Taxane-based Adjuvant Chemotherapy Research Articles

Patient-Reported Outcomes Between Whole-Breast Plus Regional Irradiation and Whole-Breast Irradiation Only in pN1 Breast Cancer After Breast-Conserving Surgery and Taxane-Based Chemotherapy: A Randomized Phase 3 Clinical Trial (KROG 17-01)

BackgroundThe role of regional node irradiation (RNI) with whole-breast irradiation (WBI) in patients with pN1 breast cancer receiving taxane-based adjuvant chemotherapy is not well defined. The KROG 1701 trial, a phase III, multicenter, non-inferiority study, aimed to compare the disease-free survival between WBI+RNI and WBI alone in this patient cohort. Comprehensive patient-reported outcomes (PROs) collected at multiple time points are reported. MethodsThe trial (NCT03269981) enrolled patients with pN1 breast cancer after breast-conserving surgery and taxane-based adjuvant chemotherapy, allocating them to receive either WBI +RNI or WBI only. PROs were assessed using EORTC QLQ-C30 and QLQ-BR23 modules at baseline, during RT, and at subsequent follow-up intervals of 3-6 months, and annually up to 4years. ResultsFrom April 2017 to December 2021, 840 patients were enrolled; 777 received intervention as assigned, and 750 completed baseline PRO questionnaires (387 in WBI+RNI, 363 in WBI only). All PRO domains showed improvements over time (p<0.001). During RT, the WBI+RNI group reported greater fatigue and nausea. Higher arm symptom scores were observed in the WBI+RNI group 3 months post-treatment (p=0.030). No other significant PRO domain differences, including arm/breast symptoms, were observed between the two groups. ConclusionIn patients with pN1 breast cancer treated with taxane-based chemotherapy, adding RNI to WBI resulted in minor, temporary declines in specific PRO domains, but these differences were not clinically significant. This indicates that overall patient experience between WBI+RNI and WBI is comparable, supporting the safety and patient tolerability of both treatments.

Patient-reported outcomes in N1 breast cancer: A phase III trial comparing whole-breast to whole-breast plus regional irradiation after taxane-based chemotherapy (KROG 1701).

577 Background: Recent randomized trials have highlighted the benefits of regional node irradiation (RNI) in high-risk node-positive or pN1 breast cancer, yet its impact in the context of modern taxane-based adjuvant chemotherapy remains unclear. In this multi-center phase III trial, we study to prove the hypothesis that there is no difference in terms of disease-free survival between standard whole-breast irradiation (WBI) with RNI and WBI alone in pN1 breast cancer patients receiving taxane-based adjuvant chemotherapy. Comprehensive patient-reported outcomes (PROs) collected at multiple time points are now reported. Methods: The KROG 17-01 trial (NCT03269981), a prospective, multicenter, non-inferiority study, randomized patients with pN1 breast cancer after breast-conserving surgery and adjuvant taxane-containing chemotherapy to WBI or WBI+RNI. Both conventional and hypofractionated radiotherapy (RT) were allowed. PROs were assessed using the EORTC QLQ-C30 and QLQ-BR23 modules. All data were collected at baseline, during RT, and at follow-up intervals of 3-6 months, 1, 2, 3, 4, and 5 years post-treatment. Linear mixed models were used to compare PROs between treatment arms. Results: From April 2017 to December 2021, 840 patients were enrolled; 777 received intervention as assigned, and 750 completed baseline PRO questionnaires (387 in WBI+RNI, 363 in WBI). Overall, PRO domains improved over time (p&lt;0.001). During RT, the WBI+RNI group experienced more fatigue, nausea, and vomiting (p&lt;0.05), and reported lower global health (p=0.090) and physical functioning (p=0.049) with borderline significance compared to the WBI group. At 3-6 months post-RT, WBI+RNI group also showed higher arm symptom scores (p=0.030). Apart from these specific timepoints, no significant differences were observed in other PRO domain scores, including arm and breast symptoms, between treatment arms. In addition, there was no significant differences in PRO domains according to RT techniques and fractionation, except for breast symptoms during RT, favoring hypofractionation and intensity-modulated RT. Conclusions: In patients with pN1 breast cancer treated with taxane-based adjuvant chemotherapy, adding RNI was associated with minor, transient declines in specific PRO domains. However, these differences were not clinically significant, indicating comparable overall patient experiences between the two treatment arms. Clinical trial information: NCT03269981 .

Abstract PS16-02: Efficacy and safety of first-line atezolizumab + bevacizumab + paclitaxel in patients with advanced triple-negative breast cancer: the ATRACTIB phase 2 trial

Abstract BACKGROUND Triple-negative breast cancer (TNBC) is an aggressive tumor characterized by poor outcomes and new treatment strategies are urgently required. The programmed cell death-ligand 1 (PD-L1) antibody (Ab) atezolizumab (ATZ) combined with first-line (1L) nab-paclitaxel (nab-PTX) is approved in multiple countries for the treatment of PD-L1-positive patients (pts) with advanced TNBC (aTNBC) based on a significant improvement in progression-free survival (PFS) and a numerically higher and clinically meaningful median overall survival (OS). A synergism between antiangiogenic therapy and immunotherapy (IO)-based strategies has been observed preclinically and in different tumor types, but data in aTNBC is lacking. METHODS ATRACTIB (NCT04408118) is an international, open-label, single-arm, phase 2 trial evaluating the efficacy and safety of 1L ATZ + BVZ + PTX for pts with aTNBC, regardless of their tumors’ PD-L1 status. Adult pts with untreated, unresectable locally advanced/metastatic TNBC were included. Pts who had received (neo)adjuvant taxane-based chemotherapy (CT) and/or IO and/or an antiangiogenic agent had to have had a relapse with a disease-free interval beyond 12 months (mo). Pts received intravenous ATZ 840 mg + BVZ 10 mg/kg on days (D)1 and D15 + PTX 90 mg/m2 on D1, 8, and 15 of every 28-day cycle until disease progression, intolerable toxicity, death, or patient withdrawal. Tumor assessments were performed every 8 weeks for the first 12 mo and every 12 weeks thereafter. Baseline PD-L1 expression was centrally assessed using 22C3 (combined positive score [CPS]) and SP142 (expression on tumor-infiltrating immune cells [ICs]) Abs. The primary endpoint was investigator-assessed PFS by RECIST v.1.1. Key secondary endpoints included OS, objective response rate (ORR), clinical benefit rate (CBR), duration of response (DoR), and safety. Median PFS was analyzed with exponential maximum likelihood estimation (H0: ≤7.0 mo; HA: ≥9.5 mo). We estimated that enrolling 100 pts would provide 80% power at one-sided α nominal level of 5%, assuming a 10% drop-out rate. RESULTS Between October 2020 and May 2022, 100 female pts from 28 centers across 5 European countries were included. Median age was 55.0 years (32.0 - 84.0), 57.0% of pts had visceral disease, 46.0% had ≥3 metastatic sites, and 70.0% had received prior treatment for early BC (taxane-based CT in 87.1% of them). A total of 82 and 85 tumor samples out of 100 pts were available for PD-L1 assessment using 22C3 and SP142 assays, respectively. Most pts had PD-L1-negative tumors (87.8% with 22C3 [CPS &amp;lt; 10] and 97.6% with SP142 [expression on &amp;lt; 1% positive of ICs]). At data cutoff (15th September 2023), 23 pts were still on therapy. With a median follow-up of 16.7 mo (1.1 - 34.1), median PFS was 11.0 mo (95% CI, 9.0 - 13.2). OS data were immature at data cutoff, with 30 events. Estimated 18-month OS was 69.4% (95% CI, 58.4% - 78.1%). ORR was 63.0% (95% CI, 52.8% - 72.4%), CBR was 79.0% (95% CI, 69.7% - 86.5%), and median DoR was 10.0 mo (95% CI, 7.2 - 13.8). Regarding safety, the most common treatment-emergent adverse events (TEAEs) were peripheral neuropathy (68.0%) and fatigue (62.0%). Grade (G) 3/4 treatment-related TEAEs occurred in 47.0% of pts, mainly peripheral neuropathy (13.0%) and neutropenia (12.0%). Any-grade immune-related TEAEs, thrombosis or embolism, and bleeding occurred in 13.0% (5.0%; G≥3), 4.0% (1.0%; G≥3), and 10.0% (0.0%; G≥3) of pts, respectively. There were no drug-related deaths. CONCLUSIONS 1L ATZ + BVZ + PTX demonstrated encouraging anti-tumor activity in aTNBC pts, most of them presenting with PD-L1-negative tumors. Median PFS seems to be much higher compared with that previously reported with other IO-based regimens in a similar patient population. The safety profile was consistent with the known safety data of ATZ and BVZ combined with CT, without significant added toxicity. These results merit further research of this combination for PD-L1-negative aTNBC. Citation Format: Maria Gion, Patricia Cortez-Castedo, Isabel Blancas, Alfonso Cortés, Frederik Marmé, Salvador Blanch, Serafin Morales Murillo, Nieves Díaz, Isabel Calvo-Plaza, Sabela Recalde, Alejandro Martínez-Bueno, Manuel Ruiz-Borrego, Elisenda Llabres, María Teresa Taberner, Michelino de Laurentiis, José Ángel García-Sáenz, Jana Repkova, Antonio Antón, Joseph Gligorov, Susana de la Cruz, Oliver Hoffmann, Jacques Medioni, Melissa Phillips, Miguel Sampayo-Cordero, Daniel Alcalá-López, José Manuel Pérez-García, Antonio Llombart-Cussac, Javier Cortés. Efficacy and safety of first-line atezolizumab + bevacizumab + paclitaxel in patients with advanced triple-negative breast cancer: the ATRACTIB phase 2 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 PS16-02.

Abstract P1-10-18: Impact of Adjuvant Chemoradiation on cardiopulmonary function and Quality of Life in Breast Cancer

Abstract Aims and Objectives – To evaluate the safety of adjuvant chemo-radiation (CTRT) for breast cancer. We report the cardio-pulmonary safety and quality of life outcome of this regimen. Methods – Stage II-III invasive breast cancer patients planned for adjuvant taxane-based chemotherapy and adjuvant radiotherapy (RT) between April 2019 to December 2020 were eligible irrespective of prior neo-adjuvant therapy. Patients received standard 3D conformal radiotherapy (40 Gy in 15 fractions over 3 weeks ± boost for breast conservation) along with the third cycle of adjuvant taxanes in a 3- weekly schedule or the eighth cycle in a weekly schedule. Troponin T, echo cardiography and pulmonary function test were done pre-RT and repeated at 6 months from RT conclusion while quality of life was evaluated pre-RT, at RT conclusion and after 6 months using EORTC QLQ C30 and BR23. Results – Sixty patients were analysed. The median ejection fraction pre and post CTRT was 60% (p=0.177). The median value of Troponin T at baseline was 37 which decreased to 20 post CTRT (p=0.009). Of the 54 patients who underwent the PFT, the functional vital capacity (FCV) was 2.29 litres at baseline which was 2.2 litres post CTRT (p=0.375). No significant difference was seen for forced expiratory volume (FEV) at 1 second (1.86 vs. 1.82: p=0.365), FEV1/FVC (81.5 vs. 81.43; p=0.9) and diffusing capacity for carbon monoxide (DLCO) (88.3 vs. 87.6; p=0.62) at baseline and post CTRT respectively. There was a significant improvement in QOL scores for nausea, vomiting, pain, constipation, loss of appetite and hair loss post RT 6 months. Conclusion- Patients treated with taxane-based adjuvant CTRT had stable cardio-pulmonary profile at 6 months compared to pre-RT. Quality of life scores improved after treatment for most of the domains compared to the pre-RT scores. Table 1. Calculated scores of EORTC QLQ-C30 and BR23 scales for breast cancer patients at baseline, post CTRT and at first follow up of six months. Citation Format: AKANKSHA ANUP, Tabassum Wadasadawala, CARLTON JOHNNY, RAJIV SARIN, RIMA PATHAK, REVATHY KRISHNAMURTHY, Sudeep Gupta, VANI PARMAR, Jaya Ghosh, JYOTI BAJPAI, SEEMA GULIA. Impact of Adjuvant Chemoradiation on cardiopulmonary function and Quality of Life in Breast Cancer [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 P1-10-18.

Abstract P1-12-05: The Impact of Adjuvant Chemotherapy, Including Taxanes, on Breast Cancer-Related Lymphedema Risk

Abstract BACKGROUND: Adjuvant chemotherapy, particularly taxane-based chemotherapies, which are used to treat high-risk breast cancers, has been shown to be efficacious in prolonging overall survival. However, the impact of such therapies on risk of breast cancer-related lymphedema (BCRL) is yet to be fully understood. Available studies have contradictory findings as to whether or not taxanes increase BCRL risk. Unfortunately, methodological flaws, such as not incorporating a preoperative baseline arm volume measurement or utilizing flawed measurement techniques and diagnostic criteria, result in misdiagnosis of the primary outcome of BCRL and it is therefore difficult to draw conclusions from these studies. As such, a more comprehensive understanding of the potential risks associated with these treatment modalities can improve quality of care as patients are better prepared to face a potentially devastating sequela of breast cancer treatment. PURPOSE: The purpose of this study is to determine if chemotherapy administered in the adjuvant setting is an independent risk factor of BCRL, as well as to assess any specific risks of taxane-based chemotherapy on BCRL. METHODS: From 2005 to 2021, 2049 patients treated for breast cancer were enrolled in a prospective BCRL screening trial and screened from preoperative baseline through last follow-up. Screening included objective arm volume measurements via perometry. Chemotherapy data and clinicopathological and demographic characteristics were collected directly from the electronic medical record. Patients who had not received neoadjuvant chemotherapy were eligible for the current study; they were classified based on whether they had received taxane-based chemotherapy, non-taxane chemotherapy only, or no chemotherapy. Relative volume change (RVC) increase ≥10% from preoperative baseline &amp;gt;3 months postoperatively was used to define BCRL. Patients were censored at cancer recurrence or most recent clinic visit. We fit a Cox regression model to estimate adjusted hazard ratios (aHR) for BCRL. The model was adjusted for baseline BMI, axillary lymph node dissection (ALND), regional lymph node radiation (RLNR), age at diagnosis, and smoking history. RESULTS: The eligible cohort included 1759 patients, including 564 (32%) who received taxane-based chemotherapy and 104 (6%) who received non-taxane chemotherapy only. The median follow-up time for the entire cohort was 58 months. 141/1759 (8%) of patients developed BCRL. The median time to develop BCRL was 21 months post-operatively. Compared to no chemotherapy, the aHR associated with taxane-based chemotherapy was 1.04 (95% CI 0.37, 1.8; p = 0.62). Compared to no chemotherapy, the aHR for non-taxane chemotherapy was 0.82 (95% CI 0.67, 1.6; p = 0.86). There was no significant difference between taxane and non-taxane therapies in terms of BCRL risk (p = 0.55). ALND, RLNR, and high BMI remained independent risk factors for BCRL, consistent with the published literature. CONCLUSION: The receipt of adjuvant chemotherapy and specifically adjuvant taxane-based chemotherapy were not associated with increased risk of BCRL in this cohort of 1759 patients at risk of and prospectively screened for BCRL. Citation Format: Amanda W. Jung, Brooke Juhel, Louisa H. Smith, Cheryl L. Brunelle, Elizabeth K. Hausman, Loryn K. Bucci, George E. Naoum, Alphonse G. Taghian. The Impact of Adjuvant Chemotherapy, Including Taxanes, on Breast Cancer-Related Lymphedema Risk [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 P1-12-05.

Prognostic significance of pretreatment 18F-fluorodeoxyglucose positron emission tomography/computed tomography in patients with T2N1 hormone receptor-positive, ERBB2-negative breast cancer who underwent adjuvant chemotherapy.

To determine whether tumor uptake of 18F-fluorodeoxyglucose (18F-FDG) is associated with invasive disease-free survival (IDFS) in patients with hormone receptor (HR)-positive ERBB2-negative early-stage breast cancer treated with adjuvant chemotherapy. This is a single-center cohort study of women with breast cancer who underwent surgery between 2008 and 2015 at Asan Medical Center, Seoul, Korea. Patients were enrolled if they were diagnosed with HR-positive ERBB2-negative breast cancer with histology of invasive ductal carcinoma, had an American Joint Committee on Cancer pathologic tumor stage of T2N1 with 1-3 positive axillary nodes, underwent preoperative 18F-FDG positron emission tomography/computed tomography (PET/CT), and underwent breast cancer surgery followed by anthracycline- or taxane-based adjuvant chemotherapy. The primary outcome measure was IDFS. The maximum standardized uptake value (SUVmax) was dichotomized using a predefined cut-off of 4.14. A total of 129 patients were included. The median follow-up period for IDFS in those without recurrence was 82months (interquartile range, 65-106). Multivariable Cox analysis showed that SUVmax was independently associated with IDFS [adjusted hazard ratio 2.49; 95% confidence interval (CI), 1.06-5.84]. Ten-year IDFS estimates via the Kaplan-Meier method were 0.60 (95% CI, 0.42-0.74) and 0.82 (95% CI, 0.65-0.91) for high and low SUVmax groups, respectively. The overall association between SUVmax and IDFS appeared to be consistent across subgroups divided according to age, progesterone receptor status, histologic grade, or presence of lymphovascular invasion. High SUVmax on preoperative 18F-FDG PET/CT was independently associated with reduced long-term IDFS in T2N1 HR-positive ERBB2-negative breast cancer patients who underwent adjuvant chemotherapy.

A Pilot Study of CONcurrent ChEmotherapy and RadioTherapy in Adjuvant Treatment of Breast Cancer (CONCERT)

<h3>Purpose/Objective(s)</h3> The study hypothesis was that concurrent adjuvant chemoradiation (CTRT) is safe in adjuvant treatment of breast cancer. This was tested in a prospective interventional pilot study with dose-limiting toxicity as the primary endpoint. It also assesses the compliance rate, toxicity rate and short-term disease related outcomes. CTRI/2019/02/017411 <h3>Materials/Methods</h3> Stage II-III invasive breast cancer patients who were planned for adjuvant taxane-based chemotherapy and adjuvant radiotherapy were screened for the study during April 2019 to December 2020. Patients received standard 3D conformal radiotherapy (40 Gy in 15 fractions over 3 weeks ± boost in case of breast conservation) which was started with the third cycle of adjuvant taxanes in a 3-weekly schedule, or with the eighth cycle of adjuvant taxanes in weekly schedule. <h3>Results</h3> Sixty patients were analyzed. Median age of the study cohort was 46 years (28-66 years). Large majority (60%) women were pre-menopausal and had ECOG performance status 0 (95%) 32 patients (54%) had right sided tumors. Patients either underwent breast conservation surgery (48%) or modified radical mastectomy (52%) with axillary sampling in only small proportion of the patients (20%). 59 patients (98%) received all four cycles of anthracycline based chemotherapy (50 in the neoadjuvant setting) All the patients were compliant with taxane based chemotherapy with dose reduction in three patients in view of peripheral neuropathy. All patients completed adjuvant radiotherapy without any treatment interruption either for taxanes or radiotherapy. No dose-limiting toxicity was documented for any patient. Minimal chemotherapy-related toxicities have been reported in the form of 7 patients (11.6%) having Grade I-II fatigue and 8 patients (13.3%) having Grade I-II peripheral neuropathy. Radiotherapy-related toxicity was also minimal. The incidence of grade 0, 1 and 2 dermatitis were 4%, 84% and 12% respectively while grade 0, 1 and 2 dysphagia were 31%, 57 and 12% respectively. There was no difference between weekly and 3-weekly regimens with respect to compliance rate or toxicity. Dermatitis as well as dysphagia subsided completely by 4 weeks post-completion of CTRT. The median duration between first and last cycle of taxanes was 74 days (range 62 to 107) and radiotherapy start and conclusion was 23 days (range 19 to 28). Four patients had recurrence, one had local and distant recurrence and rest had distant recurrence only. At the median follow up of 23 months, median DFS of 17.5 months (9-22 months) and median OS of 26 months (11-33 months). The 3-year actuarial rate of DFS and OS was 75% and 98.3% respectively. <h3>Conclusion</h3> Concurrent taxane-based adjuvant CTRT is safe and feasible alternative to sequential chemotherapy and radiotherapy. There is minimal toxicity and excellent compliance for both 3-weekly as well as weekly schedules. Hence, it will be worthwhile to test concurrent CTRT in randomized setting with health-economics and disease-related endpoints.

Risk Factors Associated with Breast Cancer-Related Lymphedema: A Systematic Review and Meta-Analysis

Background: Lymphedema is a chronic, progressive condition that commonly occurs after treatment for breast cancer. Therefore, this study aimed to assess the incidence and risk factors of breast cancer-related lymphedema (BCRL). Methods: PubMed, Web of Science, Embase, MEDLINE, CNKl, Wang Fang DATA, Vip Database, and SinoMed were searched from January 2000 to January 2022. Risk of bias was assessed using the Newcastle-Ottawa Scale. Estimates of pooled incidence and risk factors estimates were calculated with 95% confidence intervals (CI), with sub-group analyses according to country, study design, population characteristics, the definition of lymphedema, and risk of bias. Heterogeneity was measured using I2 and publication bias was analyzed by funnel plot. Results: 34 studies comprising 23,988 participants were included in this study, with a follow-up period ranging from 1 to 10.2 years. The estimated pooled cumulative incidence at 1,2,3,5 years post-operative for patients respectively was 20%, 17%, 18% and 23%. Factors like: stage III cancer (RR: 1.34; 95% Cl: 1.17-1.52), age≥50 (RR: 1.47; 95% Cl: 1.23-1.76), BMI ≥25 (RR: 2.09; 95% Cl: 1.85-2.36), ALND (RR: 2.72; 95% Cl: 1.89-3.92), axillary radiotherapy (RR: 2.19; 95% Cl: 1.64-2.92), Neo-adjuvant chemotherapy (RR: 1.61; 95% Cl: 1.08-2.39), adjuvant taxane-based chemotherapy (RR: 1.65; 95% Cl: 1.25-2.19) and postoperative wound complications (RR: 1.66; 95% Cl: 1.13- 2.43) were significantly associated with BCRL. Conclusions: Our analyses suggest that BCRL risk is significantly associated with cancer stage, age, BMI, ALND, radiotherapy, chemotherapy, and postoperative wound complications.

Safety interim analysis (SIA) of atractib: A phase 2 trial of first-line (1L) atezolizumab (A) in combination with paclitaxel (P) and bevacizumab (B) in metastatic triple-negative breast cancer (mTNBC).

1084 Background: A substantial benefit from adding an immune checkpoint inhibitor to chemotherapy (CT) was reported in mTNBC patients (pts) with PD-L1+ tumors. However, many pts still have a poor outcome. ATRACTIB is exploring the synergism between A (anti-PD-L1 antibody) and B (a VEGF-targeted antibody) with P in mTNBC irrespective of PD-L1 status. We report results from protocol-specified SIA. Methods: ATRACTIB is an open-label, single-arm, phase 2 trial (NCT04408118). Pts aged ≥18 years, with unresectable locally advanced or mTNBC, ECOG performance status of 0–1, who had received no prior systemic therapy or ≥12 months since (neo)adjuvant taxane-based CT are eligible. Pts receive A (840 mg IV, days 1, 15) with P (90 mg/m2 IV, days 1, 8, 15), and B (10 mg/kg IV, days 1, 15) on each 28-day cycle until disease progression, unacceptable toxicity, or patient withdrawal. Primary endpoint is investigator-assessed progression-free survival (PFS) as per RECIST v.1.1. Secondary endpoints include objective response and clinical benefit rates, overall survival, and safety. The trial was designed to detect a treatment effect in terms of median PFS (H0: ≤7 months; H1: ≥9.5 months) and 100 pts are needed to attain 80% power at a nominal one-sided α level of 5%. One SIA was planned for evaluating safety as per CTCAE v.5.0 on the first 20 pts who had completed a 3-month follow-up or reached the end of study. Results: From Oct 5, 2020, through Nov 21, 2021, 34 pts were enrolled at 13 sites in Spain and Germany and received at least 1 dose of study treatment. Median age was 57.5 (range 40–84) years, 23 (67.6%) pts had received prior CT for early disease, and 19 (56.0%) had visceral disease. At data cutoff (Sep 30, 2021), 25 (71.4%) pts were still receiving the drug regimen. Adverse events (AEs) led to drug discontinuation in 3 (8.8%) pts. Mean relative dose intensity was 90.2% for A, 96.5% for P, and 95.7% for B. P dose reduction was reported in 7 (20.6%) pts. Five (14.7) pts required a dose delay due to AEs (11.8% for A, 11.8% for P, and 8.8% for B). The most common AEs of any grade (G) were fatigue (47.1%; 8.8% G≥3), diarrhea (38.2%; 0% G≥3), and neurotoxicity (35.3%; 8.8% G≥3). Anemia (20.6%; 0% G≥3) and neutropenia (17.6%; 8.8% G≥3) were the most frequent hematological AEs. AEs of clinical interest (AECI) for B were hypertension (17.6%; 5.9% G≥3) and pulmonary embolism (2.9%; 0% G≥3). AECI for A were pneumonitis (2.9%; 0% G≥3), autoimmune hepatitis (2.9%; 2.9% G≥3), and alanine aminotransferase increased (2.9%; 2.9% G≥3). No treatment-related deaths were reported. Conclusions: The addition of A to P and B as 1L therapy for mTNBC shows a tolerable safety profile which is consistent with known safety profile of each agent without a significant synergistic toxicity. Based on the independent data monitoring committee recommendation, patient recruitment is ongoing. Clinical trial information: NCT04408118.

Cost-Effectiveness Analysis of Two Chemotherapy Regiments FAC vs. Taxane for Operable Breast Cancer Patients in Indonesia.

Background:Breast cancer is the deadliest cancer among women worldwide including Indonesia. Both FAC and Taxane-based chemotherapies are often used for patients with early node-positive breast cancer. However, the study regarding the cost-effectiveness of those regiments is still rare. This study aims to analyze the cost-effectiveness of Taxane versus FAC in the Indonesia setting. Methods:Twenty-four patients with stage I-IIIA breast cancer who had received surgery, FAC or Taxane-based adjuvant chemotherapy, and radiation were included in this study. Health-related quality of life was assessed using INA-BCHRQoL. INA-BCHRQoL was mapped to the EuroQoL 5D (EQ-5D) index calculator to get the utility score. All direct cost was retrieved from electronic medical records and hospital information system. Whereas, a questionnaire was designed to collect information about society cost from patients. ICER was counted to summarize the cost-effectiveness of two chemotherapy regiments (Taxane versus FAC). A sensitivity analysis was done to assess the uncertainty result. Results:The results showed there was no significant difference between the score of quality of life and utility in respondents who received FAC chemotherapy and Taxane-based chemotherapy. However, in terms of cost, Taxane was 6.5 times higher than the FAC group per patient for chemotherapy drugs only. Moreover, the total cost of treatments in Taxane-based chemotherapy was approximately 3.7 times more costly than the counterpart in the FAC arm (p=0.000). Taxane-based chemotherapy dominated with ICER IDR 765.213.092 per QALY gained. Overall, FAC was found more cost-effective compared to the Taxane regiment. Conclusion:FAC represents the value of money compared to Taxane-based for breast cancer patients with stage I-IIIA in Indonesia.

FER regulates endosomal recycling and is a predictor for adjuvant taxane benefit in breast cancer.

Elevated expression of non-receptor tyrosine kinase FER is an independent prognosticator that correlates with poor survival of high-grade and basal/triple-negative breast cancer (TNBC) patients. Here, we show that high FER levels are also associated with improved outcomes after adjuvant taxane-based combination chemotherapy in high-risk, HER2-negative patients. In TNBC cells, we observe a causal relation between high FER levels and sensitivity to taxanes. Proteomics and mechanistic studies demonstrate that FER regulates endosomal recycling, a microtubule-dependent process that underpins breast cancer cell invasion. Using chemical genetics, we identify DCTN2 as a FER substrate. Our work indicates that the DCTN2 tyrosine 6 is essential for the development of tubular recycling domains in early endosomes and subsequent propagation of TNBC cell invasion in 3D. In conclusion, we show that high FER expression promotes endosomal recycling and represents a candidate predictive marker for the benefit of adjuvant taxane-containing chemotherapy in high-risk patients, including TNBC patients.

Tumor Glucose and Fatty Acid Metabolism in the Context of Anthracycline and Taxane-Based (Neo)Adjuvant Chemotherapy in Breast Carcinomas.

Breast cancer is characterized by considerable metabolic diversity. A relatively high percentage of patients diagnosed with breast carcinoma do not respond to standard-of-care treatment, and alteration in metabolic pathways nowadays is considered one of the major mechanisms responsible for therapeutic resistance. Consequently, there is an emerging need to understand how metabolism shapes therapy response, therapy resistance and not ultimately to analyze the metabolic changes occurring after different treatment regimens. The most commonly applied neoadjuvant chemotherapy regimens in breast cancer contain an anthracycline (doxorubicin or epirubicin) in combination or sequentially administered with taxanes (paclitaxel or docetaxel). Despite several efforts, drug resistance is still frequent in many types of breast cancer, decreasing patients’ survival. Understanding how tumor cells rapidly rewire their signaling pathways to persist after neoadjuvant cancer treatment have to be analyzed in detail and in a more complex system to enable scientists to design novel treatment strategies that target different aspects of tumor cells and tumor resistance. Tumor heterogeneity, the rapidly changing environmental context, differences in nutrient use among different cell types, the cooperative or competitive relationships between cells pose additional challenges in profound analyzes of metabolic changes in different breast carcinoma subtypes and treatment protocols. Delineating the contribution of metabolic pathways to tumor differentiation, progression, and resistance to different drugs is also the focus of research. The present review discusses the changes in glucose and fatty acid pathways associated with the most frequently applied chemotherapeutic drugs in breast cancer, as well the underlying molecular mechanisms and corresponding novel therapeutic strategies.

Abstract LB203: FER regulates endosomal recycling and is a candidate predictor for taxane benefit in breast cancer

Abstract To this day, targeted treatment options for patients with triple negative metastatic breast cancer (TNBC) are still virtually absent. Previously, we showed that elevated expression of the tyrosine kinase FER is an independent prognosticator that correlates with poor survival of high-grade and basal/TNBC patients. Here, we show that high FER levels are also associated with improved outcome after adjuvant taxane-based combination chemotherapy, in high-risk, HER2-negative patients. In TNBC cells, we observed a causal relation between high FER levels and sensitivity to taxanes. Our proteomics and mechanistic studies demonstrated that FER regulates endosomal recycling, a microtubule-dependent process that underpins breast cancer cell invasion. Using chemical genetics, we identified DCTN2 as a novel FER substrate. Our work indicates that the DCTN2 tyrosine 6 is essential for tubular recycling domains development in early endosomes and subsequent propagation of TNBC cell invasion in 3D. In conclusion, we show that high FER expression promotes endosomal recycling and represents a candidate predictive marker for benefit of adjuvant taxane-containing chemotherapy in high-risk patients, including TNBC patients. Citation Format: Sandra Tavares, Nalan Liv, Milena Pasolli, Mark Opdam, Max Ratze, Manuel Saornil, Lilian Sluimer, Rutger Hengeveld, Robert van Es, Erik van Werkhoven, Harmjan Vos, Holger Rehmann, Boudewijn Burgering, Hendrika Oosterkamp, Susanne Lens, Judith Klumperman, Sabine Linn, Patrick Derksen. FER regulates endosomal recycling and is a candidate predictor for taxane benefit in breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr LB203.

Four Cycles of Docetaxel-Cyclophosphamide versus Anthracycline-Taxane as Adjuvant Chemotherapy for HER2-Negative, Axillary Lymph Node Negative Breast Cancer: A Real-World Comparison of Alberta Patients Treated 2008-2012.

Uncertainty exists around the need to include an anthracycline if taxane-based adjuvant chemotherapy is being used for human epidermal growth factor receptor-2 (HER2) negative and axillary lymph node negative (LNN) breast cancer. We identified all patients who were diagnosed with HER2-negative, LNN breast cancer treated with docetaxel-cyclophosphamide for four cycles (DC4) or an anthracycline-taxane (AT) regimen following surgical resection in Alberta from 2008 through 2012. We used propensity score methods to match each patient treated with AT to up to four patients treated with DC4 on potentially confounding clinicopathologic and treatment variables. We compared the 10-year invasive disease free survival (iDFS), breast cancer specific-survival (BCSS) and overall survival (OS) and assessed the effect of the type of adjuvant chemotherapy on these outcomes using Cox regression. Of the 726 eligible patients, 657 (90.5%) were treated with DC4 and 69 (9.5%) were treated with AT. Matching created a group of 202 women treated with DC4 and eliminated differences in clinicopathologic and treatment factors. There was no statistically significant difference for the treatment effects of matched DC4 patients compared to the AT patients on iDFS (75.7% vs. 76.8%, p = 0.75; hazard ratio (HR) = 1.05, 95% CI = 0.65 to 1.8), BCSS (88.1% vs. 87%, p = 0.8; HR = 0.91, 95% CI = 0.42 to 1.9), or OS (87.1% vs. 86.9%, p= 0.96; HR = 0.98, 95% CI = 0.46 to 2.1). Four cycles of DC as compared with an AT regimen yielded similar 10-year iDFS, BCSS and OS amongst patients with HER2-negative, LNN breast cancer.

Should MMMT still be treated with adjuvant taxane-based combination chemotherapy?

BackgroundMalignant mixed Mullerian tumors of endometrial (MMMT-E) and ovarian (MMMT-O) origin are associated with poor prognosis. Suggestively epithelial-driven tumors, their treatment has shifted from anthracycline or ifosfamide-based towards taxane-based chemotherapy. It remains unclear whether this change associates with better outcomes.Patients and methodsA conjoined Australian and Swiss patient cohort of MMMT-E (N = 103) and MMMT-O (N = 17) was compared to patients with adenocarcinoma of the endometrium (EC, N = 172) and ovary (OC, N = 189). Clinicopathological characteristics, FIGO stage, first-line treatment, and patient outcomes were analyzed. The generated hypothesis was verified in an US-American cohort with high-grade serous ovarian cancer (HGSOC, N = 1290) and MMMT-O (N = 450) using immunohistochemistry and next-generation sequencing.ResultsEarly stage I/II MMMT-E showed a survival plateau after 2.5 years, with no recurrence or death observed afterwards. Relapse-free survival was significantly worse in MMMT-E treated with platinum/taxanes (P = 0.024) compared to non-taxane regimen. Hypothesizing that also MMMT-O might benefit from an adjuvant non-paclitaxel regimen, a second independent cohort of MMMT-O and HGSOC patients was examined. p53 mutations dominated in both cancers with comparable frequency. PI3KCA and KRAS mutations were less frequent: they were more frequent in MMMT-O than in HGSOC (P = 0.015 and P = 0.018, respectively). MMMT-O responded better to a combination of carboplatin with anthracyclines than with taxanes (73.9% vs. 39.4%).ConclusionEarly stage I/II MMMT-E patients have excellent prognosis if no recurrence has appeared within the first 2.5 years. In MMMT-E, platinum/anthracycline or ifosfamide regimen associated with better outcomes than platinum/taxanes regimens. This might also apply to MMMT-O.

The taxane-based chemotherapy triplet is superior to the doublet in one to nine node-positive but not node-negative triple-negative breast cancer: results from a retrospective analysis.

Background: Taxane-based regimens that are frequently used in adjuvant chemotherapy in early triple-negative breast cancer (TNBC) include a three-drug regimen (TAC and AC-T) and a two-drug regimen (TA and TC). Whether pathological lymph node stage guides taxane-based de-escalating chemotherapies in TNBC in adjuvant setting is still unclear.Methods: We retrospectively examined 381 patients with early TNBC over a median follow-up period of 75.9 months and compared the disease-free survival (DFS) and overall survival (OS) of patients who received adjuvant taxane-based three-drug chemotherapy and two-drug chemotherapy according to pathological lymph node stage (negative, pN0; 1-3 positive, pN1; 4-9 positive, pN2).Results: In 222 pN0 patients, the taxane-based three-drug regimen was not superior to the two-drug regimen. In 159 pN1-2 patients, the taxane-based three-drug regimen significantly improved DFS (5-year DFS rate, 78.2% vs. 46.9%; log-rank p=0.0002) and OS (5-year OS rate, 90.7% vs. 64.3%; log-rank p=0.0001) compared with the two-drug regimen. In a multivariable Cox regression analysis of pN1-2 patients, after adjustment for clinical characteristics, the taxane-based three-drug regimen significantly decreased the risk of recurrence (adjusted HR, 0.37; 95% CI, 0.22 to 0.64; p=0.0004) and death (adjusted HR, 0.22; 95% CI, 0.10 to 0.48; p=0.0001) compared with the two-drug regimen.Conclusions: The taxane-based chemotherapy triplet is superior to the chemotherapy doublet in patients with one to nine positive lymph nodes but not node-negative TNBC in adjuvant setting. These data suggest that pathological lymph node stage leads to de-escalating chemotherapy strategies in operable TNBC patients.

Prospective Long-Term Follow-Up of Pulmonary Diffusion Capacity Reduction Caused by Dose-Dense Chemotherapy in Patients with Breast Cancer.

Background Our previous study of pulmonary function in 34 patients with early breast cancer without preexisting lung disease showed that anthracycline- and taxane-based adjuvant dose-dense chemotherapy (DDC) caused a significant 16.4% mean reduction in carbon monoxide diffusing capacity (DLCO). The present study reports the pulmonary and oncological outcomes of these patients on long-term follow-up. Patients and methods The primary endpoint was DLCO measured by the pulmonary function test (PFT) performed at a median of 27 months after DDC (range, 8–97) in 25 patients without disease recurrence. DLCO values were recorded as a percentage of predicted values according to age, height, and hemoglobin level and analyzed relative to baseline pre-DDC DLCO values. The secondary endpoints were symptoms, additional therapies, and cancer outcomes during a median of 11 years' follow-up (range, 4.4–11.4). Results A longitudinal general linear model showed significant effects of time on DLCO and its trend (F(1, 87) = 14.68, p < 0.001 and F(1, 87) = 10.26, p=0.002, respectively). Complementary descriptive analysis showed a significant recovery on the follow-up PFT (75.6% vs. 81.9%, p=0.002), but it was still significantly lower than the baseline DLCO (81.9% vs. 92.0%, p=0.003). Five patients (20%) still showed a >20% relative DLCO reduction from baseline. Patients with dyspnea or fatigue at later clinical follow-up had a significantly lower DLCO value on the follow-up PFT than nonsymptomatic patients (80.5% vs. 92.1%, p=0.02). DLCO recovery was inversely correlated with age (R = −0.39, p=0.05), but no significant correlation was found with the length of time until the follow-up PFT or additional therapies. There was no association of DDC-related DLCO reduction with cancer outcomes. Conclusions The significant reduction in DLCO seen after DDC in patients with potentially curable breast cancer is evident years afterwards, especially in older patients. While most patients partly recover, some will have a lasting symptomatic DLCO impairment.

Abstract 3284: Adiposity, muscle mass and delays and dose reductions on adjuvant, taxane-based chemotherapy for breast cancer

Abstract Introduction: Low muscle mass and excess adiposity are thought to increase the risk of chemotherapy toxicity, leading to dose reductions or delays. Yet, few studies of body composition and chemotherapy examine patients with breast cancer; prior studies have been small and looked mainly at toxicities. Here, we evaluate whether adiposity or muscle mass and radiodensity (a measure of intramyocellular lipid accumulation) are associated with risk of dose reductions or delays among nonmetastatic breast cancer patients receiving adjuvant taxane-based chemotherapy, and whether dose reductions are associated with cancer-specific survival. Methods: Our study included 1,403 patients with stage II-III breast cancer receiving taxane-based chemotherapy at Kaiser Permanente. We evaluated body composition from clinically-acquired CT scans at diagnosis. We defined dose reductions from infusion records as relative dose intensities &amp;lt;0.85 (delivered v. planned dose) while on taxane therapy, and dose delays as treatments received more than 3 days later than scheduled. We defined neuropathy from diagnosis codes and hematologic toxicities from laboratory values during chemotherapy. Logistic regression models adjusted for age and dosing body surface area (BSA). Cox proportional hazards models for cancer-specific survival adjusted for age, BSA, body composition and tumor characteristics. Results: Mean (standard deviation [SD]) age at diagnosis was 53 (10) years. Higher visceral adiposity was associated with a 20% increased risk of dose reductions and a 17% increased risk of dose delays on taxane-based chemotherapy (odds ratios of 1.20; 95%CI:1.02-1.42 and 1.17; 95%CI:0.99-1.39 per SD, respectively). Higher muscle radiodensity (indicating lower intramyocellular lipid infiltration, i.e., leaner muscle) was associated with a 13% lower risk of dose reductions and a 16% lower risk of dose delays (odds ratios of 0.87; 95%CI:0.75-1.00 and 0.84; 95%CI:0.72-0.98 per SD, respectively). Muscle mass and subcutaneous adiposity were not associated with dose reductions or delays, though lower muscle mass did increase risk of hematologic toxicity. Women who experienced dose reductions on taxane-based chemotherapy had a 37% increased risk of dying from breast cancer relative to those with higher relative dose intensities (hazard ratio 1.37; 95%CI:1.01-1.85; median follow-up 6 years, 203 breast cancer deaths). Conclusions: Excess visceral adiposity and lower muscle radiodensity were associated with dose reductions and delays among breast cancer patients receiving taxane-based chemotherapy, reducing the efficacy of these life-saving therapies: women who experienced dose reductions were at higher risk of dying from breast cancer. Body composition information assessed from clinically-acquired CT scans may help identify patients for supportive interventions to mitigate toxicity. Citation Format: Elizabeth M. Cespedes Feliciano, Valerie Lee, Wendy Y. Chen, Carla M. Prado, Shlomit S. Shachar, Stacey Alexeeff, Bette J. Caan. Adiposity, muscle mass and delays and dose reductions on adjuvant, taxane-based chemotherapy for breast cancer [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 3284.

Clinical Significance of Lymph-Node Ratio in Determining Supraclavicular Lymph-Node Radiation Therapy in pN1 Breast Cancer Patients Who Received Breast-Conserving Treatment (KROG 14-18): A Multicenter Study.

This study evaluated the clinical significance of the lymph-node ratio (LNR) and its usefulness as an indicator of supraclavicular lymph-node radiation therapy (SCNRT) in pN1 breast cancer patients with disease-free survival (DFS) outcomes. We retrospectively analyzed the clinical data of patients with pN1 breast cancer who underwent partial mastectomy and taxane-based sequential adjuvant chemotherapy with postoperative radiation therapy in 12 hospitals (n = 1121). We compared their DFS according to LNR, with a cut-off value of 0.10. The median follow-up period was 66 months (range, 3–112). Treatment failed in 73 patients (6.5%) and there was no significant difference in DFS between the SCNRT group and non-SCNRT group. High LNR (>0.10) showed significantly worse DFS in both univariate and multivariate analyses (0.010 and 0.033, respectively). In a subgroup analysis, the effect of SCNRT on DFS differed significantly among patients with LNR > 0.10 (p = 0.013). High LNR can be used as an independent prognostic factor for pN1 breast cancer patients treated with partial mastectomy and postoperative radiotherapy. It may also be useful in deciding whether to perform SCNRT to improve DFS.

Abstract OT2-04-02: A phase 3 study of post-lumpectomy radiotherapy to whole breast + regional lymph nodes vs whole breast alone for patients with pN1 breast cancer treated with taxane-based chemotherapy (KROG 1701): Trial in progress

Abstract Background In patients with early stage breast cancer, regional nodal irradiation (RNI) is added to whole breast irradiation (WBI) in order to control microscopic regional disease and to prevent systemic spread of cancer. According to recent randomized trials (MA.20 and EORTC 22922-10925), prophylactic RNI was associated with improvement in disease-free survival (DFS) in the patients with high-risk node negative or pN1 breast cancer. However, systemic agents now known to improve loco-regional control, such as taxane or endocrine therapy, were prescribed to a small percentage of patients in the studies. The benefit of RNI found in the previous studies might be attributed to incorporation of less effective systemic treatments. The impact of prophylactic RNI in pN1 breast cancer should be evaluated in the patients receiving modern systemic treatment. The current study was conducted to compare the effect of post-lumpectomy WBI vs WBI plus RNI on DFS in pN1 breast cancer patients who received adjuvant taxane-based chemotherapy. Methods This study is a multicenter, phase 3, randomized controlled non-inferiority trial (NCT03269981). Eligibility criteria are ≥ 20 years female; pathologically proven invasive carcinoma of the breast; one to three positive axillary lymph nodes (pN1) in pathologic specimen; receiving breast-conserving surgery followed by taxane-based chemotherapy; having adjuvant endocrine therapy or anti-HER2 treatment according to molecular subtype of tumor. Patients are randomly assigned in a 1:1 ratio to receive WBI or WBI plus RNI. Patient randomization was stratified by molecular subtype of tumor (i.e. luminal A/luminal B/luminal HER2/HER2-enriched/triple-negative) and methods of axillary management (i.e. sentinel lymph node biopsy/axillary lymph node dissection). The primary outcome is DFS. The secondary outcomes include DFS according to molecular subtype, treatment-related toxicity, and patient's quality of life per EORTC QLQ-C30 and QLQ-BR23. Patients will be followed for survival and disease recurrence for seven years. A total of 1,926 patients are planned to be enrolled, with recruitment initiated in April 2017. As of June 2018, a total of 236 patients were enrolled. Acknowledgement This study was supported by a grant from the National R&amp;D Program for Cancer Control, Ministry of Health &amp; Welfare, Republic of Korea (grant number: HA17C0043010018). Citation Format: Kim H, Park W, Choi DH, Ahn SJ, Kim SS, Kim ES, Lee JH, Lee KC, Kim JH, Lee H-S, Kim JH, Kim MY, Park HJ, Kim K, Song SH, Kwon J, Lee IJ, Kim TH, Kim TG, Chang AR, Cho O, Jeong BK, Ha B, Lee J, Ki Y. A phase 3 study of post-lumpectomy radiotherapy to whole breast + regional lymph nodes vs whole breast alone for patients with pN1 breast cancer treated with taxane-based chemotherapy (KROG 1701): Trial in progress [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 OT2-04-02.