy (NAC) for locally advanced breast cancer can improve operability and local disease control, there is a lack of reliable biomarkers that predict response to chemotherapy or long-term survival. Since expression of aldehyde dehydrogenase-1 (ALDH1) is associated with the stem-like properties of self-renewal and innate chemoresistance in breast cancer, we asked whether expression in serial tumor samples treated with NAC could identify women more likely to benefit from this therapy.MethodsWomen with locally advanced breast cancer were randomly assigned to receive four cycles of anthracycline-based chemotherapy, followed by four cycles of taxane therapy (Arm A), or the same regimen in reverse order (Arm B). Tumor specimens were collected at baseline, after four cycles, and then at surgical resection. ALDH1 expression was determined by immunohistochemistry and correlated with tumor response using Fisher’s exact test while Kaplan-Meier method was used to calculate survival.ResultsA hundred and nineteen women were enrolled into the study. Fifty seven (48%) were randomized to Arm A and 62 (52%) to Arm B. Most of the women (90%) had ductal carcinoma and 10% had lobular carcinoma. Of these, 26 (22%) achieved a pathological complete response (pCR) after NAC. There was no correlation between baseline ALDH1 expression and tumor grade, stage, hormone receptor, human epidermal growth factor receptor 2 (HER2) status and Ki67 index. ALDH1 negativity at baseline was significantly associated with pCR (P = 0.004). The presence of ALDH1(+) cells in the residual tumor cells in non-responding women was strongly predictive of worse overall survival (P = 0.024). Moreover, serial analysis of specimens from non-responders showed a marked increase in tumor-specific ALDH1 expression (P = 0.028). Overall, there was no survival difference according to the chemotherapy sequence. However, poorly responding tumours from women receiving docetaxel chemotherapy showed an unexpected significant increase in ALDH1 expression. ConclusionsALDH1 expression is a useful predictor of chemoresistance. The up-regulation of ALDH1 after NAC predicts poor survival in locally advanced breast cancer. Although the chemotherapy sequence had no effect on overall prognosis, our results suggest that anthracycline-based chemotherapy may be more effective at targeting ALDH1(+) breast cancer cells. Trial registrationACTRN12605000588695

Pathological complete response after neoadjuvant chemotherapy is an independent predictive factor irrespective of simplified breast cancer intrinsic subtypes: a landmark and two-step approach analyses from the EORTC 10994/BIG 1-00 phase III trial

Pathological complete response (pCR) following chemotherapy is strongly associated with both breast cancer subtype and long-term survival. Within a phase III neoadjuvant chemotherapy trial, we sought to determine whether the prognostic implications of pCR, TP53 status and treatment arm (taxane versus non-taxane) differed between intrinsic subtypes. Patients were randomized to receive either six cycles of anthracycline-based chemotherapy or three cycles of docetaxel then three cycles of eprirubicin/docetaxel (T-ET). pCR was defined as no evidence of residual invasive cancer (or very few scattered tumour cells) in primary tumour and lymph nodes. We used a simplified intrinsic subtypes classification, as suggested by the 2011 St Gallen consensus. Interactions between pCR, TP53 status, treatment arm and intrinsic subtype on event-free survival (EFS), distant metastasis-free survival (DMFS) and overall survival (OS) were studied using a landmark and a two-step approach multivariate analyses. Sufficient data for pCR analyses were available in 1212 (65%) of 1856 patients randomized. pCR occurred in 222 of 1212 (18%) patients: 37 of 496 (7.5%) luminal A, 22 of 147 (15%) luminal B/HER2 negative, 51 of 230 (22%) luminal B/HER2 positive, 43 of 118 (36%) HER2 positive/non-luminal, 69 of 221(31%) triple negative (TN). The prognostic effect of pCR on EFS did not differ between subtypes and was an independent predictor for better EFS [hazard ratio (HR) = 0.40, P < 0.001 in favour of pCR], DMFS (HR = 0.32, P < 0.001) and OS (HR = 0.32, P < 0.001). Chemotherapy arm was an independent predictor only for EFS (HR = 0.73, P = 0.004 in favour of T-ET). The interaction between TP53, intrinsic subtypes and survival outcomes only approached statistical significance for EFS (P = 0.1). pCR is an independent predictor of favourable clinical outcomes in all molecular subtypes in a two-step multivariate analysis. EORTC 10994/BIG 1-00 Trial registration number NCT00017095.

Interim 18F-FDG PET SUVmax Reduction Is Superior to Visual Analysis in Predicting Outcome Early in Hodgkin Lymphoma Patients

PET performed after 2 cycles of chemotherapy (PET2) allows prediction of outcome in most patients with Hodgkin lymphoma (HL). Visual analysis using a 5-point scale was proposed to assess PET response, but a semiquantitative approach using maximum standardized uptake value (SUVmax) reduction between baseline and interim PET was shown to be superior to the 5-point scale in patients with diffuse large B-cell lymphoma and may also improve the accuracy of interim PET interpretation in HL. To compare the clinical usefulness of both methods in HL patients, we analyzed PET2 according to visual and ΔSUVmax criteria in a retrospective single-center study. From 2007 to 2010, 59 consecutive patients with a first diagnosis of HL were treated with 4-8 cycles of anthracycline-based chemotherapy. Radiotherapy was performed in 19 responding patients with localized disease. PET was done at baseline (PET0) and after 2 cycles of chemotherapy, and treatment was not modified according to the PET2 result. PET2 was interpreted using the 5-point scale (positivity for score 4 or 5). The SUVmax reduction between PET0 and PET2 (ΔSUVmax) was computed for all patients, and patients with a ΔSUVmax greater than 71% were considered good responders. When the 5-point scale was used, 46 patients (78%) achieved a negative PET2 result, 7 of whom failed treatment (negative predictive value, 85%). Forty-nine patients (83%) had a ΔSUVmax greater than 71%, 6 of whom failed treatment (negative predictive value, 88%). The PET2 positive predictive value was significantly better for ΔSUVmax (70%) than for the 5-point scale (46%). When ΔSUVmax was used, 6 (46%) of the 13 PET2-positive patients could be reclassified as good responders. Although visual PET2 positivity was related to a lower 4-y progression-free survival (45%) compared with PET2 negativity (81%, P < 0.002), ΔSUVmax (>71 vs ≤71%) was more accurate for identifying patients with different 4-y progression-free survivals (82% vs. 30%; P < 0.0001). In multivariate analysis using the international prognosis score and ΔSUVmax as covariates, ΔSUVmax remained the unique independent predictor for progression-free survival (P = 0.0001; relative risk, 8.1). Semiquantitative analysis was more accurate than visual analysis based on the 5-point scale to interpret PET2 and predict the outcome of HL patients. These encouraging results warrant further confirmation in larger and prospective series.

Outcome impact of PIK3CA mutations in HER2-positive breast cancer patients treated with trastuzumab

Background:Phosphatidylinositol 3-kinase (PI3K) pathway activation has been suggested to negatively influence response to anti-HER2 therapy in breast cancer patients. The present study focused on mutations of the PIK3CA gene, encoding one of the two PI3K subunits.Methods:PIK3CA mutations were assessed by direct sequencing in 80 HER2-positive patients treated with 1 year of trastuzumab. All patients preoperatively received four cycles of anthracycline-based chemotherapy, followed by four cycles of docetaxel and 1 year of trastuzumab, starting either before surgery with the first cycle of docetaxel and continuing after surgery (neoadjuvant trastuzumab arm, n=43), or only after surgery (adjuvant trastuzumab arm, n=37).Results:PIK3CA mutations were found in 17 tumours (21.3%). Better disease-free survival (DFS) was observed in patients with PIK3CA wild-type compared with mutated tumours (P=0.0063). By combining PIK3CA status and treatment arms, four separate prognostic groups with significantly different DFS (P=0.0013) were identified.Conclusion:These results confirm that the outcome of HER2-positive patients treated with trastuzumab is significantly worse in patients with PIK3CA-mutated compared with wild-type tumours.

Phosphorylation of AKT pathway proteins is not predictive of benefit of taxane therapy in early breast cancer

Results from the NSABP B-28 trial suggest AKT activation may predict reduced benefit from taxanes following standard anthracycline therapy. Pre-clinical data support a link between PI3 K/AKT signalling and taxane resistance. Using the UK taxotere as adjuvant chemotherapy trial (TACT), we tested the hypothesis that activation of AKT or downstream markers, p70S6K or p90RSK, identifies patients with reduced benefit from taxane chemotherapy. TACT is a multi-centre open-label phase III trial comparing four cycles of standard FEC (fluorouracil, epirubicin, cyclophosphamide) followed by four cycles of docetaxel versus eight cycles of anthracycline-based chemotherapy. Samples from 3,596 patients were available for the current study. We performed immunohistochemical analysis of activation of AKT, p70S6 K and p90RSK. Using a training set with multiple cut-offs for predictive values (10 % increments in expression), we found no evidence for a treatment by marker interaction for pAKT473, pS6 or p90RSK. pAKT473, pS6 and p90RSK expression levels were weakly correlated. A robust, preplanned statistical analysis in the TACT trial found no evidence that pAKT473, pS6 or p90RSK identifies patients deriving reduced benefit from adjuvant docetaxel. This result is consistent with the recent NASBP B28 study where the pAKT473 effect is not statistically significant for the treatment interaction test. Therefore, neither TACT nor NASBP-B28 provides statistically robust evidence of a treatment by marker interaction between pAKT473 and taxane treatment. Alternative methods for selecting patients benefitting from taxanes should be explored.

Abstract 2654: A prospective study of the effects of adjuvant chemotherapy (CT) on cognition and brain function in breast cancer patients

Abstract There is an accumulating body of literature reporting that cognitive deficits, possibly long lasting, including lack of concentration, short-term memory loss and difficulties in multitasking are observed in patients receiving chemotherapy (CT) (“chemobrain”). We have used functional magnetic resonance imaging (fMRI) to determine the nature of the changes in brain function that underlie the cognitive deficits that can result from CT. This research was carried out prospectively in women being treated with adjuvant CT for early-stage breast cancer (BC). Methods: Seven healthy aged-matched control subjects (No CT) and six subjects with BC took part in this study undergoing functional fMRI scanning on a 3.0T scanner prior to initiating CT and after receiving their fourth cycle of anthracycline-based CT. Task activation (n-back) and resting-state functional connectivity (fC) scans were carried out. The N-back letter task is a continuous performance task having 3 levels of increasing cognitive load designed to probe regions of the brain activated by attention and working memory. Resting-state fC measures spontaneous low frequency oscillations in MR signal in brain and is used to create maps of fC among brain regions. Results: There were no significant differences in n-back task performance between the CT group and controls. However, significant differences (p≤0.05) in task activation and fC between the two subjects groups were observed. N-back task activation was significantly greater in the BC group compared with controls in right inferior frontal gyrus and right cerebellum. There were significant interactions between subject group and cognitive load within right inferior parietal and left inferior occipital cortex. The default mode network consists of interconnected regions of the brain that are active while the subjects are at rest and reduce activity when subjects perform specific tasks. Within this network, the BC group has significantly less deactivation during task compared to controls. There were also differences between the groups in resting-state fC. Using the left amygdala as a seed region, changes in fC were seen in the pre-chemo scans of the BC group compared to the controls. The BC subjects showed a 185% increase in intraregional fC and increased fC with the superior temporal gyrus, an area along with the amygdala that is activated by emotional stimuli. These changes in fC may be due to increased stress response in BC subjects. After four sessions of CT the BC group showed significant decreases in fC between the amygdala and the parahippocampal gyrus, an area involved in encoding and retrieving memories. This decrease in functional connectivity along with alterations in brain activation by cognitive tasks may play a part in the memory and other cognitive complaints associated with cancer and CT and may inform the search for strategies to reduce CT associated cognitive dysfunction. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2654. doi:1538-7445.AM2012-2654

Sequential taxane and anthracycline-containing neoadjuvant regimens: The sequential order impact

BackgroundOne can consider as a standard neoadjuvant treatment for breast cancer, the sequence of 4 cycles of anthracycline-based chemotherapy followed by 4 cycles of docetaxel. Based on the belief that the sequence order between anthracycline and taxane might be of interest, this study assessed the impact of the sequence order. MethodsOne hundred and twenty three patients with breast cancer were treated with neoadjuvant chemotherapy in 5 oncologic centers between 2003 and 2007. This study compared 65 patients treated with 4 cycles of docetaxel followed by 4 cycles of anthracycline-based chemotherapy (cohort T), versus another cohort of 58 patients treated with 4 cycles of anthracycline-based chemotherapy followed by 4 cycles of docetaxel (cohort A). ResultsThe overall dose intensity of docetaxel and clinical complete responses were significantly higher in cohort T. No statistically significant differences were observed in terms of conservative surgeries or histological responses. The sequence of chemotherapy did not significantly influence other treatment-related toxicities. Mild neurotoxicity was higher in patients treated in cohort T. Anemias (≥Grade 1) were higher in cohort A (52% versus 81%; p = 0.0008). ConclusionThe present study failed to identify an impact of the sequence of taxane administration on the efficacy. Nevertheless, starting neoadjuvant chemotherapy by taxane reduces the occurrence of anemia. These findings might allow a selection of the sequence order based on the toxicity profile.

Myocardial HER2 expression with 111In-DTPA-trastuzmab scan in patients shortly after anthracycline treatment

3057 Background: The monoclonal antibody trastuzumab, apart from antitumor effect, can induce cardiotoxicity, particularly when combined with anthracyclines. Myocardial HER2 upregulation may serve, transiently, as a compensatory mechanism induced by cardiac stress. Previously we showed in a xenograft model that 111In-DTPA-trastuzumab scintigraphy can detect HER2 positive lesions (Br J Pharmacol 2004;143:99–106) but that myocardial 111In-DTPA-trastuzumab uptake was found in only 1 of 17 anthracycline-pretreated HER2-positive metastatic breast cancer patients (ESMO 2004#50). This low number may be related to the long interval between anthracycline administration (median 11 months) and performed scan in these patients. To evaluate whether myocardial HER2 expression is induced by anthracyclines, we performed 111In-DTPA-trastuzumab scans in patients shortly after anthracycline treatment. Methods: Patients who completed 4–6 cycles of anthracycline-based chemotherapy (&lt; 3 weeks after last dose) underwent gammacamera imaging 48 and 96 h after iv administration of 150 MBq 111In-DTPA-trastuzumab (5mg). Results: 10 anthracycline-treated patients, 8 as adjuvant breast cancer treatment and 2 for metastatic sarcoma have been enrolled. Myocardial 111In-DTPA-trastuzumab uptake was observed in 5/10 anthracycline-treated patients who all were without symptomatic cardiac dysfunction. Conclusions: Shortly after completion of anthracycline treatment myocardial HER2 overexpression was detectable in 50% of the patients. This may be a transient phenomenon. 111In-DTPA-trastuzumab scan after anthracycline treatment prior to adjuvant trastuzumab may identify patients more susceptible for trastuzumab-induced cardiotoxicity. This important observation may add to optimal timing of trastuzumab therapy i.e. when HER2/neu expression in the heart is negative (again). [Table: see text]

Primitive neuroectodermal tumor (PNET) of thyroid

Extra skeletal Ewing’s sarcoma (EES) is rare. EES commonly arises in the soft tissues of trunk or extremities. EES is rare in the region of head and neck; most of those have been documented in nasal cavity, para nasal sinuses and neck. Prognosis and survival statistics have been poor. Our patient was diagnosed to have PNET of thyroid who presented to us with distant metastases after prior surgery and succumbed after 1st cycle of anthracycline-based chemotherapy.