HR-positive Metastatic Breast Cancer Research Articles

Prognosis in HR-positive metastatic breast cancer with HER2-low versus HER2-zero treated with CDK4/6 inhibitor and endocrine therapy: a meta-analysis

Prognosis in HR-positive metastatic breast cancer with HER2-low versus HER2-zero treated with CDK4/6 inhibitor and endocrine therapy: a meta-analysis

Combining Endocrine Therapy with Trastuzumab Emtansine Improves Progression-Free Survival and Overall Survival in HER2-Positive, Hormone Receptor-Positive Metastatic Breast Cancer.

Background and Objectives: Patients with human epidermal growth factor receptor 2 (HER2) -positive, hormone receptor-positive (HR-positive) metastatic breast cancer (MBC) usually undergo trastuzumab emtansine (T-DM1) therapy in subsequent lines. Combining endocrine therapy (ET) with T-DM1 can improve treatment outcomes in this subtype. Therefore, this study aimed to investigate the benefits of using T-DM1 with ET in HER2-positive and HR-positive MBC. This study was the first to investigate the benefits of combining ET with T-DM1. Material and Methods: This study analyzed the medical records of patients with HER2-positive and HR-positive MBC who were treated with T-DM1 from June 2010 to December 2021. The patients were divided into groups based on whether they received concomitant ET with T-DM1. The primary endpoint was to determine the progression-free survival (PFS), while the secondary endpoints were overall survival (OS), objective response rate, and safety of the treatment. Results: Our analysis examined 88 patients, of whom 32 (36.4%) were treated with T-DM1 in combination with ET. The combination therapy showed a significant improvement in median PFS (15.4 vs. 6.4 months; p = 0.00004) and median OS (35.0 vs. 23.1 months; p = 0.026) compared to T-DM1 alone. The ORR was also higher in the combination group (65.6% vs. 29.3%; p = 0.026). Patients treated with pertuzumab priorly had reduced median PFS on T-DM1 compared to those who were not treated with pertuzumab (11.7 vs. 5.4 months, respectively; p < 0.01). T-DM1 demonstrated better median PFS in HER2 3+ patients compared to HER2 2+ patients, with an amplification ratio of >2.0 (10.8 vs 5.8 months, respectively; p = 0.049). The safety profiles were consistent with previous T-DM1 studies. Conclusions: The combination of T-DM1 with ET can significantly improve PFS and OS in patients with HER2-positive and HR-positive MBC. Our study suggests that prior pertuzumab treatment plus trastuzumab treatment might decrease T-DM1 efficacy.

Abstract PO4-19-11: A Multicenter, Phase Ib/II Study of Abemaciclib in Combination with Bicalutamide for Androgen Receptor-positive, HER2-negative Metastatic Breast Cancer

Abstract Background The androgen receptor (AR) is expressed in approximately 30% of breast cancers. Phase I and II trials of bicalutamide in HR-negative and enzalutamide in both triple negative breast cancer (TNBC) and hormone receptor (HR) positive populations have shown safety and favorable clinical benefit rates (CBR). Additionally, cell cycle (CC) inhibitors, such as abemaciclib, have demonstrated improved progression free survival (PFS) for patients with HR-positive metastatic breast cancer (MBC) in combination with ET in the first line and subsequent lines of therapy. A preclinical study showed that anti-androgen therapies enhanced CKD4/6 induced cytostatic effect in AR-positive TNBC cell lines. We performed a retrospective, institutional study evaluating metastatic HR+ tumor samples with immunohistochemistry (IHC) from patients treated with CDK4/6 inhibitor, palbociclib. We found a statistically significant increase in event free survival (EFS) for those that had any expression of AR (&amp;gt;0%, median EFS 19 months vs 5 months, HR 0.26, p=0.01). Additionally, AR expression was associated with intact phosphorylated retinoblastoma (Rb) expression (100%, P=0.02), which may represent a mechanism by which CC inhibition is effective in AR+ MBC. Trial Design NCT 05095207 is an ongoing, Phase Ib/II, open label, multi-center study. The primary objective for the phase I portion is to determine the recommended phase II dose (RP2D) of abemaciclib in combination with bicalutamide. The primary objective for the phase II portion is to determine the disease control rate (DCR) at 6-month treatment with abemaciclib and bicalutamide. Patients with HER2-negative MBC who are AR+ (IHC &amp;gt;1%) are eligible. HR-positive participants must have had one prior line of ET in the metastatic setting and no more than 2 prior lines of cytotoxic chemotherapy. HR-negative participants may have had up to 4 prior lines of cytotoxic chemotherapy. In the Phase I portion, up to 12 patients are given abemaciclib 100 mg oral, twice daily on days 1 to 28 and bicalutamide 150 mg oral, daily on days 1 to 28. If there is no toxicity after cycle 1 for the first 3 patients, the dose of abemaciclib will increase to 150 mg twice daily. However, if there is a dose limiting toxicity (DLT) within the first cycle (28 days) of therapy, the dose will decrease to 50 mg twice daily. In the Phase II portion, 51 patients will receive abemaciclib at the RP2D twice daily in addition to bicalutamide 150 mg daily on days 1 to 28. The estimated study duration is 36 months. The drugs will be administered until disease progression or unacceptable toxicity. The primary end points include the DLT and the RP2D for abemaciclib administered with bicalutamide and the DCR at 6 months. The secondary end points include the frequency of adverse effects, the DCR stratified by HR status, and PFS. Exploratory endpoints are to determine whether Ki67, cyclin D1, p16, and phosphorylated Rb expression at baseline are predictors of response to abemaciclib and to determine potential mechanisms for resistance to treatment. For Phase Ib, we will utilize the Bayesian optimal interval (BOIN) design, the RP2D will be selected as the dose closest to the target toxicity rate of 0.3. The observed DLT rate at the current dose is ≤ 0.236, the next cohort will be treated at the next higher dose level, if it is ≥ 0.359 the next cohort will be treated with the next lower dose level. For Phase II, we will assess the DCR using a Simon 2 stage optimal design. If among the 46 evaluable patients, 12 or fewer achieve disease control, the treatment will be rejected, however if 13 or more have disease control, the treatment will be considered worthy for further study. We define inactivity as DCR of 0.20 and activity as DCR of 0.35. To date, the study has recruited 21 participants, the goal accrual is 60 patients. Citation Format: Nicole Casasanta, Chrystal Landry, Theresa Shao, Paula Klein, Julie Fasano, Aarti Bhardwaj, Natalie Berger, Erin Moshier, Gargi Atul Joshi, Rita Vaccaro, Joseph Sparano, Amy Tiersten. A Multicenter, Phase Ib/II Study of Abemaciclib in Combination with Bicalutamide for Androgen Receptor-positive, HER2-negative Metastatic Breast Cancer [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 PO4-19-11.

Abstract RF02-01: A Multicenter, Phase I/II Trial of Anastrozole, Palbociclib, Trastuzumab, and Pertuzumab in Hormone Receptor (HR)-Positive, HER2-Positive Metastatic Breast Cancer (ASPIRE)

Abstract Background: Among patients (pts) with HR-positive and HER2-positive breast cancer, crosstalk between HER2 and estrogen receptor (ER) signaling pathways may contribute to endocrine resistance but anti-HER2 agents in combination with endocrine therapy can restore endocrine sensitivity. Mechanistically, HER2/HER3 signaling promotes survival by way of PI3K-AKT activation whereas ER-CDK4/6-Rb signaling promotes cell cycle progression. The combination of anti-HER2 therapy with an aromatase inhibitor (AI) and a CDK 4/6 inhibitor would allow for blockade of both pathways and provide a novel, all biologic, and chemotherapy-free approach to the treatment of HR-positive, HER2-positive metastatic breast cancer (MBC). Methods: We conducted a phase I/II multi-institution trial in pts with previously untreated, HR-positive and HER2-positive MBC. In the Phase I portion, pts received escalating doses of palbociclib (100mg, 125mg) in conjunction with trastuzumab, pertuzumab and an AI anastrozole, using a 3+3 dose escalation trial design. In the phase II portion, pts received palbociclib at the maximum tolerated dose (MTD), anastrozole, trastuzumab, and pertuzumab. The primary endpoints of the Phase I and II portions were MTD and clinical benefit rate (CBR) defined as the sum of complete response, partial response, and stable disease for &amp;gt;/= 6 months, respectively. Secondary endpoints included progression free survival (PFS), objective response rate (ORR) and safety. The Phase II portion of this study was powered with 30 pts to show efficacy of palbociclib administered at the MTD in combination with anastrozole, trastuzumab and pertuzumab if the CBR achieved at 6 months exceeded 58%. The Clopper-Pearson method was used to calculate confidence intervals for ORR and CBR. The PFS distribution was estimated using the Kaplan-Meier method. Results: In the Phase I portion, a total of 9 pts were enrolled. No DLTs were observed at the 100mg dose (N=3) or the 125mg dose (N=6) level, and thus, 125mg was established as the MTD. An additional 24 pts were enrolled to the Phase II portion at the MTD, with a total of 30 pts in the modified intention-to-treat population included in the efficacy analysis. The median age of the population was 57.6 years (range 50.5-63.8) and 27% of pts were premenopausal and received ovarian function suppression as part of treatment. As shown in Table 1, the primary endpoint, CBR, was 97% (95% CI: 0.83-1.0, p&amp;lt;0.0001). ORR was 70% (95% CI: 0.51-0.85). Median time to objective response was 2.8 months with earliest response at 3 months. Median duration of response was not reached with range of 5.1-42.2 months. Median PFS was also not reached with range of 8-44.8 months. Safety data were consistent with known toxicity profiles of agents. Most common adverse events included diarrhea (80%), neutropenia (77%), leukopenia (70%), anemia (67%), and fatigue (60%). Grade 3-4 events occurred in 63% (19/30) of pts and included neutropenia (68%), leukopenia (32%), decrease in absolute neutrophil count (21%), and anemia (21%). Conclusions: The combination of anastrozole, palbociclib, trastuzumab, and pertuzumab was well tolerated and effective with a clinical benefit rate of 97% in pts with previously untreated HR-positive, HER2-positive MBC. The combination provides a chemotherapy-free alternative for pts with triple positive breast cancers. Further follow up will determine impact on PFS. Table 1. Results in Patients on Anastrozole, Palbociclib, Trastuzumab, and Pertuzumab Citation Format: Rima Patel, Krystal Cascetta, Paula Klein, Erin Moshier, Maryann Kwa, Julie Fasano, Anupama Goel, Melissa Accordino, Charles Shapiro, Rita Vaccaro, Gargi Atul Joshi, Joseph Sparano, Amy Tiersten. A Multicenter, Phase I/II Trial of Anastrozole, Palbociclib, Trastuzumab, and Pertuzumab in Hormone Receptor (HR)-Positive, HER2-Positive Metastatic Breast Cancer (ASPIRE) [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 RF02-01.

Impact of HER2-low expression on the efficacy of endocrine therapy with or without CDK4/6 inhibitor in HR-positive/HER2-negative metastatic breast cancer: A prospective study.

CDK4/6 inhibitors in combination with traditional endocrine therapy (ET) have become the recommended first-line therapy for HR-positive/HER2-negative metastatic breast cancer (MBC). The aim of this prospective study was to evaluate the relationship between HER2-low expression and clinical outcomes in HR-positive/HER2-negative MBC patients receiving ET with or without CDK4/6 inhibitors. Between April 2016 and November 2019, 233 women with HR-positive/HER2-negative MBC who received ET with or without CDK4/6 inhibitors were enrolled into the study. The primary endpoint was progression-free survival (PFS). Statistical analysis included descriptive statistics, Kaplan-Meier curves, and Cox proportional hazards models. HER2-low and HER2-zero subgroups in the CDK4/6 inhibitor plus ET cohort showed no significant difference in the median PFS (10.9 vs. 8.0 months; hazard ratio: 0.92; 95% confidence interval [CI]: 0.64-1. 30; p = 0.65), while HER2-low subgroup showed a significantly shorter median PFS compared to the HER2-zero subgroup in the ET alone cohort (5.6 vs. 17.0 months; hazard ratio: 2.82; 95% CI: 1.34-5.93; p = 0.0044). Moreover, the objective response rate was significantly lower in the HER2-low subgroup than the HER2-zero subgroup in the ET alone cohort (10.5% vs. 40.0%, p = 0.047). Lastly, no significant difference was observed in the overall survival between the HER2-low and HER2-zero subgroups in both cohorts. This study suggested that HER2-low expression may predict the efficacy of ET but not that of CDK4/6 inhibitor plus ET in HR-positive/HER2-negative MBC patients. The results of this study highlight the importance of integrating HER2 status in tailoring personalized treatment strategies for HR-positive MBC.

Efficacy of anlotinib in Chinese patients with metastatic breast cancer: A retrospective observational study.

Anlotinib, a multitarget tyrosine kinase inhibitor, can inhibit tumour angiogenesis proliferation, metastasis, promote vascular normalization, increase T cell and NK cell activity and infiltration, remodel tumour microenvironment and synergistic immune enhancement. Our study aimes to evaluate the efficacy of anlotinib in the treatment of advanced metastatic breast cancer (MBC) after multiple lines of therapy. Patients included were treated with anlotinib for advanced MBC in the Affiliated Cancer Hospital of Zhengzhou University from 1 January 2019 to 30 June 2023. The objective remission rate, disease-free progression survival and adverse reactions were analysed. We compared and analysed the efficacy of anlotinib in the treatment of advanced metastatic breast cancer, which showed that ORR was 23.6% and DCR was 69.1%. The DCR of monotherapy was 66.7% and that of combination therapy was 69.6% in MBC patients. The combination therapy, combined with chemotherapy had the best effect (79.3%), combined with immunotherapy came second. In addition, the DCR (88.9%) was higher in MBC patients having received prior antiangiogenic therapy. According to the Kaplan-Meier (K-M) survival estimate analysis, the mPFS was 4.17 months (95% CI, 1.758-6.582 months) in Her-2 positive MBC patients, and 7.83 months (95% CI, 2.416-9.104) in Her-2 negative MBC patients. The mPFS was 5.76 months (95% CI, 3.231-8.298 m) in HR positive MBC patients, 7.83 months (95% CI, 3.182-12.478 m) in TNBC patients. Fatigue (20.0%), hypertension (21.8%) and liver dysfunction (18.2%) were common adverse reactions, followed by bone marrow suppression (16.4%), anorexia (14.5%), hypothyroidism (14.5%) and diarrhoea (14.5%). Altogether, Anlotinib monotherapy or combination therapy provides a viable third (or above)-line therapeutic strategy in patients with metastatic breast cancer. The adverse reactions of anlotinib are well tolerated and controllable.

Pyrotinib in combination with letrozole for hormone receptor-positive, human epidermal growth factor receptor 2-positive metastatic breast cancer (PLEHERM): a multicenter, single-arm, phase II trial

BackgroundHuman epidermal growth factor receptor 2 (HER2) targeted therapy combined with endocrine therapy has been recommended as an alternative treatment strategy for patients with hormone receptor (HR)-positive, HER2-positive metastatic breast cancer (MBC). This study aimed to evaluate the role of pyrotinib, an oral pan-HER irreversible tyrosine kinase inhibitor, in combination with letrozole for patients with HR-positive, HER2-positive MBC.MethodsIn this multi-center, phase II trial, HR-positive and HER2-positive MBC patients who were not previously treated for metastasis disease were enrolled. Patients received daily oral pyrotinib 400 mg and letrozole 2.5 mg until disease progression, unacceptable toxicity, or withdrawal of consent. The primary endpoint was the clinical benefit rate (CBR) assessed by an investigator according to the Response Evaluation Criteria in Solid Tumors version 1.1.ResultsFrom November 2019 to December 2021, 53 patients were enrolled and received pyrotinib plus letrozole. As of August 2022, the median follow-up duration was 11.6 months (95% confidence interval [CI], 8.7–14.0 months). The CBR was 71.7% (95% CI, 57.7–83.2%), and the objective response rate was 64.2% (95% CI, 49.8–76.9%). The median progression-free survival was 13.7 months (95% CI, 10.7–18.7 months). The most common treatment-related adverse event of grade 3 or higher was diarrhea (18.9%). No treatment-related deaths were reported, and one patient experienced treatment discontinuation due to adverse event.ConclusionsOur preliminary results suggested that pyrotinib plus letrozole is feasible for the first-line treatment of patients with HR-positive and HER2-positive MBC, with manageable toxicities.Trial registrationClinicalTrials.gov, NCT04407988.

Cyclin-Dependent Kinase 4/6 Inhibitors Beyond Progression in Metastatic Breast Cancer: A Retrospective Real-World Biomarker Analysis.

As the continuation beyond progression (BP) of cyclin-dependent kinase 4/6 inhibitors (CDK4/6i) is becoming increasingly attractive for the treatment of patients with hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative metastatic breast cancer (MBC), the definition of resistance factors is crucial. The aim of the study was to investigate the impact of CDK 4/6i BP and to explore potential genomic stratification factors. We retrospectively analyzed a multi-institutional cohort of patients with HR-positive HER2-negative MBC characterized for circulating tumor DNA through next-generation sequencing before treatment start. Differences across subgroups were analyzed by chi-square test, and survival was tested by univariable and multivariable Cox regression. Further correction was applied by propensity score matching. Among the 214 patients previously exposed to CDK4/6i, 172 were treated with non-CDK4/6i-based treatment (non-CDK) and 42 with CDK4/6i BP. Multivariable analysis showed a significant impact of CDK4/6i BP, TP53 single-nucleotide variants, liver involvement, and treatment line on both progression-free survival (PFS) and overall survival (OS). Propensity score matching confirmed the prognostic role of CDK4/6i BP both for PFS and OS. The favorable impact of CDK4/6i BP was consistent across all subgroups, and a differential benefit was suggested for ESR1-mutated patients. ESR1 and RB1 mutations were more represented in the CDK4/6i BP subgroup with respect to CDK4/6i upfront. The study highlighted a significant prognostic impact of the CDK4/6i BP strategy with a potential added benefit in patients with ESR1 mutations suggesting the need for an extensive biomarker characterization.

Treatment of palbociclib in hormone receptor positive breast cancer: a real-world study and efficacy prediction model

Objective: To summarize the clinical use of palbociclib and evaluate its efficacy and safety in hormone-receptor (HR)-positive advanced breast cancer patients. Methods: We retrospectively analyzed data from 66 HR-positive metastatic breast cancer patients treated with palbociclib and endocrine therapy at the Department of Oncology in the First Affiliated Hospital with Nanjing Medical University between 2018 and 2020. We evaluated the factors affecting the efficacy of palbociclib using Kaplan-Meier method and Log-rank test for survival analysis and Cox regressions for multivariate analysis. Nomogram model was built for predicting prognosis among HR-positive breast cancer patients who received palbociclib. Concordance index (C-index) and calibration curve were used for internal validation to assess the predictive ability and conformity of the model. Results: Of the 66 patients treated with palbociclib, 33.3%(22), 42.4%(28) and 24.2%(16) patients were treated without endocrine therapy, first-line endocrine therapy, second-line or above endocrine therapy after recurrence, respectively. 36.4%(24) patients had hepatic metastasis, 16.7% (11) patients were sensitive to previous endocrine therapy, 27.3%(18/66) patients had primary resistance to endocrine therapy, while 56.1% (37) patients had secondary resistance to endocrine therapy. The overall response rate was 14.3% (95% CI: 6.7%, 25.4%) and clinical benefit rate was 58.7% (95% CI: 45.6%, 71.0%). Better clinical outcomes were associated with non-hepatic metastasis (P=0.001), sensitive/secondary resistant to previous endocrine therapy (P=0.004), no or only one line of chemotherapy for metastatic breast cancer (P=0.004), recent pathological confirmation of immunohistochemical analysis (P=0.025). Hepatic metastasis (P=0.005) and primary resistance to endocrine therapy (P=0.016) were the independent risk factors of progression free survival. The C-index of predictive probability for the nomogram constructed from the patient clinical characteristics (whether liver metastasis, whether primary endocrine resistance, lines of chemotherapy after metastasis, lines of endocrine therapy, number of metastatic sites, and time to last immunohistochemistry) to predict the progression-free survival at 6 and 12 months for patients was 69.7% and 72.1%, respectively. The most common adverse events were hematologic toxicities. Conclusions: Our report indicates that palbociclib combined with endocrine therapy for HR-positive recurrent metastatic breast cancer is effective and safe; patients with hepatic metastases and primary resistance to endocrine therapy have worse prognoses and are independent risk factors for progression after palbociclib therapy. The constructed nomogram could help predict the survival and guide the use of palbociclib.

Fulvestrant plus palbociclib in advanced or metastatic hormone receptor-positive/human epidermal growth factor receptor 2-negative breast cancer after fulvestrant monotherapy: Japan Breast Cancer Research Group-M07 (FUTURE trial)

PurposeThe combination of cyclin-dependent kinase 4/6 inhibitors and endocrine therapy is a standard treatment for hormone receptor (HR)-positive/human epidermal growth factor receptor 2 (HER2)-negative metastatic breast cancer (MBC); however, their toxicities and financial burden are major issues, especially for prolonged treatment. We investigated fulvestrant plus palbociclib in patients with HR-positive MBC resistant to fulvestrant monotherapy.MethodsPatients who initially received fulvestrant as their first- or second-line endocrine therapy were assigned to group A. Patients with disease progression during fulvestrant monotherapy who subsequently received fulvestrant plus palbociclib were assigned to group B. The primary endpoint was progression-free survival (PFS1) in group B. We set the threshold median PFS of 5 months (null hypothesis).ResultsBetween January 2018 and February 2020 we enrolled 167 patients in group A (January 2018–February 2020) from 55 institutions, of whom 72 subsequently received fulvestrant plus palbociclib and were enrolled in group B. The median follow-up was 23.8 and 8.9 months in groups A and B, respectively. The median PFS in group B (combination therapy) was 9.4 (90% confidence interval [CI]: 6.9–11.2) months (p < 0.001). This was 25.7 (90% CI: 21.2–30.3) months in group A (fulvestrant monotherapy). The TTF in group B was 7.2 (90% CI: 5.5–10.4) months. In the post-hoc analysis, the median PFS1 in group B among patients with longer-duration fulvestrant monotherapy (> 1 year) was longer than that of patients with shorter-duration monotherapy (≤ 1 year) (11.3 vs. 7.6 months). No new toxicities were observed.ConclusionOur findings suggest that palbociclib plus fulvestrant after disease progression despite fulvestrant monotherapy is potentially safe and effective in patients with HR-positive/HER2-negative advanced MBC.

Abstract PD18-07: Omission of chemotherapy in the treatment of HER2-positive and hormone-receptor positive metastatic breast cancer – interim results from the randomized phase 3 DETECT V trial

Abstract Background: Metastatic breast cancer (MBC) is an incurable disease and both the improvement of survival and maintenance of quality of life (QoL) are equally important aims of treatment planning. In patients with HER2-positive MBC, taxane-based chemotherapy in combination with dual HER2 targeted therapy with trastuzumab (T) and pertuzumab (P) is the standard of care first line therapy. However, adverse events are well-known side effects of any cytostatic treatment and can seriously impact the patients’ QoL. In addition, in HER2-positive MBC activated estrogen receptor (ER) signaling is associated with primary or secondary resistance. Thus, for patients with HER2-positive and hormone-receptor (HR) positive MBC, the synergistic combination of dual HER2-targeted therapy plus endocrine therapy might offer a better treatment option compared to cytotoxic chemotherapy-based treatments. Methods: Between 9/2015 and 11/2022, the multicenter phase III DETECT V trial randomized patients with HER2-positive and HR-positive (i.e. ER positive and/or progesterone-receptor positive) MBC in the 1st-3rd line setting 1:1 to receive T and P combined with either endocrine therapy or chemotherapy followed by maintenance therapy with T, P and endocrine therapy. Chemotherapy and the endocrine agents could be chosen from a variety of available regimens according to physicians’ choice. Based on emerging data strongly suggesting an additional benefit of CDK4/6 inhibitors, an amendment came into effect in January 2019 with the addition of ribociclib to both treatment arms after 124 patients had been randomized. The primary objective of DETECT V is to compare tolerability between the chemotherapy-free and chemotherapy-containing treatment arm; secondary objectives comprise the comparison of PFS, OS and safety. Here we report results of an unplanned interim analysis with data cut off June 22th 2022. Results: The results reported here are based on 153 patients for whom end of study was documented at the time of data cut off for this interim analysis (120 patients randomized before and 33 patients randomized after the addition of ribociclib; 115 patients in the 1st line setting; 77 and 76 patients in the chemotherapy-free and chemotherapy-containing arm, respectively). Overall survival (OS) and progression-free survival (PFS) did not differ between patients receiving chemotherapy-free and chemotherapy-containing treatment (median OS not yet reached vs. 37.2 months, hazard ratio 0.87, 95% CI 0.51 – 1.50, p = 0.63; median PFS 15.6 vs. 14.9 months, hazard ratio 0.98, 95% CI 0.64 – 1.52, p = 0.93). Study treatment was terminated prematurely significantly less often in the chemotherapy-free treatment arm (43.9% vs. 72.2%, p = 0.001). Furthermore, tolerability was better for the chemotherapy-free treatment as there were less adverse events (AEs) of any grade (585 vs. 793; 70 vs. 71 patients affected), less AEs grade 3 or higher (66 vs. 90; 33 vs. 48 patients affected) and less serious adverse events (45 vs. 52; 28 vs. 29 patients affected) reported in the chemotherapy-free treatment arm as compared to the chemotherapy-containing treatment arm. Conclusion: These preliminary results suggest that chemotherapy-free treatment for patients with triple-positive MBC might be an effective and well tolerated option. Citation Format: Wolfgang Janni, Tanja Fehm, Volkmar Müller, Fabienne Schochter, Amelie De Gregorio, Thomas Decker, Andreas Hartkopf, Marianne Just, Jacqueline Sagasser, Marcus Schmidt, Pauline Wimberger, Maggie Banys-Paluchowski, Peter A. Fasching, Brigitte Rack, Sabine Riethdorf, Andreas Schneeweiss, Diethelm Wallwiener, Franziska Meier-Stiegen, Natalia Krawczyk, Oliver Hoffmann, Jens-Uwe Blohmer, Dieter Niederacher, Hans Neubauer, Klaus Pantel, Thomas W. Friedl, Jens Huober. Omission of chemotherapy in the treatment of HER2-positive and hormone-receptor positive metastatic breast cancer – interim results from the randomized phase 3 DETECT V trial [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 PD18-07.

Abstract P5-14-04: Genomic characterization of hormone receptor-positive advanced breast cancer with high tumor mutational burden: fresh-frozen tissue genomic analysis from MUTATION-1 study (KCSG BR17-04)

Abstract Background The hormone receptor (HR)-positive metastatic breast cancer (MBC) patients show a diverse range of tumor mutational burden (TMB), but its biological and clinical implication has been largely unrevealed. Here we report genomic landscape of 117 HR+ MBC patients who were included in the pre-screening tissue genomic analysis of MUTATION-1 study (SABCS 2021; Abs P1-19-03) according to TMB of tumors. Patients and method The MUTATION-1 study (NCT03608865) enrolled HR-positive MBC patients who received prior ≥ 1 line of systemic therapy, and performed prescreening with whole exome sequencing (WES) and RNA-seq of fresh-frozen tissue of metastatic or recurred tumors. Patients who met upper 30% of TMB were eligible for treatment phase and received durvalumab plus tremelimumab. This study analyzed 117 prescreening tissues of MUTATION-1 study patients for mutation and transcriptomic landscape analysis. (WES, n=117; RNA-seq, n=107) Results The 117 patients showed diverse TMB (range 0~21.7 mut/Mb, median 2.0 mut/Mb) and genomic alterations. The most frequently mutated gene included PIK3CA (29.1%), TP53 (27.4%), ESR1 (23.9%), GATA3 (19.7%), and MAP3K1 (12.0%). There was no association between patient survival and TMB. We estimated single base substitution (SBS) mutational signature of patients with SigMA algorithm. The patients were classified according to their dominant mutational signatures: APOBEC (25.6%), HRD (41.0%), clockwise (28.2%), SBS8, and SBS17. The APOBEC patients showed higher TMB (median 3.47 mut/Mb) and higher mutation prevalence in PIK3CA (63.3% vs. 29.1%), ARID1A (16.7% vs. 6.0%), and NF1 (16.7% vs. 6.8%) compared with other patients. The high TMB positively correlated with time from MBC diagnosis to biopsy. Tumors with TMB ≥ 5 mut/Mb were exclusively found in patients diagnosed as MBC ≥ 36 months before the timing of biopsy. In the matched RNA-seq analysis, TMB was higher in luminal B and HER2-enriched intrinsic subtype patients than basal or luminal A subtype. The high TMB (≥ 3.16 mut/Mb, cutoff used for treatment phase patient selection) patients showed upregulation of G2/M checkpoint, MYC, E2F1, and MTORC1 signature compared to low TMB patients. In the tumor microenvironment analysis by CIBESORT, PIK3CA mutant patients showed lower score of cytotoxic T cell than others. Conclusions The high TMB in HR+ breast cancer was associated with longer time duration from MBC diagnosis to biopsy, high APOBEC signature, and cell cycle/MYC signature gene upregulation. Further therapeutic targeting of high TMB patients is warranted based on their genomic and immunologic characteristics. Citation Format: Min Hwan Kim, Yohan Yang, Eunyoung Kim, Yong Wha Moon, Gun Min Kim, Seul-Gi Kim, Yee Soo Chae, Jieun Lee, Jae Ho Jeong, Kyung-Hun Lee, Han Jo Kim, Joo Young Jung, Su-Jin Koh, Kyoung Eun Lee, Hee-Jun Kim, Kyong Hwa Park, Seungtaek Lim, Yeon Hee Park, Sangwoo Kim, Joo Hyuk Sohn. Genomic characterization of hormone receptor-positive advanced breast cancer with high tumor mutational burden: fresh-frozen tissue genomic analysis from MUTATION-1 study (KCSG BR17-04) [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 P5-14-04.

Treatment Sequencing Patterns and Associated Direct Medical Costs of Metastatic Breast Cancer Care in the United States, 2011 to 2021

Advances in treatment of metastatic breast cancer (MBC) led to changes in clinical practice and treatment costs in the US over the past decade. There is limited information on current MBC treatment sequences and associated costs by MBC subtype in the US. To identify treatment patterns by MBC subtype and associated anticancer and supportive drug costs from health care sector and Medicare perspectives. This economic evaluation analyzed data of patients with MBC obtained from the nationwide Flatiron Health database, an electronic health record-derived, deidentified database with data from community and academic practices across the US from 2011 to 2021. Participants included women aged at least 18 years diagnosed with MBC, who had at least 6 months of follow-up data, known hormone receptor (HR) and human epidermal growth factor receptor 2 (ERBB2) receptor status, and at least 1 documented line of therapy. Patients with documented receipt of clinical study drugs were excluded. Data were analyzed from June 2021 to May 2022. Outcomes of interest were frequency of different drug regimens received as a line of therapy by subtype for the first 5 lines and mean medical costs of documented anticancer treatment and supportive care drugs per patient by MBC subtype and years since metastatic diagnosis, indexed to 2021 US dollars. Among 15 215 patients (10 171 patients [66.85%] with HR-positive and ERBB2-negative MBC; 2785 patients [18.30%] with HR-positive and ERBB2-positive MBC; 802 patients [5.27%] with HR-negative and ERBB2-positive MBC; 1457 patients [9.58%] with triple-negative breast cancer [TNBC]) who met eligibility criteria, 1777 (11.68%) were African American, 363 (2.39%) were Asian, and 9800 (64.41%) were White; the median (range) age was 64 (21-84) years. The mean total per-patient treatment and supportive care drug cost using publicly available Medicare prices was $334 812 for patients with HR-positive and ERBB2-positive MBC, $284 609 for patients with HR-negative and ERBB2-positive MBC, $104 774 for patients with HR-positive and ERBB2-negative MBC, and $54 355 for patients with TNBC. From 2011 to 2019 (most recent complete year 1 data are for patients diagnosed in 2019), annual costs in year 1 increased from $12 986 to $80 563 for ERBB2-negative and HR-positive MBC, $99 997 to $156 712 for ERBB2-positive and HR-positive MBC, and $31 397 to $53 775 for TNBC. This economic evaluation found that drug costs related to MBC treatment increased between 2011 and 2021 and differed by tumor subtype. These findings suggest the growing financial burden of MBC treatment in the US and highlights the importance of performing more accurate cost-effectiveness analysis of novel adjuvant therapies that aim to reduce metastatic recurrence rates for early-stage breast cancer.

228P Fulvestrant with additional palbociclib in advanced or metastatic hormone receptor-positive HER2-negative breast cancer after progression to fulvestrant monotherapy: JBCRG- M07 (FUTURE trial)

Fulvestrant is one of the standard treatments for first- or second-line endocrine therapy for hormone receptor (HR)-positive metastatic breast cancer (MBC). We investigated whether the addition of palbociclib to fulvestrant was effective and safe in patients with HR-positive MBC and advanced breast cancer (ABC) who relapsed with fulvestrant monotherapy. Patients were primary registered during fulvestrant treatment as 1st or 2nd endocrine therapy. Patients were secondary registered when patients had disease progression during fulvestrant monotherapy and received fulvestrant and palbociclib as the study treatment. The primary endpoint was progression free survival(PFS) from the start of the study treatment. The secondary endpoints included the time to treatment failure(TTF) from the start of the study treatment and adverse events. Our null hypothesis was a median PFS of 5 months, which was the value reported in the PALOMA 3 study. Assuming the median PFS of 8 months for the alternative hypothesis, 63 patients were required to reject the null hypothesis with 80% power under a one-sided alpha of 0.05. (UMIN 000029294). Between January, 2018 and February, 2020, we enrolled 167 patients from 55 institutions as 1st registration. However, nine cases were excluded from analysis for not meeting inclusion criteria. Of these, 72 patients were enrolled in 2ndary registration. Median follow up time were 23.8 months from 1st registration and 8.9 months from 2nd registration. Median PFS of the study treatment in patients with resistance to fulvestrant monotherapy was 9.4 months (90% Confidence interval 6.9- 11.2 months, p<0.001). TTF from 2nd registration was 7.2 months (90% CI 5.5- 10.4 months). No new adverse events were observed. Our data suggest that palbociclib plus fulvestrant beyond disease progression to fulvestrant monotherapy is possibly effective and safe in patients with HR-positive HER2-negative ABC/MBC.

268P Results from a real-world study of patients (pts) with hormone-receptor (HR)-positive HER2-negative metastatic breast cancer (MBC) treated with CDK4/6 inhibitors (CDK 4/6i) in three institutions

CDK 4/6i combined with endocrine therapy have become the gold standard in HR-positive HER-negative MBC treatment. Pts included in randomized clinical trials (RCT) are often not representative of real population. Real word data (RWD) can be used to confirm reproducibility of evidence from RCTs in routine clinical practice. We report results from retrospective analysis of a RWD cohort of pts.

Prospective Cohort Study of Palbociclib Treatment in Postmenopausal Patients With Unresectable and Metastatic Hormone Receptor-Positive Breast Cancer: Study Protocol for a CSPOR-BC Palbociclib Cohort Trial.

BackgroundCombining palbociclib with letrozole or fulvestrant improved progression-free survival in hormone receptor (HR)-positive and human epidermal growth factor receptor-negative metastatic breast cancer. However, combining palbociclib to endocrine treatment increases toxicity and cost compared with the endocrine treatment alone. Moreover, palbociclib treatment may affect the outcome of the subsequent treatment because its benefit in terms of overall survival has not been observed yet. Therefore, it is crucial to examine whether palbociclib can improve clinical outcomes and quality of life (QoL) of patients in the real world.MethodsA prospective observational study with palbociclib is planned in 3 cohorts (A, B, and C) as per the line of endocrine treatment (i.e., first-line, second-line, or third-line or later-line treatment) for postmenopausal metastatic or unresectable breast cancer. The primary endpoint is progression-free survival in each treatment line, the most commonly used endpoint for global phase 3 studies. As per the results of these studies, the planned sample size is 700 cases: cohort A, 340 cases; cohort B, 200 cases; and cohort C, 130 cases. The secondary endpoints are overall survival, clinical benefit rate, time to chemotherapy, adverse events (AEs), patient-reported outcomes (PROs), and health-related QoL (HRQoL). These endpoints are evaluated again during the subsequent treatment. This study will examine whether the efficacy, safety, and QoL effects of palbociclib treatment in daily clinical practice are not inferior compared to those in clinical trials and whether palbociclib treatment affects the efficacy and safety of the subsequent treatment. Moreover, this study would provide information on the most effective time of adding palbociclib to endocrine treatment.DiscussionThe reproducibility of randomized clinical trials (RCTs) using real-world data must be confirmed to evaluate whether real-world treatment benefits are similar to those observed in RCTs. Although the efficacy of palbociclib has been confirmed in RCTs, Aes of this drug, including its toxicities and cost, are not comparable to those of mono-hormone therapies. Thus, PROs/HRQoL is an important element of this study because several patients with HR-positive metastatic breast cancer have diseases for which sequential hormone therapy is preferential.

Clinical characteristics and real-world progression-free survival (rwPFS) of patients with HER2-positive and hormone receptor (HR)-positive metastatic breast cancer (MBC) initiating endocrine therapy (ET) in combination with the first line of treatment: An analysis of electronic health records in the United States.

e13028 Background: Dual HER2 blockade with pertuzumab (P) + trastuzumab (H), combined with taxane induction therapy, is the standard of care for the first-line treatment of patients with HER2-positive MBC. In clinical practice, after achieving clinical benefit with approximately 4–6 cycles of PH + taxane induction, maintenance therapy is continued with PH only until disease progression or unmanageable toxicity. Approximately 50–60% of patients with HER2-positive MBC also have concurrent HR expression and may receive ET in combination with PH. This study investigated the clinical characteristics and outcomes of patients initiating ET combined with PH as maintenance therapy after completion of PH + taxane induction. Methods: We conducted a retrospective cohort study using a nationwide US electronic health record-derived de-identified database (Flatiron Health). Patients with HER2-positive and HR-positive MBC who initiated an ET between Jan 1, 2012 and Feb 28, 2021 with concomitant PH after receiving at least four cycles of first-line PH + taxane induction were included. The index date was the date of ET initiation. Progression data were abstracted from the medical charts. Mortality data were abstracted and combined with patient-level structured data (obituaries and Social Security Death Index). rwPFS was defined as the time from index date until first progression event &gt; 14 days after the index date, or date of death; otherwise, patients were censored on the date of last clinical note abstraction. Baseline characteristics were described using summary statistics, and rwPFS in the maintenance setting was described using a Kaplan–Meier estimator from the index date. Results: Of 24,690 patients diagnosed with MBC in the database, 252 (1%) met the eligibility criteria. All patients were female. The median age was 56.6 years; 149 patients (59%) were diagnosed with de novo MBC; 248 (98%), with estrogen receptor-positive disease; and 182 (72%), with progesterone receptor-positive disease. One hundred ninety-three patients (77%) received an aromatase inhibitor as ET. The median number of taxane cycles received prior to the index date was six. Median maintenance rwPFS was 21.4 months (95% confidence interval = 16.1, 25.3). Conclusions: Given the therapeutic opportunity presented by HER2/HR co-expression and the favorable maintenance rwPFS shown here with PH + ET following taxane induction, the investigation of more potent ETs combined with PH is justified in order to further improve outcomes in first-line HER2-positive/HR-positive MBC.

The effect of BMI on the outcomes of CDK 4/6 inhibitor therapy in HR-positive metastatic breast cancer patients.

e13010 Background: The standard of care in patients with hormone receptor (HR) -positive metastatic breast cancer is a cyclin-dependent kinase (CDK) 4/6 inhibitor combined with endocrine therapy (ET). Preclinical studies show that metabolic processes and cell metabolism such as adipogenesis, lipid synthesis and glucose regulation is affected by cell cycle regulators such as CDK 4 and 6. There are limited data regarding the impact of body mass index (BMI) on the efficacy of cyclin-dependent kinase 4/6 inhibitors plus endocrine therapy (ET) in metastatic breast cancer. We aimed to investigate the effect of BMI on the progression-free survival (PFS) in HR-positive metastatic breast cancer who received CDK4/6 inhibitor. Methods: This study was conducted as a retrospective cohort study, and data were obtained from three institution medical records. Patients with metastatic HR-positive breast cancer receiving CDK 4/6 inhibitor (palbociclib or ribociclib) plus ET (letrozole, anastrozole, or fulvestrant) were enrolled in the study. 179 patients were enrolled in the study between the January 2018 and December 2021. The patients were divided into three groups according to BMI level as follows; group 1: 18.5-24.9 kg/m2, group 2: 25-29.9 kg/m2 and group 3: ≥ 30 kg/m2. Median follow-up was 10.94 months. Categorical variables were compared using the chi-square test or two-sided Fisher’s exact test. Comparison of PFS and BMI categories were performed through Kaplan-Meier curve and log-rank test. Results: 179 patients were included the study (42 [24%] in group 1, 65 [36%] in group 2, and 72 [40%] in group 3). The 12-month PFS was 52.9% in group 1, was 72.2% in group 2 and was 56.5% in group 3. There was no significant different between the groups (p = 0.054). However, group 2 patients tend to have a better outcome in term of PFS. When palbociclib plus ET and ribociclib plus ET were evaluated separately, the 12-month PFS rates between the BMI groups were higher in group 2 patients who received palbociclib plus ET, but there was no statistical significance (Ribociclib plus ET: 63.2% in group 1, 73.3% in group 2, 59.7% in group 3, p = 0.51. Palbociclib plus ET: 44.3% in group 1, 71.5% in group 2, 52.8% in group 3, p = 0.07). Hematological and non-hematological toxicity were similar between BMI groups (p &gt; 0.05, for all). Adverse events of grade 3 or 4 occurred in 18 (42.9%) of 42 patients in group 1 and in 20 (30.8%) of 65 patients in group 2 and in 22 (30.6%) of 72 patients in group 3 (p = 0.34). Dose reduction for CDK4/6 inhibitors was also similar between groups (p = 0.42). Median PFS was not reached due to a limited number of events in each group. Conclusions: In this study, we demonstrated the tendency that overweight patients with metastatic breast cancer may benefit more from CDK4/6 inhibitors in term of PFS from interim analyses of our data. Similar toxicity rates and adverse events were observed in all BMI groups with CDK4/6 inhibitors plus ET.

Palbociclib plus letrozole induces a complete metabolic response in metastatic breast cancer patient with idiopathic thrombocytopenia.

Breast cancer is still the leading cause of cancer-related deaths among women aged 20-59 and metastatic breast cancer remains an incurable disease. The therapeutic paradigm of patients with HR-positive HER2-negative metastatic breast cancer has been expanded by the introduction of the inhibitors of cyclin-dependent kinases 4/6. Three compounds, palbociclib, ribociclib, and abemaciclib, have already been approved by the Food and Drug Administration (FDA) for use together with endocrine therapy; abemaciclib is also approved as a single agent. In the first-line setting, all three agents - together with an aromatase inhibitor (AI) - substantially prolonged progression-free survival. Hematologic toxicities are the most common adverse events associated with CDK4/6i, mainly with palbociclib and ribociclib. Due to the hematologic toxicity, the prescribing information of palbociclib (P) recommends monitoring complete blood counts before starting therapy and at the beginning of each cycle, as well as on day 15 of the first 2 cycles. However, there are no guidelines regarding the management of patients candidate to CDK4/6i who have bone marrow impairment. Neutropenia frequently occurs during the treatment with P, whereas thrombocytopenia represents a rare event. We here report a case of a 60-year-old woman with idiopathic thrombocytopenia treated with P plus letrozole, who presented a metabolic complete response.

Dalpiciclib Combined With Pyrotinib and Letrozole in Women With HER2-Positive, Hormone Receptor-Positive Metastatic Breast Cancer (LORDSHIPS): A Phase Ib Study.

PurposeThe LORDSHIPS study aimed to explore the safety and efficacy of a novel fully oral triplet combination of dalpiciclib (a potent cyclin-dependent kinase 4/6 inhibitor), pyrotinib (a HER2 tyrosine kinase inhibitor) and endocrine therapy letrozole in patients with HER2-positive, hormone receptor (HR)-positive metastatic breast cancer (MBC) in the front-line setting.Patients and MethodsPostmenopausal women with HER2-positive, HR-positive MBC were recruited in the dose-finding phase Ib trial. A standard 3 + 3 design was used to determine safety, tolerability, and recommended phase II dose (RP2D) for the combination.ResultsA total of 15 patients were enrolled to three dose combination cohorts (letrozole/pyrotinib/dalpiciclib, level/I: 2.5/400/125 mg, n=5; level/L1: 2.5/400/100 mg, n=6; level/L2: 2.5/320/125 mg, n=4). Three patients experienced dose-limiting toxicities (level/I, n=2; level/L1, n=1) and level/L2 was identified as RP2D. The most frequent grade 3-4 adverse events were neutropenia (46.7%), leukopenia (40.0%), oral mucositis (26.7%) and diarrhea (20.0%). The confirmed objective response rate (ORR) was 66.7% (95% CI: 38.4% to 88.2%). The confirmed ORR of study treatment as first line (1L) and second line (2L) HER2-targeted therapy was 85.7% (6/7) and 50.0% (4/8), respectively. Median progression-free survival (PFS) was 11.3 months (95% CI: 5.3 months to not reached). PFS in 1L setting was not reached yet, while PFS in 2L setting was 10.9 months (95% CI: 1.8 to 13.7 months).ConclusionsThe fully oral combination of dalpiciclib, pyrotinib and letrozole is a promising chemotherapy-sparing treatment option for HER2-positive, HR-positive MBC patients. The planned dose-expansion phase II study is ongoing.Clinical Trial Registration ClinicalTrials.gov, identifier NCT03772353.