Non-anthracycline Chemotherapy Research Articles

Abstract PO5-01-02: A retrospective review of pathological complete response and toxicity rates to a modified version of TCHP (Paclitaxel, Trastuzumab, Pertuzumab, Carboplatin) for HER2 positive breast cancer stage II and III

Abstract Background In 2018 the TRAIN-2 clinical trial demonstrated that in stage II–III HER2-positive breast cancer, the use of a neoadjuvant non-anthracycline chemotherapy regimen of 9 cycles of TCHP [paclitaxel and carboplatin (AUC 6 mg/mL/min) with trastuzumab and pertuzumab resulted in lower toxicity and comparable pathological complete responses to an anthracycline based regimen. A pathological complete response was recorded in 141 (67%) of 212 patients in the anthracycline group and in 140 (68%) of 206 in the non-anthracycline group. Our primary aim was to identify rates of pathological complete response and rates of toxicity with a less intensive regimen of 6 cycles of TCHP where carboplatin was dose adjusted to AUC5. Methods In this single center cohort study, we reviewed patients with stage II-III Her2-positive breast cancer who received a modified chemotherapy regimen of 6 cycles of neoadjuvant paclitaxel (80 mg/m2 days 1 and 8) and reduced dose of carboplatin (AUC= 5 mg/mL/min) with trastuzumab (6 mg/kg; loading dose 8 mg/kg) and pertuzumab (420 mg intravenously; loading dose 840 mg) every 3 weeks from 2021- June 2023. Clinicopathologic data, the number and length of treatment delays, treatment related toxicities of all grades, and pCR rate were extracted from the electronic medical record. Results 32 patients were included in the analysis. The median age of the cohort was 51 years (30-65). No patient had a BRCA mutation. 20 (62.5%) had T1-2 disease and 12 (37.5%) had T3-4 disease. 14(43.75%) patients had N0 disease and 20 (62.5%) had N1-3 disease. ECOG Performance status was 0, 1 and 2 in 26 patients (81.25%), 4 (12.5%) patients and 2(6.25%) patients respectively. At the time of analysis, 2 patients (6.25%) were continuing active treatment, while 30 (93.75%) had completed planned neoadjuvant therapy and underwent surgery. Of patients who completed planned neoadjuvant therapy, 6 patients (18.75%) had 1 or more hospitalisations due to toxicity. 10 patients (31.25%) required dose reductions and 3(9.38%) had early treatment discontinuation. Rates of adverse events will be presented. pCR rate was 60 % (N=18/30). 19 (63%) of 30 patients underwent mastectomy and 11 (36.7%) underwent breast-conserving surgery. Updated analysis will be included at time of presentation. Conclusion In this single-center retrospective study of patients receiving a modified version of TCHP we found a 60% pCR rate. The rate of dose reductions and treatment discontinuations appears favorable with use of this modified regimen. This was in a heterogeneous population of patients treated in routine clinical practice where there was a high rate of patients with locally advanced disease. Limitations of our study include immaturity of data and small sample size; however, these data warrant further exploration through longer-term follow-up and multi-center validation. Citation Format: Carolyn Moloney, Maggie Louise O'Connor, Caroline O'Leary, Aislinn Reilly, Simon Barry, David O'Reilly, Philip Bredin, Hadia Paryani, David Solaligue, Bryan Hennessy, Megan Greally, Patrick G. Morris. A retrospective review of pathological complete response and toxicity rates to a modified version of TCHP (Paclitaxel, Trastuzumab, Pertuzumab, Carboplatin) for HER2 positive breast cancer stage II and III [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 PO5-01-02.

Abstract PO2-16-08: Adjuvant Treatment Selection for County-Level Patients with HR+/HER2- Early Breast Cancer in a Real-Life Setting in China

Abstract Background: CHASE001 (NCT05544123), a prospective, non-interventional multicenter study exploring real-world treatment and referral behavior of Chinese county patients (pts) with HER2+ or HR+/HER2– breast cancer is ongoing since September 2022. A prespecified interim analysis (IA) on 750 HER2+ and HR+/HER2- early breast cancer (eBC) was reported at the ESMO Congress 2023. In the 2nd IA from CHASE001, adjuvant treatment selection for patients with HR+/HER2- eBC will be evaluated. Methods: The study was designed to enroll 2500 pts, including four cohorts (HER2+ eBC, HR+/HER2-eBC, HER2+ advanced BC, and HR+/HER2- aBC). In this IA, HR+/HER2- eBC pts after surgery were included. Descriptive statistics reported patient demographics, clinical and disease characteristics and treatment patterns. To investigate the factors associated with chemotherapy-free regimen, non-anthracycline chemotherapy regimen and ovarian function suppression (OFS), univariate and multivariate logistic regression analyses were conducted. Results: At data cutoff (May 17, 2023), 697 HR+/HER2- eBC pts (median age 52 years, 45.77% pT2, 50.93% pN0, 56.10% G2) were included from 26 institutions in China county areas, 338 (48.49%) were premenopausal. 584 (83.79%) received adjuvant chemotherapy, with a few (47/584, 8.05%) initially developing their treatment plan at a higher level hospital (national or provincial tertiary hospital). AC-T (309/584, 52.91%) was the most commonly used regimen. 181 (30.99%) pts received non-anthracycline chemotherapy regimen (mainly TC), and pts with N0, age≥65 years and ki67 < 20% had the strongest association to this regimen (multivariate OR=0.082, 95%CI [0.037,0.179], OR=0.463, 95%CI [0.250,0.859], and OR=0.642, 95%CI [0.418,0.985], respectively). Interestingly, on univariate analysis pts initially diagnosed in a higher level hospital were significantly associated with non-anthracycline regimen (P=0.0109), however on multivariate analysis it was no longer significant. 483 pts received endocrine therapy, including 234 (48.45%) premenopausal pts. The most commonly used endocrine regimen for premenopausal pts was OFS/OFS+ (122/234, 52.14%) ,of which half (61, 50%) were prescribed OFS+TAM/TOR; followed by TAM/TOR monotherapy (69/234, 29.49%). The proportions of patients classified as low, intermediate, and high clinical risk for recurrence (investigator assessed)were 33.62%, 42.67% and 23.71%. The OFS rate were 39.74% in low, 61.62% in intermediate and 70.91% in high risk pts, respectively. Multivariable analyses found that high clinical risk, age < 45 years and ki67 < 20% were strongly associated with the use of OFS (OR=0.210, 95%CI [0.066,0.674], OR=0.327, 95%CI [0.165,0.649], and OR=0.405, 95%CI [0.194,0.845], respectively). For postmenopausal pts, AI monotherapy (84.74%) was the most commonly used endocrine regimen. Conclusions: To our knowledge, this is the first real-world study evaluating the treatment patterns and referral behavior of BC pts in China counties. The 2nd IA results presented showed the current systemic adjuvant treatment preferences and influence factors from a large sample of HR+/HER2- eBC pts in China counties, which were generally consistent with China BC treatment guidelines. Table 1. Utilization of adjuvant systemic therapy regimens in 697 HR+/HER2− eBC pts, China counties AC-T: (dd)doxorubicin/epirubicin, cyclophosphamide, followed by (dd)paclitaxel/docetaxel; TC: paclitaxel/docetaxel, cyclophosphamide; AC: doxorubicin/epirubicin, cyclophosphamide; TAC: docetaxel, doxorubicin/epirubicin, cyclophosphamide; TAM: tamoxifen; OFS: ovarian function suppression; AI: aromatase inhibitors; TOR: toremifene; CDK4/6i: cyclin-dependent kinase 4/6 inhibitors; “Other” category includes various therapies used in <1% of patients each Citation Format: Yinghua Ji, Honglan Qu, Feidu Zhou, Juan Wang, Qianfu Wu, Guohua Dai, Mengyou Liu, Wenbo He, Wei Liang, Qiuli Meng, Yun Ren, Guoxiang Luo, Hongjian Wang, Hui Liu, Zien Qin, Yingguo Tian, Huali Tang, Hongmei Liu, Jun Luo, Zengfeng Yu, Guinv Hu, Jianzhi Gao, Xiang Tan, Yi Liu, Yuanjiang Zhang, Ming Wang, Min Zhang, Ping Lu. Adjuvant Treatment Selection for County-Level Patients with HR+/HER2- Early Breast Cancer in a Real-Life Setting in China [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 PO2-16-08.

Abstract LBO1-03: Randomized Phase II Study of Neoadjuvant Nivolumab (N) 2 week lead-in followed by 12 weeks of concurrent N+carboplatin plus paclitaxel (CbP) vs concurrent N+CbP in Triple Negative Breast Cancer (TNBC): (BCT1902/IBCSG 61-20 Neo-N)

Abstract Background: A previous clinical study suggested that a priming dose of programmed cell death ligand 1 (PD-L1) inhibitor monotherapy 2 weeks prior to addition of chemotherapy could be more efficacious than starting all agents concurrently. Furthermore, the addition of checkpoint therapy may allow shorter chemotherapy duration in selected patients. The aim of this study was to investigate the strategies of lead-in Nivolumab (N) monotherapy and starting concurrent N with 12 weeks of carboplatin and paclitaxel in TNBC. Methods: In this multicenter Phase II study, eligible patients with stage I (cT1c)-II TNBC were randomized to receive either Arm A (lead-in): N 240 mg monotherapy, followed 2 weeks later by N 360mg + carboplatin (AUC 5) every 21 days x 4 cycles + weekly paclitaxel (80 mg/m2) for 12 weeks; or Arm B (concurrent): same agents initiated concurrently given over 12 weeks, followed 2 weeks later by N 240mg monotherapy, prior to surgery. The primary endpoint was pathological complete response (pCR ypT0/Tis ypN0). Secondary endpoints are residual cancer burden (RCB), safety, response according to baseline stromal tumor infiltrating lymphocytes (sTILs) quantity and PD-L1 expression and event-free survival (EFS). sTIL high was defined as ≥30% and PD-L1 positive as ≥1% (SP142 assay). A non-comparative Simon two-stage design was used to test the null hypothesis, in each Arm separately, of a pCR rate ≤40% vs an alternative pCR rate of ≥60% with 90% Confidence Intervals (CI). No adjuvant N was given, and adjuvant chemotherapy was at the discretion of the investigator in case of non-pCR. Results: 110 patients were randomized from July 2020 to April 2022; 108 patients who initiated treatment were analyzed. Baseline characteristics: median age was 49yrs (IQR 43-60yrs), 16.7% had node-positive disease, 34.3/64.8% had stage I/II disease, 33.3% were sTIL high and 47.2% were PD-L1 positive. For Arms A and B respectively, pCR rates were 50.9% (90% CI:39.0-63.2) and 54.5% (90% CI:42.7-66.2) with an overall pCR rate of 52.8% (90% CI:44.4-61.0). The RCB 0+1 rates were overall 68.5% (90% CI: 60.4-75.9); with 64.2% (90% CI: 52.0-75.1) and 72.7% (90% CI: 61.2-82.4) for Arms A and B respectively. Overall, in the sTIL high vs low subgroups, pCR was 66.7% (CI: 51.7-79.5) vs 45.7% (CI: 35.5-56.2%), and in the PD-L1 positive vs negative subgroups, pCR was 70.6% (CI: 58.4-80.9) vs 33.3% (CI: 21.8-46.6) respectively. pCR was 48.6% in stage I and 54.9% in stage II. Treatment-related adverse events were similar in both arms, with grade 3-4 adverse events in 64.8% patients. Early discontinuation of N occurred in 17 patients (15.7%). Immune related endocrine dysfunction (any grade) was observed in 22 patients (20.4%). Conclusion: The pCR rates exceeding 50% support that 12 weeks of a neoadjuvant non-anthracycline chemotherapy regimen with nivolumab is efficacious for Stage I/II TNBC with either concurrent or lead-in N. This study did not support the hypothesis that lead-in N was associated with a pCR advantage. The regimen was well tolerated, with no new safety signals. Patients with immune enriched tumors, identified by high sTILs or PD-L1 positivity, had very high pCR rates, identifying a subpopulation for whom a 12 week anthracycline-free chemotherapy regimen with N may be appropriate. EFS results are still maturing. Citation Format: Sherene Loi, Samuel Niman, Nicholas Zdenkowski, Prudence Francis, Sally Baron Hay, William Fox, Kevin Punie, Alexander M Menzies, Rebecca Angus, Carlie Mavin, Lauren Rennie, Isobel Stoodley, Bruce Mann, Marion JJ Kuper-Hommel, Meredith Regan. Randomized Phase II Study of Neoadjuvant Nivolumab (N) 2 week lead-in followed by 12 weeks of concurrent N+carboplatin plus paclitaxel (CbP) vs concurrent N+CbP in Triple Negative Breast Cancer (TNBC): (BCT1902/IBCSG 61-20 Neo-N) [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr LBO1-03.

Predicting Patterns of Distant Metastasis in Breast Cancer Patients following Local Regional Therapy Using Machine Learning.

Up to 30% of breast cancer (BC) patients will develop distant metastases (DM), for which there is no cure. Here, statistical and machine learning (ML) models were developed to estimate the risk of site-specific DM following local-regional therapy. This retrospective study cohort included 175 patients diagnosed with invasive BC who later developed DM. Clinicopathological information was collected for analysis. Outcome variables were the first site of metastasis (brain, bone or visceral) and the time interval (months) to developing DM. Multivariate statistical analysis and ML-based multivariable gradient boosting machines identified factors associated with these outcomes. Machine learning models predicted the site of DM, demonstrating an area under the curve of 0.74, 0.75, and 0.73 for brain, bone and visceral sites, respectively. Overall, most patients (57%) developed bone metastases, with increased odds associated with estrogen receptor (ER) positivity. Human epidermal growth factor receptor-2 (HER2) positivity and non-anthracycline chemotherapy regimens were associated with a decreased risk of bone DM, while brain metastasis was associated with ER-negativity. Furthermore, non-anthracycline chemotherapy alone was a significant predictor of visceral metastasis. Here, clinicopathologic and treatment variables used in ML prediction models predict the first site of metastasis in BC. Further validation may guide focused patient-specific surveillance practices.

Pathological complete response and survival of HER2-positive invasive breast cancer following docetaxel, carboplatin, and trastuzumab neoadjuvant therapy: a Vietnamese experience

Introduction. Neoadjuvant chemotherapy for HER2-positive breast cancer consists of a chemotherapy regimen plus trastuzumab with or without pertuzumab. The use of trastuzumab has been shown to improve pathological complete response (pCR), disease-free survival (DFS), and overall survival (OS). Purposes: To evaluate the efficacy and safety of neoadjuvant docetaxel, carboplatin, and trastuzumab (TCH) in the treatment of HER2-positive breast cancer in Vietnamese patients. Material and methods. This retrospective study reviewed stage II–III HER2-positive breast cancer patients who received neoadjuvant docetaxel, carboplatin, and trastuzumab (TCH) at the Vietnamese National Cancer Hospital. The primary endpoint was the pCR rate which was defined as the absence of invasive tumor in the breast and axillary nodes (ypT0/is, ypN0). The secondary endpoints were DFS, OS, and toxicities. Results. The complete and partial clinical response of 51 patients were 33.3% and 58.8%, respectively. The pCR rate was 41.2%; there was a significantly higher response in cT1-2 patients compared to cT3-4 ones (61.1% vs. 39.3%, p = 0.033). Three-year estimated DFS and OS rates were 81.3% and 93.0%, respectively. Treatment was generally well tolerated. Grade 3/4 neutropenia and anemia were uncommon (21.6% and 7.8%). No symptomatic cardiac dysfunction occurred. Conclusions. Neoadjuvant TCH, non-anthracycline chemotherapy with single anti-HER2 regimen achieved high efficacy, with a good pCR rate and favorable tolerability in stage II or III HER2-positive breast cancer patients.

Anthracycline-containing and taxane-containing chemotherapy for early-stage operable breast cancer: a patient-level meta-analysis of 100 000 women from 86 randomised trials

Anthracycline-taxane chemotherapy for early-stage breast cancer substantially improves survival compared with no chemotherapy. However, concerns about short-term and long-term side-effects of anthracyclines have led to increased use of taxane chemotherapy without anthracycline, which could compromise efficacy. We aimed to better characterise the benefits and risks of including anthracycline, and the comparative benefits of different anthracycline-taxane regimens. We did an individual patient-level meta-analysis of randomised trials comparing taxane regimens with versus without anthracycline, and updated our previous meta-analysis of anthracycline regimens with versus without taxane, as well as analysing 44 trials in six related comparisons. We searched databases, including MEDLINE, Embase, the Cochrane Library, and meeting abstracts to identify trials assessing anthracycline and taxane chemotherapy. Adjuvant or neoadjuvant trials were eligible if they began before Jan 1, 2012. Primary outcomes were breast cancer recurrence and cause-specific mortality. Log-rank analyses yielded first-event rate ratios (RRs) and CIs. 28 trials of taxane regimens with or without anthracycline were identified, of which 23 were deemed eligible, and 15 provided data on 18 103 women. Across all 15 trials that provided individual data, recurrence rates were 14% lower on average (RR 0·86, 95% CI 0·79-0·93; p=0·0004) with taxane regimens including anthracycline than those without. Non-breast cancer deaths were not increased but there was one additional acute myeloid leukaemia case per 700 women treated. The clearest reductions in recurrence were found when anthracycline was added concurrently to docetaxel plus cyclophosphamide versus the same dose of docetaxel plus cyclophosphamide (10-year recurrence risk 12·3% vs 21·0%; risk difference 8·7%, 95% CI 4·5-12·9; RR 0·58, 0·47-0·73; p<0·0001). 10-year breast cancer mortality in this group was reduced by 4·2% (0·4-8·1; p=0·0034). No significant reduction in recurrence risk was found for sequential schedules of taxane plus anthracycline when compared with docetaxel plus cyclophosphamide (RR 0·94, 0·83-1·06; p=0·30). For the analysis of anthracycline regimens with versus without taxane, 35 trials (n=52 976) provided individual patient data. Larger recurrence reductions were seen from adding taxane to anthracycline regimens when the cumulative dose of anthracycline was the same in each group (RR 0·87, 0·82-0·93; p<0·0001; n=11 167) than in trials with two-fold higher cumulative doses of non-taxane (mostly anthracycline) in the control group than in the taxane group (RR 0·96, 0·90-1·03; p=0·27; n=14 620). Direct comparisons between anthracycline and taxane regimens showed that a higher cumulative dose and more dose-intense schedules were more efficacious. The proportional reductions in recurrence for taxane plus anthracycline were similar in oestrogen receptor-positive and oestrogen receptor-negative disease, and did not differ by age, nodal status, or tumour size or grade. Anthracycline plus taxane regimens are most efficacious at reducing breast cancer recurrence and death. Regimens with higher cumulative doses of anthracycline plus taxane provide the greatest benefits, challenging the current trend in clinical practice and guidelines towards non-anthracycline chemotherapy, particularly shorter regimens, such as four cycles of docetaxel-cyclophosphamide. By bringing together data from almost all relevant trials, this meta-analysis provides a reliable evidence base to inform individual treatment decisions, clinical guidelines, and the design of future clinical trials. Cancer Research UK, UK Medical Research Council.

Early detection and serial monitoring during chemotherapy-radiation therapy: Using T1 and T2 mapping cardiac magnetic resonance imaging.

To confirm the ability of native T1 and T2 values in detecting and monitoring early myocardial injuries of chest radiotherapy in neoplasm patients. Fifteen participants received non-anthracycline chemotherapy and chest radiotherapy, and 30 age/gender-matched controls were enrolled in this prospective study. Cardiac magnetic resonance scans were performed within 2 days, 3 months, and 6 months after chest radiotherapy. Myocardial native T1 and T2 values were measured in irradiated and nonirradiated areas. Meanwhile, the parameters of left ventricular function and left ventricular myocardial strain were obtained. There were no significant differences in left ventricular function, native T1, T2, and strain between patients and controls before chest radiotherapy. In 15 participants who were followed up for 6 months, there was a significant change only in left ventricular ejection fraction (LVEF) among baseline and the first follow-up (P = 0.021), while the adjusted P-value was higher than 0.05 after Bonferroni correction, as well as other parameters. Native T1 values were elevated at 3 and 6 months in irradiated areas compared with baseline (1,288.72 ± 66.59 ms vs. 1,212.51 ± 45.41 ms; 1,348.01 ± 54.16 ms vs. 1,212.51 ± 45.41 ms; P < 0.001 for both). However, T2 values only changed at 3 months in irradiated areas compared with baseline (44.21 ± 3.35 ms vs. 39.14 ± 1.44 ms; P = 0.006). Neither the native T1 nor T2 values changed in nonirradiated areas during the follow-up period (all P > 0.05). There were no significant differences in strain changes during the follow-up period (all P > 0.05). Native T1 and T2 values elevated at 3 months after chest radiotherapy, whereas LVEF showed no significant change during the 6-month follow-up.

Cardiac safety of dual anti-HER2 blockade with pertuzumab plus trastuzumab in early HER2-positive breast cancer in the APHINITY trial

Trastuzumab increases the incidence of cardiac events (CEs) in patients with breast cancer (BC). Dual blockade with pertuzumab (P) and trastuzumab (T) improves BC outcomes and is the standard of care for high-risk human epidermal growth factor receptor 2 (HER2)-positive early BC patients. We analyzed the cardiac safety of P and T in the phase III APHINITY trial. Left ventricular ejection fraction (LVEF) ≥ 55% was required at study entry. LVEF assessment was carried out every 3 months during treatment, every 6 months up to month 36, and yearly up to 10 years. Primary CE was defined as heart failure class III/IV and a significant decrease in LVEF (defined as ≥10% from baseline and to <50%), or cardiac death. Secondary CE was defined as a confirmed significant decrease in LVEF, or CEs confirmed by the cardiac advisory board. The safety analysis population consisted of 4769 patients. With 74 months of median follow-up, CEs were observed in 159 patients (3.3%): 83 (3.5%) in P+ T and 76 (3.2%) in T arms, respectively. Most CEs occurred during anti-HER2 therapy (123; 77.4%) and were asymptomatic or mildly symptomatic decreases in LVEF (133; 83.6%). There were two cardiac deaths in each arm (0.1%). Cardiac risk factors indicated were age > 65 years, body mass index ≥ 25 kg/m2, baseline LVEF between 55% and <60%, and use of an anthracycline-containing chemotherapy regimen. Acute recovery from a CE based on subsequent LVEF values was observed in 127/155 patients (81.9%). Dual blockade with P+ T does not increase the risk of CEs compared with T alone. The use of anthracycline-based chemotherapy increases the risk of a CE; hence, non-anthracycline chemotherapy may be considered, particularly in patients with cardiovascular risk factors.

Anthracycline-Induced Cardiotoxicity in Breast Cancer Patients: A Five-Year Retrospective Study in 10 Centers.

Cardiotoxicity as a result of anthracycline chemotherapy has been linked to increased morbidity and mortality in breast cancer patients. There is a need for early detection through risk factor identification. To date, no large multicenter study has been conducted to describe the incidence, risk factors and clinical and demographic profiles of breast cancer patients with anthracycline-induced cardiotoxicity (AIC) in the Philippines. This was a nationwide multicenter retrospective cohort study among adult breast cancer patients who underwent anthracycline chemotherapy from 2015 to 2020 in 10 sites in the Philippines. Baseline characteristics and possible risk factors for AIC were retrieved from medical records and cancer registries. AIC was defined as a reduction of left ventricular ejection fraction (LVEF) by > 10% from baseline to a value of < 53% or the development of overt left ventricular systolic dysfunction or heart failure (HF). Odds ratios from logistic regression were computed to determine risk factors associated with AIC using STATA-15.0 software. Out of 341 patients included, 33 had AIC, accounting for an incidence of 9.68%. Nine patients (2.6%) had clinical HF. AIC patients had a mean age of 53.91 ± 10.84 years. Breast cancer AIC patients were significantly older and had lower body mass index (BMI) than those without AIC. AIC patients had significantly more comorbidities, especially hypertension and atrial fibrillation. Multivariate analysis showed that patients with any preexisting comorbidity are approximately 12.37 times as likely to have AIC, while those with concurrent chemotherapy are 0.07 times or 93% less likely to have AIC. Among adult breast cancer patients undergoing anthracycline chemotherapy, we determined a high incidence of cardiotoxicity at 9.68%. Having preexisting comorbidities gave patients 12 times increased odds of developing anthracycline cardiotoxicity. The presence of concurrent non-anthracycline chemotherapy showed an inverse association with the development of AIC which we attribute largely to patient selection in a retrospective study. The significantly higher propensity for AIC development in patients with preexisting comorbidities may warrant closer monitoring and control of patient comorbidities such as hypertension among patients undergoing anthracycline chemotherapy.

Metaplastic Breast Cancer: Characteristics and Survival Outcomes.

ObjectivesMetaplastic breast cancer (MBC) is a rare neoplasm accounting for <1% of all breast cancer. We evaluated the clinical characteristics and survival outcomes of MBC.MethodsPatients diagnosed with pathologically proven MBC were reviewed from the institutional breast cancer database from 2000 to 2017.ResultsA total of 136 patients diagnosed with MBC were included in the study. The median age of the diagnosis was 60 years, and 60% of patients were stage II at diagnosis, and 22% were stage III. About two-thirds of the patients were triple-negative; 93% had nuclear grade III, and 25% had a lymphovascular invasion. Squamous differentiation (29%) was the most common histologic subtype, followed by the spindle subtype (21%). The most common distant metastases were lung (22%), followed by bone (13%). Moreover, 60% had a mastectomy, 19% had endocrine therapy, 58% had radiation, 51% received anthracycline-based chemotherapy, 26% had non-anthracycline chemotherapy, and 22% received no chemotherapy. In the entire cohort, the two-year overall survival (OS) and five-year OS were 79% and 69%, respectively, and the two-year progression-free survival (PFS) and five-year PFS were 72% and 61%, respectively. On multivariable analysis, the stage of MBC (stage III: hazard ratio (HR), 5.065 (95% confidence interval (CI), 1.02-25.27) (p=0.048)), poor functional status (Eastern Cooperative Oncology Group (ECOG) score, 2; HR, 24.736 (95% CI, 1.92-318.73) (p=0.014)), and distant metastasis to the brain (HR, 8.453 (95% CI, 1.88-38.04) (p=0.005)) and lung (HR, 42.102 (95% CI, 7.20-246.36) (p<0.001)) were significant predictors of decreased OS.ConclusionsMBC demonstrated early disease progression and poor overall survival. The stage of MBC, decreased performance status, and metastasis to the lung and brain were independent poor prognostic factors.

Outcomes of neoadjuvant (NA) and adjuvant (A) chemotherapy in geriatric patients with stage I-III triple-negative breast cancer (TNBC): A single institution experience.

e12522 Background: Older breast cancer patients have greater risk for toxicity with perioperative chemotherapy and poorer outcomes for stage I-III TNBC due to medical comorbidities and declining organ function. It is not clear whether use of anthracycline based chemotherapy regimens (ABC) delivers better outcomes than non-anthracycline taxane-based chemotherapy regimens (TBC) in this population. Methods: A single institution retrospective review of TNBC patients ≥65 treated with adjuvant and neoadjuvant chemotherapy at Moffitt Cancer Center from 2009 to December 2018 was conducted. Demographic, comorbidity, treatment, and toxicity variables were collected. Treatment toxicity was defined as dose reductions, dose delays, early discontinuations, unplanned hospitalizations, and grade 3-4 heme and non-heme toxicities. Eligible patients had stage I-IIII TNBC, were ≥65, and received NA or A chemotherapy at MCC. A validated frailty index (FI) was used to calculate comorbidity score. Kaplan Meier was used to estimate overall survival by regimen received, with log rank test to compare ABC and TBC groups. Results: A total of 79 patients met criteria for analysis, with mean age of patients receiving treatment was 71 (range 65-88). 41.8% of patients had stage I disease, 36.7% with stage II, and 21.5% with Stage III. 76% of patients with Stage III, 51.7% of Stage II, and 18% of stage I disease received ABC. There was a trend toward higher toxicity events in patients receiving ABC compared to TBC regimens, although not statistically significant (see Table). The mOS for patients receiving ABC was 43.5mo and 63.0 mo for patients receiving TBC, although not statistically significant (p=0.212). Conclusions: Geriatric patients with stage I-III TNBC were mostly able to successfully receive NA or A chemotherapy, although TBC may have better tolerability. Patients receiving TBC also had better survival, although not statistically significant and potentially confounded by patients with earlier stage or less aggressive tumors receiving TBC.[Table: see text]

Cardiac Anthracycline Accumulation and B-Type Natriuretic Peptide to Define Risk and Predictors of Cancer Treatment-Related Early Diastolic Dysfunction.

Diastolic dysfunction (DD) was reported to precede heart failure (HF) in patients with cancer who were treated with chemotherapy. We aimed at defining risk versus dose relationships and risk predictors in patients with cancer treated mainly with anthracyclines. Data from 67 patients without comorbidities (60 treated with anthracyclines, 7 with nonanthracycline chemotherapy) were retrospectively incorporated in a mathematical function that correlated DD risk with experimental indices of anthracycline accumulation in human myocardium. Risk was calculated for all patients and for subgroups stratified by intertreatment levels of the endogenous cardiac relaxant agent, B-type natriuretic peptide (BNP). Grade I DD (impaired relaxation) occurred in 14 of 67 patients, and 5% risk doses were much lower for DD than HF (mg of anthracycline/m2: 210 vs. 470 or 190 vs. 450 for all patients or anthracycline-treated patients in isolation, respectively; P ≤ 0.01 for DD vs. HF). Patients with transient BNP elevations showed the lowest 5% risk dose (150 mg/m2), whereas patients with persistent elevations showed the highest risk dose (280 mg/m2; P < 0.05). Patients with or without DD were similar for systemic and cardiac exposure to anthracyclines; however, high-risk patients with transient BNP elevations and DD were older and presented at baseline with lower indices of transmitral flow. In conclusion, DD risk develops after lower anthracycline doses than HF and intertreatment levels of BNP help to identify patients with high or low DD risk. These findings are of potential value to monitor or treat the patient with cancer at risk of DD. SIGNIFICANCE STATEMENT: DD is an early manifestation of cardiotoxicity from anthracyclines and nonanthracycline chemotherapeutics. We show that merging preclinical characterization of cardiac anthracycline accumulation with clinical data from patients treated primarily with anthracyclines identifies DD risk from very low anthracycline doses. DD risk is associated with older age, baseline diastolic indices toward the lower limit of normal, and transient intertreatment elevations of the endogenous cardiac relaxant agent, BNP. These findings have numerous pharmacological implications.

Genetic Polymorphisms and Correlation with Treatment-Induced Cardiotoxicity and Prognosis in Patients with Breast Cancer.

Cardiac toxicity is a serious potential complication of HER2-directed therapies and anthracyclines. HER2 codon 655 and SLC28A3 gene polymorphisms have been reported to be associated with cardiac toxicity from anti-HER2 and anthracycline therapy, respectively. Association of the polymorphism at HER2 codon 655 with prognosis has also been reported. Whole blood samples from patients treated on a randomized adjuvant breast cancer trial (BCIRG-006) that compared chemotherapy with or without trastuzumab plus either anthracycline or nonanthracycline chemotherapy were tested for genetic polymorphisms in HER2 codon 655 and SLC28A3. Genotypes were correlated with cardiac function and disease-free survival (DFS) outcomes. Of 3,222 patients enrolled in BCIRG-006, 662 patient samples were successfully genotyped for the rs1136201 allele in HER2 (codon 655): 424 (64%) were AA, 30 (4.5%) were GG, and 208 (31%) were AG genotype. In addition, 665 patient samples were successfully genotyped for the rs7853758 allele in the SLC28A3 gene: 19 (3%) were AA, 475 (71%) were GG, and 171 (26%) were AG genotype. Follow-up time was 10 years. No correlation between DFS, cardiac event rate, or mean left ventricular ejection fraction (LVEF) and rs1136201 genotype was seen in the trastuzumab-treated or non-trastuzumab-treated patients. Moreover, mean LVEF and cardiac event rates were similar in all rs7853758 genotype groups treated with anthracycline-based therapy. In the largest study to date to evaluate whether two polymorphisms are associated with DFS and/or cardiac toxicity in HER2-positive breast cancer treated with trastuzumab and/or anthracyclines, we observed no correlation.

Perioperative HER2 targeted treatment in early stage HER2-positive breast cancer.

Although human epidermal growth factor receptor 2 (HER2)-positive breast cancer was associated with poor prognosis, it has been changed after the development of trastuzumab. There has been great progress in perioperative HER2-targeting treatment, and investigations of several novel drugs and their combinations are ongoing. Adjuvant trastuzumab with or without pertuzumab for 1 year in combination with concomitant chemotherapy has become a standard treatment in high-risk node-negative tumors or node-positive HER2-positive early breast cancer patients without residual disease or who have not received neoadjuvant treatment. For low-risk HER2-positive early breast cancer patients, adjuvant paclitaxel and 1-year trastuzumab are possible alternatives. For residual disease after neoadjuvant treatment, adjuvant trastuzumab emtansine (T-DM1) for 14 cycles is a standard treatment. Non-anthracycline chemotherapy with dual anti-HER2 targeting of trastuzumab and pertuzumab represents one of the preferred neoadjuvant regimens to achieve higher pathologic complete response (pCR) rates and better clinical outcomes. Further research is needed to develop and validate potential biomarkers to predict pCR, which could help escalate or de-escalate anti-HER2 therapy. Trials incorporating novel agents such as T-DM1, trastuzumab deruxtecan (T-DXd), and immune checkpoint inhibitors and trying to de-escalate treatments in neoadjuvant setting are ongoing. In the future, tailored treatments such as no adjuvant therapy, various HER2-directed therapies alone with chemotherapy, combinations of various HER2-directed therapies and chemotherapy, addition of immune checkpoint inhibitors, and omission of surgery will be individualized in HER2-positive early breast cancer patients.

Lymphoma Patients Treated without Anthracyclines Have Negligible Risk of Cardiotoxicity: A Nationwide Cohort Study

▪AbstractObjective: For more than two decades,CHOP (and later R-CHOP) has been the standard frontline treatment for diffuse large b-cell lymphoma (DLBCL). However, anthracycline-based chemotherapy regimens increase risk of cardiotoxicity with congestive heart failure (HF) being the best documented cardiovascular complication of anthracycline use. However, cardiotoxicity has also been associated with other chemotherapeutic drugs. In this nationwide cohort study, we compared the incidence of development of HF in patients with DLBCL or follicular lymphoma (FL) treated with or without anthracyclines.Methods: DLBCL and FL patients > 16 years both receiving anthracycline in the form of R-CHOP/CHOEP or non-anthracycline chemotherapy regiments were identified in the Danish National Lymphoma Registry (LYFO) from 2000-2012. Anthracycline exposed patients were required to receive ≥3 cycles of R-CHOP or R-CHOEP upfront. The non-anthracycline exposed patients consisted of patients receiving non-anthracycline containing chemotherapy (such as CVP, CEOP and Bendamustine). Exclusion criteria were i) treatment with chemo therapy regimens more intensive than R-CHOP/CHOEP, ii) up-front high dose autologous stem cell transplantation and iii) the following heart comorbidities prior to the beginning of the study: HF (ICD-10 code: “I50”), Ischemic Heart Disease (ICD-10 code: “I20-I25”), Arrhythmic Heart Disease (ICD-10 code: “I48-I49”) and Cardiomyopathy (ICD-10 code: “I42”). Information on heart comorbidities in our study population were retrieved from the Danish National Patient Registry. Patient follow-up started from 30 days after ended chemotherapy to minimize confounding by early HF on the planned number of R-CHOP treatments. Follow-up ended when HF occurred, on the day of emigration from Denmark, day of death or the end of the study on 31th. December 2014, whichever came first. Univariate and multivariable cox regression analyses were performed to assess the association between cumulative anthracycline treatments and HF (adjusted analysis included gender, age, Ann Arbor stadium, radiotherapy, comorbidities and type of lymphoma). Cumulative R-CHOP treatments were stratified into groups of “3-5”, “6” and “>6” treatments. Cumulative incidence curves were computed to illustrate risk of HF over time according to number of treatments.Results: The study included 2,696 patients; 2,007 received anthracycline and 689 received non-anthracycline containing chemotherapy. In total, 1979 patients were diagnosed with DLBCL and 717 with follicular lymphoma. Anthracycline users were slightly younger (median age 64.03 vs 65.2 years (p-value <0.01)), received radiotherapy more often (21.03% vs 6.82% (p-value <0.01)) and were more frequently diagnosed with DLBCL (87.94% vs 31.06% (p-value <0.01)) (table 1). For patients not treated with anthracycline, the cumulative risk of HF within 1, 5 and 8 years were 0%, 0.89% and 1.77%, respectively. For patients treated with 3- 5 cycles of R-CHOP/CHOEP, the corresponding cumulative risk were 0.54%, 4.58% and 5.18%. For patients treated with 6 cycles, the cumulative risks were 1.02%, 4.49% and 8.02 % and for patients treated with >6 cycles, the cumulative risks were 4.01 %, 7.86% and 9.33% (fig 1).Compared to patients receiving non-anthracycline containing chemotherapy (reference), patients receiving anthracycline containing chemotherapy had a higher risk of developing HF during follow-up with adjusted hazard ratio (HR) of 3.73 (95% CI 1.38-10.09) for patients receiving 3-5 cycles, 4.38 (95% CI 1.83-10.48) for patients receiving 6 cycles, and 8.22 (95% CI 3.50-19.31) for patients receiving >6 cycles of anthracycline treatment.Conclusion: This present studyconfirms that inclusion of anthracyclines in a multi-agent chemotherapy regimen is responsible for the increased risk of HF observed after treatment for lymphoma and that the rate of HF is correlated to the number of treatment cycles. Patients treated without anthracyclines had a negligible risk of HF supporting the safety of these regimens in patients considered at substantial risk of cardiotoxicity. [Display omitted] DisclosuresJørgensen:Roche: Research Funding. Poulsen:Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees. El-Galaly:Roche: Other: Travel funding; Takeda: Other: Travel funding.

Cardiac safety of dual anti-HER2 blockade with pertuzumab plus trastuzumab (P+T) in the APHINITY trial.

510 Background: Trastuzumab (T) increases the incidence of cardiac events (CEs) in patients (pts) with early breast cancer (BC). Dual blockade with P+T improves BC outcomes and is the standard of care for high-risk HER2-positive BC pts following the phase 3 APHINITY trial that evaluated the addition of P or placebo (Pla) to T and chemotherapy (CT). We analyzed the cardiac safety of P+T in APHINITY. Methods: APHINITY eligibility required a left ventricular ejection fraction (LVEF) ≥55% at study entry. LVEF assessment was performed every 3 months (mos) during treatment, every 6 mos up to month 36, and yearly thereafter. Primary CE was defined as heart failure (HF) class III/IV and a significant decrease in LVEF of at least 10 percentage points from baseline and to &lt;50%, or cardiac death. Secondary CE was defined as a confirmed significant decrease in LVEF or CEs confirmed by the cardiac advisory board. Results: The safety analysis population consists of 4,769 pts. With 74 mos median follow-up (FU), CEs were observed in 159 pts (3.3%): 83 (3.5%) in the P+T and 76 (3.2%) in Pla+T arms, respectively. Most CEs occurred during anti-HER2 therapy: 123/159 (77.4%) and were asymptomatic or mildly symptomatic LVEF decrease (133/159; 83.6%) (Table 1). There were 2 cardiac deaths in each arm (0.1%). More CEs occurred in pts receiving an anthracycline-based CT compared to those receiving non-anthracycline CT (139 vs. 20 CEs, respectively). Acute recovery from a CE based on subsequent LVEF values was observed in 127/155 pts (81.9%). Conclusions: Dual blockade with P+T does not increase the risk of CE compared to Pla+T alone. The use of anthracycline-based CT increases the risk of a CE; hence non-anthracycline CT may be considered particularly in pts with other cardiovascular risk factors. Clinical trial information: NCT01358877. [Table: see text]

Trastuzumab-dkst versus trastuzumab: Real-world pCR rates in patients with HER2+ breast cancer treated with neoadjuvant chemotherapy plus trastuzumab from Alberta, Canada.

e12569 Background: Biosimilars are defined as medical products that contains a version of the active substance with similar biological characteristics, efficacy, and safety as the original product. Differences however, exist between biosimilars and their original comparator. Unlike small-molecule drugs, identical generic versions cannot be mass produced since manufacturers often have proprietary rights to living cell lines and processes involved in producing biologics. Due to this inherent alteration in production, the potential for clinically meaningful differences may exists. These risks are reduced from bench to clinic through a minimum of one phase 1 study to demonstrate comparability of PK and PD between the biosimilar and the original product, and one phase 3 study to demonstrate equivalency for at least one indication. To date, studies have mainly looked at trastuzumab-dkst in the metastatic setting. This retrospective study compared the pathological complete response (pCR) rates of trastuzumab-dkst to trastuzumab in the neoadjuvant setting for HER2+ early breast cancer (EBC) in Alberta. Methods: Neoadjuvant patients with HER2+ EBC treated with trastuzumab from November 2018 -October 2019 and trastuzumab-dkst from December 2019 - September 2020 were identified. There was no crossover between products. Logistic regression was used to control for variables potentially associated with pCR: trastuzumab product (trastuzumab vs trastuzumab-dkst), age ( &lt; 40 vs 40+), pre-operative T (T1/2 vs T3/4) and N stage (negative vs positive), grade (I/II vs III), HR status (ER and/or PR positive vs ER/PR negative), HER2 (3+ vs SISH+), chemotherapy (anthracycline containing vs not), and chemotherapy completion (yes vs no). Results: 136 patients were identified (56% trastuzumab; 43% trastuzumab-dkst) and there were no significant differences in baseline characteristics except more patients in the trastuzumab-dkst group were clinically N negative; 39% vs 14.3% trastuzumab (p = 0.001). pCR was 35.6% for patients treated with trastuzumab-dkst versus 40.3% with trastuzumab (p = 0.598). In the logistic regression model, there was no significant difference in the odds of a pCR for patients treated with trastuzumab-dkst versus trastuzumab after controlling for the variables selected a priori (OR 1.1, 95% CI 0.5-2.4, p = 0.850). There was a trend for decreased odds of pCR for anthracycline use (OR 0.72 95% CI 0.3-1.6, p = 0.417). Conclusions: pCR rates were similar for patients treated with trastuzumab-dkst compared to trastuzumab in our real world study of HER2+ neoadjuvant EBC and comparable to pivotal phase 3 trials. For a 65 kg patient, the estimated cost savings of trastuzumab-dkst therapy is $22,000, and approximately $240-300 for a non-anthracycline chemotherapy backbone.

A novel scoring system to estimate chemotherapy-induced myocardial toxicity: Risk assessment prior to non-anthracycline chemotherapy regimens.

BackgroundMyocardial toxicity is a common side effect of chemotherapy and is associated with adverse outcomes in cancer patients. Sufficient prediction of chemotherapy-induced myocardiotoxicity (CIMC) is desirable. Therefore, we sought to develop a feasible scoring system to predict CIMC in cancer patients undergoing non-anthracycline chemotherapy.MethodsWe determined a scoring system, the “Cardiotoxicitiy Score” (the CardTox-Score), by multivariable regression of the parameters considered relevant to the development of CIMC, based on previously published data and current guidelines. Variables of the risk model consist of clinical (age, presence of cardiovascular risk conditionsconditions), blood tests (NT-proBNP), and echocardiographic parameters (left ventricular (LV) ejection fraction, LV strain analysis). The CardTox-Score was examined in an internal validation cohort by use of ROC and regression analysis.ResultsWe prospectively investigated 225 patients (58.21 ± 6.3 years, 52.8% female) who received non-anthracycline myocardiotoxic anticancer agent as a derivation cohort. All patients underwent echocardiography before, during and after anticancer therapy. The mean follow-up duration was 25 ± 4 months. We found the CardTox-Score (>6 points) to be a strong independent predictor (AUC: 0.983, OR: 6.38, 95% CI: 1.6 2.8, p < 0.001) for the development of CIMC with high sensitivity (100%) and specificity (84.2%) in the validation cohort (n = 30, 59.2 ± 6.5 years, 57% female). Moreover, the CardTox-Score appropriately predicted all-cause mortality with high specificity (93.7%) and sensitivity (92.9%) as well (OR: 4.85, AUC: 0.978, p = 0.01).ConclusionThe CardTox-Score offers a promising, feasible, and easy-to-handle scoring system for predicting CIMC in cancer patients undergoing non-anthracycline regimes, independent from the type of cancer.

Factors Impacting on the Early Versus Late Major Adverse Cardiovascular Events Amongst Oncology Patients Receiving Non-Anthracycline Chemotherapy

Cardiovascular (CV) events following commencement of cancer treatment are becoming increasingly recognised. The extent to which baseline CV factors influence the onset of major adverse cardiovascular events (MACE) in patients treated with non-anthracycline chemotherapy is not well characterised. The aim of our study was to examine the association between baseline cardiovascular risk factors and early and late complications of non-anthracycline chemotherapy.

Patient-reported symptom severity, interference with daily activities, and adverse events in older and younger women receiving chemotherapy for early breast cancer.

To the authors' knowledge, it is unknown whether patient-reported symptom severity and symptom interference with daily activities differ between younger (aged <65 years) and older (aged ≥65 years) women receiving similar chemotherapy regimens for early breast cancer (EBC). Study participants rated 17 side effects of chemotherapy regimens currently in use in clinical practice (2014-2019). Of 284 women with EBC (stage I-III), approximately 57% were aged <65 years and 43% were aged ≥65 years. For anthracycline-based regimens, a higher percentage of younger women reported moderate, severe, or very severe (MSVS) hot flashes (49% vs 18%) (P < .001). For nonanthracycline regimens, a higher percentage of younger women reported MSVS hot flashes (38% vs 19%) (P = .009) and a lower percentage reported MSVS arthralgia (28% vs 49%) (P = .005). With regard to symptom interference with daily activities, a higher percentage of younger women being treated with anthracycline-based regimens reported MSVS hot flashes (32% vs 7%) (P = .001) and myalgia (38% vs 18%) (P = .02). For nonanthracycline chemotherapy, a higher percentage of younger women reported MSVS interference for hot flashes (26% vs 9%) (P = .006) and lower percentages reported abdominal pain (13% vs 28%) (P = .02). Overall, there were no significant differences noted among younger versus older patients with regard to hospitalizations (19% vs 12%; P = .19), dose reductions (34% vs 31%; P = .50), dose delays (22% vs 25%; P = .59), or early treatment discontinuation (16% vs 16%; P = .9546). Older and younger women with EBC who were treated with identical chemotherapy regimens generally experienced similar levels of symptom severity, symptom-related interference with daily activities, and adverse events. In this study, women receiving chemotherapy for early breast cancer rated the severity of 17 symptoms and symptom interference with their activities of daily living. Older (aged ≥65 years) and younger (aged <65 years) women who received identical chemotherapy regimens generally experienced similar levels of symptom severity, symptom-related interference with daily activities, and adverse events.