Negative Advanced Breast Cancer Research Articles

Abstract P3-01-05: Laboratory monitoring in patients with hormone receptor–positive/human epidermal growth factor receptor 2–negative (HR+/HER2–) advanced breast cancer treated with palbociclib in a real-world setting: Results from POLARIS

Abstract Background: Palbociclib (PAL) is a cyclin-dependent kinase 4/6 inhibitor indicated for the treatment of HR+/HER2– advanced breast cancer (ABC) in combination with an aromatase inhibitor (AI) as initial endocrine-based therapy or with fulvestrant (FUL) in patients whose disease progressed on prior endocrine therapy (ET). Neutropenia was the most commonly reported adverse event in clinical trials. Per the prescribing information for PAL, complete blood counts (CBCs) should be monitored before initiation of PAL (Cycle 1, Day 1 [C1D1]), at the beginning of each subsequent cycle, on Day 15 of the first 2 cycles, and as clinically indicated for at least the first 6 cycles. Methods: POLARIS is a prospective, observational, multicenter, real-world study of patients with HR+/HER2‒ ABC who received PAL as deemed appropriate by the treating physician. CBC collected at baseline, anytime during the first 3 cycles, then on Day 1 (or before the start of a new cycle) of subsequent cycles as per standard of care were recorded. We analyzed the frequency of laboratory monitoring for patients with HR+/HER2– ABC receiving PAL in routine clinical practice. Lab collections outside these windows were also obtained (data not shown). Results: At data cutoff (March 30, 2022), 1242 patients were treated with PAL + ET; 902 patients as first-line (1L) and 340 as second-line or later (≥2L) therapies for ABC; 90% of all patients received 125 mg of PAL in the first cycle. The frequency of laboratory collection, overall and by site category (academic vs. community), within the first 6 months of treatment is reported in the Table. CBC collection reported by investigators and analyzed within the defined window of day 1 of each cycle (C1–C6). Day 1 CBC collection was 87% at C1D1, 69.4% at C2D1, 66.5% at C3D1, 63.2% at C4D1, 61.4% at C5D1, to 59.9% at C6D1. Reports of CBC collection on Day 15 for the first two cycles was 37.3% (C1D15) and 31.2% (C2D15). CBC collection pattern was comparable across the community and academic sites. Conclusions: In this real-world CBC monitoring data set analyzed in a defined cycle window, most sites reported CBC collection prior to PAL initiation, and over two thirds of sites in the subsequent cycles. Day 15 of Cycles 1 and 2 monitoring was conducted in one third of the patients. These results suggest that CBC collections in real-world clinical practice are performed less frequently than in clinical trials, which may reflect the sites’ desire to reduce patient and/or clinic procedural burden, and treating physician’s familiarity with PAL safety profile and their comfort level of managing patients in clinical practice. Clinical trial identification: Pfizer; NCT03280303 Table 1 Citation Format: Gabrielle B. Rocque, Joanne L. Blum, Jennifer M. Specht, Carrie Dul, Steven Corso, Daniel Cuevas, Eric Gauthier, Monica Z. Montelongo, Zhe Zhang, Yao Wang, Debu Tripathy. Laboratory monitoring in patients with hormone receptor–positive/human epidermal growth factor receptor 2–negative (HR+/HER2–) advanced breast cancer treated with palbociclib in a real-world setting: Results from POLARIS [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 P3-01-05.

Abstract P4-01-03: Progression-free survival and patient-reported outcomes in HR+, HER2– ABC patients treated with first-line ribociclib + endocrine therapy (ET) or ET monotherapy or chemotherapy in real world setting: 5th interim analysis of RIBANNA

Abstract Background: Ribociclib in combination with endocrine therapy (ET) has demonstrated survival benefits in a broad patient population with hormone receptor–positive (HR+), human epidermal growth factor receptor 2–negative (HER2–) advanced breast cancer (ABC). RIBANNA (CLEE011ADE03) is an ongoing, prospective, noninterventional study assessing the efficacy and safety of first-line (1L) ribociclib in combination with ET in routine clinical practice in women with HR+, HER2– ABC. This study will provide insights into the use of ribociclib in combination with ET with regard to effectiveness and patient-reported outcomes (PRO) in the real-world setting in a large patient population. Methods: Patients with HR+, HER2– ABC starting their 1L treatment with ribociclib + ET, or ET monotherapy, or chemotherapy (CT) were included. Data after disease progression to second-line (2L) and further lines of therapy are being collected too. The progression-free survival (PFS) in 1L, 2L and PFS2 (time from inclusion into the trial in the 1L setting until progression from 2L to third-line therapy) for individual treatment sequences will be analyzed using the Kaplan–Meier method. PRO for all the patients in the 1L and 2L treatment cohorts are being evaluated using the Morisky Medication Adherence Scale (MMAS-8), questionnaires related to quality-of-life (EORTC QLQ-C30) and its breast cancer–specific module (EORTC QLQ-BR23) as well as the Hospital Anxiety and Depression Scale (HADS). Data were collected at baseline and at every 3 months until the end of treatment. Results: By the cutoff date (October 11, 2021) of the fourth interim analysis, data were available for 2187 patients (Table 1). Overall, 633 patients progressed after 1L therapy, including 27.6%, 30.6%, and 43.4% of patients from the 1L ribociclib + ET, ET monotherapy, and CT cohorts, respectively. A total of 286 patients received CDK4/6 inhibitors in 2L, which represents 48.3%, 37.3%, and 27.0% of patients from the 1L ribociclib + ET, ET monotherapy, and CT cohorts, respectively. The PFS in 1L, 2L and PFS2 results for individual treatment sequences will be presented at SABCS 2022. PRO compliance rates at baseline were 88.2%, 89.8%, and 89.4% for EORTC QLQ-C30 global health status, QLQ-BR23, and HADS-D/A, respectively, in the overall population, and 84.5% for MMAS-8 in the 1L ribociclib + ET cohort. Data for patient-reported adherence to 1L ribociclib + ET and for questionnaires related to global health-related quality of life, functioning, and symptoms from patients receiving treatment in 1L and 2L settings will be analyzed and presented at SABCS 2022. Conclusion: The RIBANNA study has shown diverse population characteristics among patients who received ribociclib treatment in a real-world setting. The 5th interim analysis is planned in October 2022. Data on PFS, PFS2, specific therapy sequences and PRO from 1L and 2L that will provide insights on therapy sequencing strategy will be presented at SABCS 2022. Table 1. Patient disposition at the data cutoff date (October 11, 2021). Citation Format: Peter A. Fasching, Cosima Brucker, Thomas Decker, Anne Engel, Thomas Göhler, Christian Jackisch, Jan Janssen, Andreas Köhler, Kerstin Lüdtke-Heckenkamp, Diana Lüftner, Marion van Mackelenbergh, Frederik Marmé, Arnd Nusch, Beate Rautenberg, Toralf Reimer, Marcus Schmidt, Rudolf Weide, Pauline Wimberger, Christian Roos, Achim Wöckel. Progression-free survival and patient-reported outcomes in HR+, HER2– ABC patients treated with first-line ribociclib + endocrine therapy (ET) or ET monotherapy or chemotherapy in real world setting: 5th interim analysis of RIBANNA [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P4-01-03.

Abstract P5-02-22: Circulating Tumor DNA Genotyping of Intrinsic and Acquired Gene Alterations in Patients With Advanced Breast Cancer Receiving the Cyclin-Dependent Kinase 4/6 Inhibitor Palbociclib: Biomarker Results from POLARIS

Abstract Background: POLARIS is a prospective, real-world study of palbociclib in patients with hormone receptor–positive (HR+)/human epidermal growth factor receptor 2–negative (HER2–) advanced breast cancer (ABC) in the United States and Canada. We present results from analyses of serial circulating tumor gene alteration profiles from patients treated with palbociclib in the first and second or later lines of ABC treatment to illustrate the potential mutagenic drivers of resistance (intrinsic/acquired) and carrier-mutations (intrinsic/maintained). Methods: The clinical database cutoff date was March 30, 2022. Patients in the biomarker analysis group provided consent for serial blood sample collection, received ≥1 dose of initial palbociclib combination treatment, and had ≥1 circulating tumor DNA (ctDNA) measurement available. The Guardant360 platform with somatic single-nucleotide variants in complete or critical exons of 73 genes was used. Tumor gene alteration profiles (at baseline, on-treatment at Cycle 2 Day 1 [C2D1], and at end of treatment [EOT]) were evaluated. Cox proportional hazard models were used to estimate hazard ratios and 95% CIs. Results: Patient samples (n=345) were analyzed and gene alterations were detected in 85% of baseline samples (n=337), 72% of on-treatment samples (n=280), and 85% of EOT samples (n=104). Most frequently altered genes were PIK3CA (38%), TP53 (28%), and ESR1 (15%) at baseline; TP53 (28%), PIK3CA (24%), and NF1 (10%) at C2D1; and TP53 (40%), PIK3CA (40%), and ESR1 (33%) at EOT. Most frequent gene amplifications (amp) were detected in CCND1 (8.3%), FGFR1 (7.7%), and EGFR (5.9%) at baseline; FGFR1 (5.0%), CCND1 (4.3%), and EGFR (3.2%) at C2D1; and CCND1 (13.5%), FGFR1 (9.6%), and EGFR (9.6%) at EOT. Baseline mutations of ESR1 and PIK3CA led to shorter real-world progression-free survival (rwPFS) than wild-type (hazard ratio [95% CI], 1.99 [1.38, 2.86] and 1.67 [1.24, 2.25], respectively). Baseline amp of CCND1 and FGFR1 also led to shorter rwPFS than wild-type (2.13 [1.36, 3.34] and 1.93 [1.20, 3.10]). Acquired mutations in ESR1, ATM, and RB1 were observed at EOT. Most frequently acquired ESR1 mutations at EOT were D538G, Y537N, and Y537S. Patients with all mutations cleared at C2D1, had longer rwPFS than those without (hazard ratio [95% CI], 0.58 [0.41, 0.83]). Conclusion: Patients with mutated ESR1 and PIK3CA or CCND1 and FGFR1 amp at baseline had shorter rwPFS than patients with wild-type genes. Genotyping analysis of progression ctDNA highlights the emergence of mutations in estrogen receptor and cell cycle pathways under selective therapeutic pressure and could guide monitoring and therapeutic sequencing for patients with HR+/HER2– MBC. ClinicalTrials.gov: NCT03280303 Citation Format: Debu Tripathy, Joanne L. Blum, Shibing Deng, Steven L. McCune, Kamal Patel, Yao Wang, Shailendra Lakhanpal, Meghan S. Karuturi, Zhe Zhang, Chetan Deshpande, Monica Z. Montelongo, Eric Gauthier, Yuan Liu, Gabrielle B. Rocque, Aditya Bardia. Circulating Tumor DNA Genotyping of Intrinsic and Acquired Gene Alterations in Patients With Advanced Breast Cancer Receiving the Cyclin-Dependent Kinase 4/6 Inhibitor Palbociclib: Biomarker Results from POLARIS [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 P5-02-22.

Abstract P5-02-14: Identification of mechanisms of acquired resistance to ribociclib plus endocrine therapy using baseline and end-of-treatment circulating tumor DNA samples in the MONALEESA-2, -3, and -7 trials

Abstract Background: Genetic alterations that contribute to resistance to therapy may be acquired during treatment (tx) for hormone receptor−positive/human epidermal growth factor receptor−negative (HR+/HER2−) advanced breast cancer (ABC). A previous pooled analysis of circulating tumor DNA (ctDNA) in MONALEESA (ML)-2, -3, and -7 identified potential predictive biomarkers for response and resistance to ribociclib (RIB) at baseline (BL). Here, we describe an analysis of paired BL and end of treatment (EOT) samples from ML-2, -3, and -7 to identify acquired mechanisms that may impact resistance to RIB + endocrine therapy (ET) vs placebo (PBO) + ET. Methods: ML-2 (NCT01958021), ML-3 (NCT02422615), and ML-7 (NCT02278120) evaluated efficacy and safety of RIB + ET vs PBO + ET in pre- and postmenopausal patients (pts) with HR+/HER2− ABC treated in first-line (1L) and second-line (2L) settings. Plasma samples were collected at cycle 1 day 1 (C1D1; prior to first therapy exposure) and at EOT (± 28 days of recorded progression). ctDNA was sequenced using a targeted next-generation sequencing panel of ≈550 genes. Genes with an alteration frequency of >5% at EOT, regardless of their frequency at BL, were included. Tumor mutational burden (TMB) was assessed by tx arm; a TMB cutoff of 10 mutations/MB was used to categorize pts as TMB high vs low. To assess differences in the presence of alterations, a McNemar test was performed on paired samples and adjusted (adj) for multiple testing using the false discovery rate (FDR). A Bayesian mixed effects model was used to account for ctDNA fraction and trial and to test for tx-specific resistance by including a tx × visit interaction term. Results: A total of 905 paired samples from ML-2, -3, and -7 were included in this analysis, 441 and 464 samples from pts treated with RIB + ET and PBO + ET, respectively. Overall, 17 genes had an alteration frequency of >5% at EOT. The ctDNA fraction was higher at EOT vs C1D1 in both the RIB (P=.037) and PBO (P=.033) arms. The frequency of alterations in RB1 (10.4% vs 2.0%), ATM (11.3% vs 8.4%), FAT1 (4.8% vs 3.0%), and FAT3 (5.0% vs 2.5%) was higher at EOT vs C1D1 in the RIB arm (FDR-adj P<.10). Alterations in ESR1 were also higher at EOT vs C1D1 in both the RIB (26.3% vs 9.1%) and PBO arms (28.9% vs 5.4%) (FDR-adj P<.0001). Conversely, alterations in GATA3 were higher at EOT in the PBO arm (FDR-adj P=.11). These results were consistent after adjusting for ctDNA fraction. The most common ESR1 mutations were D538G, Y537S/N/C/D, E380Q, and L536H/P/R. Tx × visit interaction effects were observed for RB1 in the RIB arm and GATA3 in the PBO arm, suggesting tx-specific resistance. A tx × visit interaction for ESR1 was also observed, suggesting a larger relative increase in ESR1 mutations with PBO vs RIB. The percentage of pts with high TMB (>10) at EOT increased from 1.1% to 5.7% in the RIB arm and from 1.7% to 3% in the PBO arm. After accounting for ctDNA fraction and trial, a larger numerical increase in TMB was observed for RIB (odds ratio [OR], 9.0; 95% CI, 2.9-32.7) vs PBO (OR, 2.1; 95% CI, 0.7-6.5); however, the model did not support a differential tx effect. Conclusions: This comprehensive analysis of pooled samples from ML-2, -3, and -7 identified acquired gene alterations in pts with HR+/HER2− ABC treated with 1L or 2L RIB + ET or PBO + ET. The frequency of several genes known to contribute to resistance (ESR1, RB1, ATM, FAT1, and FAT3) was higher at EOT vs C1D1 in pts treated with RIB + ET, while ESR1 and GATA3 alterations were higher at EOT vs C1D1 in pts treated with PBO + ET. This paired dataset of BL and EOT samples from pts with HR+/HER2− ABC treated with a CDK4/6 inhibitor and ET is the largest to date and could be used to validate and confirm acquired resistance mechanisms with low alteration frequency. Citation Format: Fabrice Andre, Nadia Solovieff, Faye Su, Aditya Bardia, Patrick Neven, Yoon-Sim Yap, Debu Tripathy, Yen-Shen Lu, Dennis Slamon, Stephen K. Chia, Mukta Joshi, Arunava Chakravartty, Agnes Lteif, Tetiana Taran, Carlos Arteaga. Identification of mechanisms of acquired resistance to ribociclib plus endocrine therapy using baseline and end-of-treatment circulating tumor DNA samples in the MONALEESA-2, -3, and -7 trials [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 P5-02-14.

Abstract P5-02-48: Identifying immune-related predictive factors for paclitaxel + bevacizumab therapy in patients with HER2-negative advanced breast cancer- A multicenter retrospective study

Abstract Background: In IMpassion 130 trial, programmed death-ligand 1 (PD-L1) expression was seen in about 40% of participated patients with triple negative advanced breast cancer (TN-ABC) [Schmid, 2018, N Engl J Med], however, actual situation of PD-L1 expression in patients HER2-negative ABC patients including with TN-ABC has not been well studied. Furthermore, no biomarker related to chemotherapy for HER2-negative ABC patients except for PD-L1 in TN-ABC has been identified. Recently, several reports regarding the relationship between peripheral immune-related markers; such as absolute lymphocyte count (ALC) or neutrophil-to-lymphocyte ratio (NLR), and efficacy of eribulin therapy [Miyoshi, 2020, Breast Cancer; Watanabe, 2020, Breast Cancer Res Treat] or paclitaxel plus bevacizumab (PB) therapy [Nakamoto, 2021, Sci Rep], however, the relationship between the efficacy of PB therapy and peripheral immune related markers including dynamic change during the therapy or local immune-related markers is unclear. Therefore, we conducted multi-institutional, retrospective study 1) to evaluate the actual situation of PD-L1 expression and other immune-related markers of the primary site by central review, and 2) to explore biomarkers for first-line PB therapy using peripheral and local immune-related markers. Patients and methods: We retrospectively reviewed medical records of HER2-negative ABC patients who received PB therapy as first-line (1L) or second-line chemotherapy for ABC. Clinical data including ALC, NLR and serum albumin (Alb) were extracted from medical records, and the pathology of archived tissues of primary and metastatic site (if available) were centrally reviewed including PD-L1 (VentanaR SP142). Statistical analyses were performed using Kaplan-Meier method, log-rank test, Wilcoxon’s test, and Cox hazard model. Mixed-effects model for repeated measures (MMRM) to evaluate the relationships between dynamic change in immune-related markers and time-to treatment termination (TTT) of PB therapy. Results: We identified 156 HER2-negaive ABC patients who underwent PB therapy, and 114 out of 156 patients were eligible for analyses. Of 114 patients, 63 patients (55.3%) had recurrent disease, and 65 (57.0%) patients had visceral disease. Eighty-seven out of 114 (76.3%) patients received PB therapy as 1L chemotherapy. Eighty-four specimens (73.7%) were diagnosed as estrogen-receptor (ER) positive, and PD-L1 positivity rate were 3.6% (1/84) in ER+ subgroup and 30.0% (6/20) in ER- subgroup, respectively. Paired biopsy specimens were eligible in 14 patients, and significant elevation of Ki67 labeling index was noted. In patients who received 1L PB (n = 87), there was no positive relationship between maintained ALC (>1,500 or >1,000/μL at baseline) or low NLR (< 2.5 or < 3) at the initiation of 1L PB therapy and TTTs. However, low NLR (cut-off at 2.5 and 3) at the initiation of second cycle of PB therapy reduced the risk for treatment-termination as; hazard ratio [HR], 0.427; 95% CI 0.218-0.843; P = 0.0147 and HR, 0.344; 95% CI 0.170-0.731; P = 0.0066, respectively. PD-L1 positive patients (n = 5) showed numerically increased risk of treatment-termination (HR, 2.68; 95% CI, 0.922-6.196; P = 0.0674) for 1L PB therapy, however, there was no significant difference in mortality risk regarding PD-L1 statuses. Multivariate analysis using MMRM disclosed that increase of Alb level was predictive factor for 1L PB therapy (HR, 0.41; 95%CI, 0.18-0.93; P = 0.0338). Conclusion: According to our real-world study, 1) PD-L1 positive rate was lower than that of previous reports, 2) low NLR at the initiation of second cycle of PB therapy and dynamic change in albumin level were identified as predictive factors and 3) PD-L1 overexpression was not a prognostic or a predictive factor for PB therapy in patients with HER2-negative ABC. Funding: Chugai Pharmaceutical CO., LTD. Citation Format: Junichiro Watanabe, Takashi Sugino, Koji Muramatsu, Satoshi Morita, Yu Hidaka, Shogo Nakamoto, Mitsuya Ito, Shoichiro Ohtani, Masahiko Ikeda. Identifying immune-related predictive factors for paclitaxel + bevacizumab therapy in patients with HER2-negative advanced breast cancer- A multicenter retrospective study [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 P5-02-48.

Abemaciclib-associated Diarrhea: An Exploratory Analysis of Real-life Data.

Abemaciclib is a cyclin-dependent kinase 4/6 inhibitor approved in combination with endocrine therapy for treating hormone receptor-positive and human epidermal growth factor receptor 2-negative early and advanced breast cancer patients. The safety profile of abemaciclib is characterized by frequent gastrointestinal toxicity, especially diarrhea. Therefore, we performed an exploratory analysis of clinical factors that may be potentially associated with diarrhea in patients treated with abemaciclib plus endocrine therapy. Factors potentially predisposing to diarrhea were selected, such as age ≥70 years, concomitant medications and diseases, diet, and use of laxatives. These variables were correlated with the onset of grade 2/3 diarrhea in a cohort of patients treated with abemaciclib from advanced breast cancer. Univariate and multivariate analysis was performed. Sensitivity and specificity were tested using the ROC curve. Eighty women with advanced breast cancer were included in the study. The univariate analysis found a statistically significant correlation between grade 2/3 diarrhea and age ≥70 years, polypharmacy, and concomitant gastrointestinal diseases (p<0.05). In the multivariate analysis, the number of risk factors significantly correlated with the outcome of interest (p<0.0001). ROC analysis showed our model's 82% sensitivity and 75% specificity. Taking into account specific pre-existing factors, it is possible to estimate the risk of diarrhea in hormone receptor-positive and human epidermal growth factor receptor 2-negative - advanced breast cancer patients, candidates for abemaciclib plus endocrine therapy. In these subjects, implementing proactive prevention and adopting a dose-escalation strategy may represent practical approaches to decrease the abemaciclib toxicity burden.

On-treatment derived neutrophil-to-lymphocyte ratio and survival with palbociclib and endocrine treatment: analysis of a multicenter retrospective cohort and the PALOMA-2/3 study with immune correlates

BackgroundCyclin-dependent kinase 4 and 6 (CDK4/6) inhibitors have been established as a standard treatment for hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative advanced breast cancer (ABC); however, predictive biomarkers with translational relevance have not yet been elucidated.MethodsData from postmenopausal women who received the CDK4/6 inhibitor palbociclib and letrozole for HR-positive, HER2-negative ABC from tertiary referral centers were analyzed (N = 221; exploratory cohort). Pre- and on-treatment neutrophil-to-lymphocyte ratio (NLR) and derived NLR (dNLR; neutrophil/[leukocyte-neutrophil]) were correlated with survival outcomes. Data from the PALOMA-2 (NCT01740427) and PALOMA-3 studies (NCT01942135) involving patients treated with endocrine treatment with or without palbociclib were also analyzed (validation cohort). Prospectively enrolled patients (N = 20) were subjected to immunophenotyping with circulating immune cells to explore the biological implications of immune cell dynamics.ResultsIn the exploratory cohort, palbociclib administration significantly reduced leukocyte, neutrophil, and lymphocyte counts on day 1 of cycle 2. Although the baseline dNLR was not significantly associated with progression-free survival (PFS), higher on-treatment dNLRs were associated with worse PFS (hazard ratio = 3.337, P < 0.001). In the PALOMA-2 validation cohort, higher on-treatment dNLRs were associated with inferior PFS in patients treated with palbociclib and letrozole (hazard ratio = 1.498, P = 0.009), and reduction in the dNLR after treatment was predictive of a survival benefit (hazard ratio = 1.555, P = 0.026). On-treatment dNLRs were also predictive of PFS following palbociclib and fulvestrant treatment in the PALOMA-3 validation cohort. Using flow cytometry analysis, we found that the CDK4/6 inhibitor prevented T cell exhaustion and diminished myeloid-derived suppressor cell frequency.ConclusionsOn-treatment dNLR significantly predicted PFS in patients with HR-positive, HER2-negative ABC receiving palbociclib and endocrine treatment. Additionally, we observed putative systemic immune responses elicited by palbociclib, suggesting immunologic changes upon CDK4/6 inhibitor treatment.

The pan-immune-inflammation value is associated with clinical outcomes in patients with advanced TNBC treated with first-line, platinum-based chemotherapy: an institutional retrospective analysis.

Advanced triple-negative breast cancer (aTNBC) has a poor prognosis; thus, there is a need to identify novel biomarkers to guide future research and improve clinical outcomes. We tested the prognostic ability of an emerging, complete blood count (CBC)-based inflammatory biomarker, the pan-immune-inflammation value (PIV), in patients with aTNBC treated with first-line, platinum-based chemotherapy. This was a retrospective, monocentric, observational study. We included consecutive aTNBC patients treated with platinum-based, first-line chemotherapy at our Institution, and for whom baseline (C1) CBC data were available. We collected CBC data early on-treatment, when available. PIV was calculated as: (neutrophil count × platelet count × monocyte count)/lymphocyte count. Patients with hormone receptor-positive (HR+), human epidermal growth factor receptor 2 (HER2)-negative advanced breast cancer (aBC) were included in a control, non-TNBC cohort. A total of 78 aTNBC patients were included. When evaluated as a continuous variable, PIV-C1 was associated with worse overall survival (OS; p < 0.001) and progression-free survival (PFS; p < 0.001). On the other hand, when PIV-C1 was assessed on the basis of its quantile distribution, patients with 'high PIV-C1' experienced worse OS [adjusted hazard ratio (HR): 4.46, 95% confidence interval (CI): 2.22-8.99; adjusted p < 0.001] and PFS (adjusted HR: 2.03, 95% CI: 1.08-3.80; adjusted p = 0.027) when compared to patients with 'low PIV-C1'. Higher PIV-C1 was also associated with primary resistance to chemotherapy. Similarly, a higher PIV calculated from CBC at C2D1 (PIV-C2) was associated with worse survival outcomes. We also created a PIV-based score combining information about both PIV-C1 and PIV-C2 and allowing the stratification of patients at low, intermediate, and high risk of death. No association was observed between PIV-C1 and clinical outcomes of HR+/HER2- aBC patients. PIV has a promising prognostic discrimination ability in aTNBC patients treated with first-line, platinum-based chemotherapy. Both baseline and early on-treatment PIV are associated with clinical outcomes and may be exploited for creating PIV-based risk classifiers if further validated.

Rationale and trial design of NATALEE: a Phase III trial of adjuvant ribociclib + endocrine therapy versus endocrine therapy alone in patients with HR+/HER2- early breast cancer.

Ribociclib has demonstrated a statistically significant overall survival benefit in pre- and postmenopausal patients with hormone receptor positive/human epidermal growth factor receptor 2 negative (HR+/HER2-) advanced breast cancer. New Adjuvant Trial with Ribociclib [LEE011] (NATALEE) is a trial evaluating the efficacy and safety of adjuvant ribociclib plus endocrine therapy (ET) versus ET alone in patients with HR+/HER2- early nonmetastatic breast cancer (EBC). NATALEE is a multicenter, randomized, open-label, Phase III trial in patients with HR+/HER2- EBC. Eligible patients include women, regardless of menopausal status, and men aged ⩾18 years. Select patients with stage IIA, stage IIB, or stage III disease (per the anatomic classification in the AJCC Cancer Staging Manual, 8th edition) with an initial diagnosis ⩽18 months prior to randomization are eligible. Patients receiving standard (neo)adjuvant ET are eligible if treatment was initiated ⩽12 months before randomization. Patients undergo 1:1 randomization to ribociclib 400 mg/day (3 weeks on/1 week off) +ET (letrozole 2.5 mg/day or anastrozole 1 mg/day [investigator's discretion] plus goserelin [men or premenopausal women]) or ET alone. Ribociclib treatment duration is 36 months; ET treatment duration is ⩾60 months. The primary end point is invasive disease-free survival. The 36-month treatment duration of ribociclib in NATALEE is extended compared with that in other adjuvant cyclin-dependent kinases 4 and 6 (CDK4/6) inhibitor trials and is intended to maximize efficacy due to longer duration of CDK4/6 inhibition. Compared with the 600-mg/day dose used in advanced breast cancer, the reduced ribociclib dose used in NATALEE may improve tolerability while maintaining efficacy. NATALEE includes the broadest population of patients with HR+/HER2- EBC of any Phase III trial currently evaluating adjuvant CDK4/6 inhibitor treatment. ClinicalTrials.gov identifier: NCT03701334 (https://clinicaltrials.gov/ct2/show/NCT03701334).

Real-world patient-reported outcomes and physician satisfaction with poly (ADP-ribose) polymerase inhibitors versus chemotherapy in patients with germline BRCA1/2-mutated human epidermal growth factor receptor 2–negative advanced breast cancer from the United States, Europe, and Israel

BackgroundIn clinical trials, poly (ADP-ribose) polymerase inhibitors (PARPi) versus chemotherapy resulted in significantly improved progression-free survival, manageable adverse event profiles, and favorable patient-reported outcomes (PROs) in patients with human epidermal growth factor receptor 2–negative (HER2−) advanced breast cancer (ABC) and germline BRCA1/2 mutations (gBRCA1/2mut). The objective of this study was to evaluate PROs and physician satisfaction with treatment in patients with gBRCA1/2mut HER2− ABC receiving PARPi or physician’s choice of chemotherapy in a multi-country, real-world setting.MethodsThis retrospective analysis used data from the Adelphi Real World ABC Disease Specific Programmes in the United States, European Union, and Israel. PROs were assessed at a single timepoint using the EuroQol 5-Dimensions 5-Level (EQ-5D-5L) scale, Cancer Therapy Satisfaction Questionnaire (CTSQ), and European Organization for Research and Treatment of Cancer Quality-of-Life Questionnaire Core 30 (EORTC QLQ-C30) and the breast cancer−specific module (QLQ-BR23). Baseline PROs were not assessed. Physician satisfaction with treatment scores was dichotomized to a 0/1 variable (0 = very dissatisfied/dissatisfied/moderately satisfied; 1 = satisfied/very satisfied). Scores were compared using inverse-probability−weighted regression adjustment, controlling for multiple confounding factors.ResultsThe study included 96 patients (PARPi, n = 38; platinum/non–platinum-based chemotherapy, n = 58). Patients receiving PARPi versus chemotherapy reported significantly better scores on the EQ-5D-5L Health Utility Index. On the EORTC QLQ-C30 functional scales, patients receiving PARPi reported significantly better scores (mean ± SE) for physical functioning (80.0 ± 2.4 vs 71.9 ± 3.4; p < 0.05) and social functioning (82.0 ± 6.2 vs 63.6 ± 3.7; p < 0.05) and, on the symptom scales, reported significantly better scores for constipation (1.9 ± 1.8 vs 18.7 ± 3.2; p < 0.001), breast symptoms (0.4 ± 3.9 vs 13.3 ± 2.6; p < 0.01), arm symptoms (2.6 ± 1.3 vs 11.4 ± 2.4; p = 0.001), and systemic therapy side effects (13.5 ± 1.8 vs 29.4 ± 2.3; p < 0.001). In contrast, patients receiving chemotherapy scored significantly better on the nausea/vomiting scale (18.3 ± 2.8 vs 34.5 ± 5.1; p < 0.01). Patients receiving PARPi reported numerically better satisfaction scores on the CTSQ scales. Physicians were more likely to be satisfied/very satisfied with PARPi versus chemotherapy (95.4% ± 7.3% vs 40.8% ± 6.2%; p < 0.001).ConclusionsThe PRO findings in this real-world population of patients with gBRCA1/2mut HER2− ABC complement those from the pivotal clinical trials, providing further support for treatment with PARPi in these patients.

Evaluation of alpelisib-induced hyperglycemia prophylaxis and associated risk factors in PIK3CA-mutated hormone-receptor positive, human epidermal growth factor-2 negative advanced breast cancer.

SOLAR-1 investigated alpelisib-fulvestrant (ALP + FLV) in patients with HR + /HER2-, PIK3CA-mutated advanced breast cancer and demonstrated a clinically significant increase in all-grade and grade (G) 3-4 hyperglycemia (HG) compared to placebo-fulvestrant. Given high rates of HG, a preventative protocol and identification of associated risk factors was implemented. This single-center, retrospective study included patients receiving ALP + FLV. One week before ALP initiation, patients started an insulin-sensitizer. Patients had fasting plasma glucose (FPG) levels drawn day 8, 15, 28, then monthly. Primary outcome was incidence of G2-4 HG by day 28. Risk factors assessed included age, BMI, FPG, and HbA1c. Number of risk factors were compared between patients with and without HG. Sixteen women were included with median age of 59years. The cohort was 69% White, 25% Black, 75% with BMI ≥ 25kg/m2, and 50% with history of diabetes. By day 28, 9 patients (56%) had G2-4 HG, with only 3 (19%) G3 and zero G4. Patients with G2-4 HG had a median of 2 risk factors compared to only 1 if no HG (p = 0.03). 5 patients (31%) required a temporary hold of ALP and 3 (19%) required dose reduction due to HG. 13 patients permanently discontinued ALP-9 due to disease progression and 4 from an adverse event (only 1 HG). Implementation of a HG prophylaxis protocol with ALP in a single-center study demonstrated fewer G3-4 HG events compared to that seen in SOLAR-1 (19% vs 36.6%). An increase in HG-associated risk factors correlated with a higher incidence of G2-4 HG.

Effect of palbociclib plus endocrine therapy on time to chemotherapy across subgroups of patients with hormone receptor‒positive/human epidermal growth factor receptor 2‒negative advanced breast cancer: Post hoc analyses from PALOMA-2 and PALOMA-3

BackgroundPrevious analyses from the PALOMA-2 and PALOMA-3 studies showed that palbociclib (PAL) plus endocrine therapy (ET) prolongs time to first subsequent chemotherapy (TTC) versus placebo (PBO) plus ET in the overall population of patients with hormone receptor‒positive/human epidermal growth factor receptor 2‒negative (HR+/HER2−) advanced breast cancer (ABC). Here, we evaluated TTC in relevant patient subgroups. MethodsThese post hoc analyses evaluated TTC by subgroup using data from 2 randomized, phase 3 studies of women with HR+/HER2− ABC. In PALOMA-2, postmenopausal patients previously untreated for ABC were randomized 2:1 to receive PAL (125 mg/day, 3/1-week schedule) plus letrozole (LET; 2.5 mg/day; n = 444) or PBO plus LET (n = 222). In PALOMA-3, premenopausal or postmenopausal patients whose disease had progressed after prior ET were randomized 2:1 to receive PAL (125 mg/day, 3/1-week schedule) plus fulvestrant (FUL; 500 mg; n = 347) or PBO plus FUL (n = 174). ResultsFirst subsequent chemotherapy was received by 35.5% and 56.2% in PALOMA-2 and PALOMA-3 after progression on palbociclib plus ET or placebo plus ET. Across all subgroups analyzed, the median progression-free survival (PFS) was longer in the PAL plus ET arm than the PBO plus ET arm. TTC was longer with PAL plus ET versus PBO plus ET across the same patient subgroups in both studies. ConclusionsAcross all subgroups, PAL plus ET versus PBO plus ET had longer median PFS and resulted in prolonged TTC in both the PALOMA-2 and PALOMA-3 studies.Pfizer Inc (NCT01740427, NCT01942135).

Real-world data for the renal safety of abemaciclib combined with bisphosphonate in HR+/HER2- advanced breast cancer.

Our study evaluated the renal safety of abemaciclib plus endocrine therapy (ET) with bisphosphonate as a treatment option for hormone receptor positive, human epidermal growth factor receptor 2 (HER-2) negative (HR+/HER2-) advanced breast cancer (ABC), especially with bone metastasis. Data were collected from HR+/HER2- ABC patients who received abemaciclib with ET between March 2021 and May 2022 in a single medical center in China. We performed an analysis of the change in serum creatine (Cr) and creatine clearance (CrCl), time to first abnormal Cr value, and Common Terminology Criteria for Adverse Events grade of increased creatinine. A total of 210 patients were included in the final analysis, with a median age of 56 years and a median weight of 65 kg. Any grade laboratory-assessing increased Cr occurred in 87.1% of patients, while CrCl rarely went down to 30 ml/min. Associations between start dose with grade of increased Cr and menopausal status with alert value, which is defined as creatinine clearance <30 ml/min, were indicated. This study shows that abemaciclib combined with bisphosphonate would be safe for renal function in HR+/HER2- ABC patients with bone metastases.

208 (PB-032) Poster - Intrinsic tumor subtype in hormone receptor (HR) positive, human epidermal growth factor receptor 2 (HER2)-negative advanced breast cancer (ABC) treated with cyclin-dependent kinase 4/6 inhibitors (CDK 4/6i) and endocrine therapy (ET) – a retrospective analysis of real world data

Background: CDK 4/6 inhibitors significantly improve outcomes for patients (pts) with HR positive, HER2-negative ABC. In this group of patients, the HER2-Low (HER2-L) subtype represents 50–60% and is characterized by poor prognosis. In this retrospective analysis we explore the role of intrinsic tumor subtype (luminal A, luminal B and HER2-L) as a predictor of clinical outcomes in patients treated with ET plus CDK 4/6 inhibitors.

The Renaissance of CDK Inhibitors in Breast Cancer Therapy: An Update on Clinical Trials and Therapy Resistance.

Cyclin-dependent kinases (CDKs) govern cell-cycle checkpoint transitions necessary for cancer cell proliferation. Recent developments have illustrated nuanced important differences between mono CDK inhibitor (CDKI) treatment and the combination therapies of breast cancers. The CDKIs that are currently FDA-approved for breast cancer therapy are oral agents that selectively inhibit CDK4 and CDK6, include palbociclib (Ibrance), ribociclib (Kisqali), and abemaciclib (Verzenio). CDKI therapy is effective in hormone receptor positive (HR+), and human epidermal growth factor receptor two negative (HER2-) advanced breast cancers (ABC) malignancies, but remains susceptible due to estrogen and progesterone receptor overexpression. Adding a CDK4/6I to endocrine therapy increases efficacy and delays disease progression. Given the side effects of CDKI, identifying potential new treatments to enhance CDKI effectiveness is essential. Recent long-term studies with Palbociclib, including the PALLAS and PENELOPE B, which failed to meet their primary endpoints of influencing progression-free survival, suggest a deeper mechanistic understanding of cyclin/CDK functions is required. The impact of CDKI on the anti-tumor immune response represents an area of great promise. CDKI therapy resistance that arises provides the opportunity for specific types of new therapies currently in clinical trials.

206 (PB-030) Poster - Cost-effectiveness of first-line ribociclib use vs palbociclib in the treatment of postmenopausal women with HR+/HER2− advanced breast cancer: analysis based on final OS results of MONALEESA-2 and PALOMA-2

Background: The combination of a cyclin-dependent kinase 4/6 inhibitor (CDK4/6i) plus aromatase inhibitor is the standard of care in first-line (1L) treatment of hormone receptor–positive/human epidermal growth factor receptor–negative (HR+/HER2−) advanced breast cancer (ABC). Among the 3 CDK4/6is, only ribociclib has shown a statistically significant benefit in overall survival (OS) (MONALEESA [ML]-2 and -7) in 1L use: palbociclib did not demonstrate a significant OS benefit (PALOMA-2 [PAL-2]) and the final OS results for abemaciclib (MONARCH-3) are pending.

Real-World Study of Regional Differences in Patient Demographics, Clinical Characteristics, and BRCA1/2 Mutation Testing in Patients with Human Epidermal Growth Factor Receptor2-Negative Advanced Breast Cancer in the United States, Europe, and Israel.

Genetic mutations in breast cancer susceptibility gene1 or 2 (BRCA1/2) confer a high risk for developing breast cancer; however, at least 50% of women with BRCA1/2 mutations go undiagnosed. This study evaluated differences in patient demographics, clinical characteristics, and BRCA1/2 mutation testing in the USA, European Union (EU4), and Israel in a real-world population of patients with human epidermal growth factor receptor2-negative (HER2-) advanced breast cancer (ABC). This study was a retrospective analysis of data from the Adelphi Real World ABC Disease Specific Programme in the USA, EU4, and Israel. Medical oncologists completed a patient record form, which included detailed questions on demographics, clinical assessments and outcomes, and treatment history. Eligible patients were at least 18years of age and receiving therapy for stageIIIb-IV ABC. Among the 2527 study patients, 407 were from the USA, 1926 were from the EU4, and 194 were from Israel; 86% had hormone receptor-positive (HR+)/HER2- ABC and 14% had triple-negative breast cancer (TNBC). Israeli patients had a higher rate of family history of BRCA-related cancer (69%) compared with patients in the EU4 (18%; p < 0.0001) and USA (18%; p < 0.0001). Among patients with HR+/HER2- ABC, the BRCA1/2 testing rate was 99% in Israel, 37% in the EU4, and 68% in the USA (p < 0.0001 vs Israel and the EU4). The age of tested patients was significantly younger in Israel (56years) compared with the EU4 (59years; p = 0.016 vs Israel) and USA (64years; p < 0.0001 vs Israel and the EU4). Among patients with TNBC, the BRCA1/2 testing rate was 100% in Israel, 78% in the EU4 (p < 0.0001 vs Israel), and 93% in the USA (p < 0.002 vs the EU4). Among tested patients, genetic counseling rates were also higher in Israel (98%) compared with the EU4 (40%; p < 0.0001) and USA (38%; p < 0.0001). Testing and genetic counseling ratesfor BRCA1/2 mutations were very high in Israel, potentially due to the high rate of family history of BRCA-related cancer in this population and higher general awareness of genetic testing. In the EU4 and USA, overall rates of testing for BRCA1/2 mutations and genetic counseling were significantly lower compared with Israel. Given the high risk of breast cancer in BRCA1/2 mutation carriers and the efficacy of new therapies in treating ABC with a BRCA1/2 mutation, efforts should be made to improve BRCA1/2 testing rates in Europe and the USA.

Real-world study of patients with germline BRCA1/2-mutated human epidermal growth factor receptor 2‒Negative advanced breast cancer: Patient demographics, treatment patterns, adverse events, and physician-reported satisfaction in the United States, Europe, and Israel

BackgroundCurrent guidelines for the treatment of human epidermal growth factor receptor 2‒negative (HER2−) advanced breast cancer (ABC) are informed by tumor characteristics and include platinum- and non–platinum-based chemotherapy, chemotherapy plus immunotherapy, endocrine monotherapy, or endocrine therapy plus a targeted therapy. In addition, poly(adenosine diphosphate-ribose) polymerase inhibitors (PARPi) have recently demonstrated improved clinical and patient-reported outcomes and manageable toxicity profiles compared with chemotherapy in patients with germline breast cancer susceptibility gene 1 or 2 (gBRCA1/2)‒mutated HER2− ABC in clinical trials and are now approved to treat this patient population. This study provides complementary real-world data regarding treatment patterns, adverse events, and physician-reported treatment satisfaction in this population. MethodsThis retrospective analysis using the Adelphi Real World ABC Disease Specific Programme in the United States, European Union, and Israel included patients aged ≥18 years receiving therapy for stage IIIb or IV gBRCA1/2-mutated HER2− ABC. Oncologists completed a patient record form detailing patient demographics, clinical assessments, and treatment history and a survey regarding their use of and satisfaction with treatments. ResultsAmong the 543 patients, mean age was 55 years, 25% were premenopausal, 70% had hormone receptor‒positive (HR+) ABC, and 30% had triple-negative breast cancer (TNBC). PARPi were used in 5%, 11%, and 12% of first-line, second-line, and third-line therapies, respectively, for patients with HR+ ABC; for TNBC, percentages were 18%, 44%, and 36%. Across treatment lines, neutropenia, anemia, and nausea occurred in 16%, 24%, and 32% of patients receiving PARPi, respectively; 22%, 38%, and 33% of patients receiving platinum chemotherapy; and 20%, 20%, and 33% of patients receiving non–platinum-based chemotherapy. Physician satisfaction was highest with PARPi and with chemotherapy plus immunotherapy. ConclusionsFindings in this real-world population complement clinical trial observations and provide further support for treatment of patients with PARPi in gBRCA1/2-mutated HER2− ABC.

Palbociclib plus letrozole versus placebo plus letrozole in Asian postmenopausal women with oestrogen receptor–positive/human epidermal growth factor receptor 2–negative advanced breast cancer: Primary results from PALOMA-4

BackgroundThe cyclin-dependent kinase 4/6 inhibitor palbociclib has demonstrated efficacy and a manageable safety profile in combination with endocrine therapy in women with oestrogen receptor–positive (ER+)/human epidermal growth factor receptor 2–negative (HER2–) advanced breast cancer (ABC) in international phase 3 trials. The phase 3 PALOMA-4 trial evaluated the efficacy and safety of palbociclib plus letrozole versus placebo plus letrozole in Asian women with ER+/HER2– ABC. MethodsPostmenopausal women (n = 340) with no prior systemic treatment for advanced disease were randomised 1:1 to palbociclib (125 mg/d orally; 3 weeks on, 1 week off) plus letrozole (2.5 mg/d orally; continuously) or placebo plus letrozole. The primary end-point was investigator-assessed progression-free survival (PFS). Secondary end-points included tumour response and safety. ResultsMedian (95% CI) PFS was 21.5 (16.6–24.9) months with palbociclib plus letrozole and 13.9 (13.7–16.6) months with placebo plus letrozole (hazard ratio, 0.68 [95% CI, 0.53–0.87]; P = 0.0012). Consistent with the established safety profile, the most common adverse events (AEs) with palbociclib plus letrozole were neutropenia, leukopenia, thrombocytopaenia, and anaemia. Grade 3/4 neutropenia was reported in 84.5% of patients in the palbociclib arm versus 1.2% in the placebo arm. One serious AE of febrile neutropenia in the palbociclib group was reported. ConclusionsFindings from PALOMA-4 support the efficacy and safety of first-line palbociclib plus letrozole in postmenopausal Asian women with ER+/HER2– ABC. No new safety concerns of palbociclib plus letrozole were identified. Trial registrationClinicaltrials. gov, NCT02297438.

Clinico-Immunological Effects of a Single-Agent CDK4/6 Inhibitor in Advanced HR+/HER2- Breast Cancer Based on a Window of Opportunity Study.

Background: Cyclin-dependent kinase 4/6 inhibitors (CDK4/6 i), abemaciclib, palbociclib, and ribociclib, have been FDA-approved for the treatment of hormone receptor-positive (HR+), HER2−negative (HER2−) advanced breast cancer (aBC). This targeted therapy has revived hope in those aBC patients who did not respond to standard therapies. Interestingly, when administered as a single agent, CDK4/6 modulated several peripheral blood cells after a short-course treatment of 28 days. However, the impact of these immune effects has yet to be thoroughly investigated. Methods: We administered abemaciclib, palbociclib, and ribociclib monotherapy to 23 patients with HR+/HER2− metastatic breast cancer. The aim is to investigate the impact of on-treatment modifications on peripheral blood cells and their composite scores in patients after a 28-day course of CDK4/6 i alone. Results: In the current study, we observed a significant decrease in neutrophils (p-value < 0.001) for patients treated with abemaciclib, palbociclib, and ribociclib. An overall decrease of Tregs was observed and potentially linked to palbociclib treatment. The neutrophile to lymphocyte (N/L) ratio was also decreased overall and potentially linked to abemaciclib and palbociclib treatment. Platelets were decreased in patients administered with abemaciclib. Notably, the radiometabolic response was available only for those patients treated with ribociclib and abemaciclib, and only those lesions treated with ribociclib reached statistical relevance. Conclusions: Our study strongly supports the notion that CDK4/6 inhibitors induce tumour immune modulation. N/L ratio and platelet levels decreased due to treatment. Future studies should test whether patients would benefit from immunomodulators in association with CDK4/6 agents in a larger clinical trial. Moreover, the CDK4/6-induced immune modulation could also be considered a potential predictive clinical factor in HR+/HER2− advanced breast cancer.