Second-line Hormonal Therapy Research Articles

The different sequences of CDK4/6 inhibitor and mTOR inhibitor in HR+/HER2-advanced breast cancer: A multicenter real-world study

BackgroundCyclin-dependent kinase 4/6 inhibitor (CDK4/6i) and everolimus (EVE) are effective for patients with hormone receptor–positive (HR+), human epidermal growth factor receptor 2-negative (HER2-) metastatic breast cancer (MBC). However, the efficacy of different sequences of CDK4/6i and EVE are largely unknown. The study aimed to explore the efficacy of different sequences in China. Methods146 patients with HR+/HER2- MBC who received both CDK4/6i and EVE in salvage setting were collected. Objective response rate (ORR), clinical benefit rate (CBR), progression-free survival (PFS), and overall survival (OS) were investigated. Results56 patients received CDK4/6i prior to EVE (Group A), 90 patients received CDK4/6i subsequent to EVE (Group B). The median PFS of CDK4/6i and EVE in Group A vs Group B were 8.4m and 2.5m vs 4.6m and 6.1m respectively. The total PFS of first-line and second-line endocrine therapy were not different between Group A and Group B [13.1m vs 17.7m (P = 0.330, HR = 0.738, 95%CI: 0.399–1.365)]. The 5y OS of patients in Group A or Group B were 62.0 % vs 57.4 %, P = 0.569. ConclusionsWe found that no matter CDK4/6i or EVE was used first, the survival were not significantly different between Group A and Group B. Both can be clinical options.

A phase 3 study (PATHWAY) of palbociclib plus tamoxifen in patients with HR-positive/HER2-negative advanced breast cancer

Palbociclib combined with endocrine therapy is approved for treating patients with hormone-receptor-positive/human epidermal growth factor receptor 2-negative (HR+/HER2−) advanced breast cancer; however, data on palbociclib combined with tamoxifen are limited. We investigated the efficacy and safety of palbociclib–tamoxifen in patients with HR+/HER2− advanced breast cancer. This double-blind phase 3 study included 184 women who were randomly assigned 1:1 to receive palbociclib–tamoxifen or placebo–tamoxifen. Pre/perimenopausal women also received goserelin. The primary endpoint was investigator-assessed progression-free survival (PFS). Secondary endpoints included overall survival (OS) and safety. Median PFS was 24.4 months (95% confidence interval [CI], 13.1–32.4) with palbociclib–tamoxifen and 11.1 months (95% CI, 7.4–14.6) with placebo–tamoxifen (hazard ratio [HR], 0.60; 95% CI, 0.43–0.85; P = 0.002). Palbociclib–tamoxifen improved PFS in patients who were treated with first-line or second-line endocrine therapy and pre-, peri-, and postmenopausal patients. Though OS data are still immature (median not reached in both groups), an overall risk reduction of 27% (HR, 0.73; 95% CI, 0.44–1.21) with palbociclib–tamoxifen was observed at the time of PFS analysis. The most common grade 3/4 adverse event with palbociclib–tamoxifen was neutropenia (89.0% [none were febrile] versus 1.1% with placebo–tamoxifen). There were no deaths owing to adverse events in either group. Among patients with HR+/HER2− advanced breast cancer, palbociclib–tamoxifen resulted in significantly longer PFS than tamoxifen alone. Early OS data showed a trend favoring palbociclib–tamoxifen. Trial registration: ClinicalTrials.gov number, NCT03423199. Study registration date: February 06, 2018.

The treatment pattern of advanced HR-positive and HER2-negative breast cancer in central southern China: a hospital-based cross-sectional study

AimsThis investigation aims to elucidate the treatment status of advanced HR+/HER2- breast cancer patients in Hunan Province of Central Southern China from November 2021 to December 2022.MethodsData from 301 patients with advanced HR+/HER2- breast cancer were collected from the breast cancer investigation project in Hunan under the guidance of the Chinese Society of Clinical Oncolfogy (CSCO). The data included the clinical characteristics of patients and the status of first-line and second-line rescue treatment.ResultsFirst-line chemotherapy and endocrine therapy for mBC accounted for 40% (121/301) and 60% (180/301) of treatments, respectively. AI (21%), AI plus CDK4/6 inhibitor (28%), and fulvestrant (24%) or fulvestrant plus CDK4/6 inhibitor (18%) were the most common first-line endocrine therapies. Taxane-based chemotherapy was the most common first-line chemotherapy (59%). Second-line chemotherapy and endocrine therapy for mBC accounted for 43% (72/166) and 57% (94/166) of treatments, respectively. Fulvestrant (23%) or fulvestrant plus CDK4/6 inhibitor (29%) were the most common second-line endocrine therapies. The prevalences of AI and AI plus CDK4/6 inhibitor decreased to 19% and 11%, respectively. T (taxane)-based chemotherapy was still the most common chemotherapy regimen (46%). Third-line chemotherapy was more prevalent than endocrine therapy (57% vs. 41%). T (taxane)-based chemotherapy was still the most common chemotherapy regimen (46%). Fulvestrant plus CDK4/6 inhibitor was the most common endocrine therapy (33%). AI, AI plus CDK4/6 inhibitor, and fulvestrant accounted for 21%, 12% and 18% of third-line endocrine therapies, respectively.ConclusionsCompared to chemotherapy, endocrine therapy was a more favorable choice for first-line and second-line treatment for HR+/HER2- advanced breast cancer patients in Hunan Province.

First- vs second-line CDK 4/6 inhibitor use for patients with hormone receptor positive, human epidermal growth-factor receptor-2 negative, metastatic breast cancer in the real world setting

PurposeTo compare CDK4/6 inhibitor (CDK4/6i) with endocrine therapy (ET) in the first- versus second-line setting for treatment of hormone receptor positive (HR+), HER2 negative, metastatic breast cancer (MBC) using real-world evidence.MethodsPatients with HR+, HER2 negative MBC, diagnosed between 2/3/2015 and 11/2/2021 and having ≥ 3 months follow-up were identified from the nationwide electronic health record-derived Flatiron Health de-identified database. Treatment cohorts included: (1) first-line ET with a CDK 4/6i (1st-line CDK4/6i) versus (2) first-line ET alone followed by second-line ET with a CDK4/6i (2nd-line CDK4/6i). Differences in baseline characteristics were tested using chi-square tests and two-sample t-tests. Time to third-line therapy, time to start of chemotherapy, and overall survival were compared using Kaplan-Maier method.ResultsThe analysis included 2771 patients (2170 1st-line CDK4/6i and 601 2nd-line CDK4/6i). Patients receiving 1st-line CDK4/6i were younger (75% vs 68% < 75 years old, p = 0.0001), less likely uninsured or not having insurance status documented (10% vs. 13%, p = 0.04), of better performance status (50% vs 43% with ECOG 0, p = 0.03), and more likely to have de novo MBC (36% vs. 24%, p < 0.001). Time to third-line therapy (49 vs 22 months, p < 0.001) and time to chemotherapy (68 vs 41 months, p < 0.001) were longer in those receiving first-line CDK4/6i. Overall survival (54 vs 49 months, p = 0.33) was similar between groups.ConclusionUse of CDK4/6i with first-, vs second-, line ET was associated with longer time to receipt of 3rd-line therapy and longer time to receipt of chemotherapy.

Second-line Endocrine Therapy of Hormone Receptor-positive/HER2- negative Advanced Breast Cancer: A Systematic Review and Network Meta-analysis.

The optimal second-line therapy for hormone receptor-positive (HR+)/ human epidermal growth factor receptor 2 negative (HER2-) advanced or metastatic breast cancer is yet to be established. Therefore, we conducted a network meta-analysis (NMA) of marketed drugs to compare their efficacy. We searched the literature in PubMed, Embase, Web of Science databases, and the main international conferences in the past 5 years to find phase III clinical trials on drugs available in the market. Network meta-analysis of progression-free survival (PFS), overall survival (OS), and the objective response rate (ORR) was performed using R software. The efficiency of treatment options was compared using hazard ratios and 95% credibility intervals. Overall, 12 studies with 6120 patients were included in the analysis. In an indirect comparison of the five regimens, cyclin-dependent kinase 4 and 6 inhibitors (CDK4/6i) plus 500 mg fulvestrant (Ful500) gave the best PFS results; palbociclib ranked first with a surface under the cumulative ranking (SUCRA) of 94.99%, followed by mammalian target of rapamycin inhibitor (mTORi) plus everolimus (SUCRA=73.07%), phosphoinositide 3-kinase inhibitor (PI3Ki) plus Ful500 (SUCRA=66.73%), Ful500 alone (SUCRA=44.55%), and histone deacetylase inhibitor (HDACi) plus exemestane (SUCRA= 43.49%). However, no significant difference was found in the PFS rates of CDK4/6i, mTORi, and PI3Ki. For OS, CDK4/6i plus Ful500 ranked first; the SUCRA of ribociclib, abemaciclib, and palbociclib were 86.20%, 83.98%, and 78.52%, respectively. Alpelisib plus Ful500 (SUCRA=66.91%) ranked second but was not statistically different from CDK4/6i. The mTORi plus everolimus group had the best ORR (SUCRA=88.73%). In terms of safety, 81.56% of patients in the tucidinostat plus exemestane regimen developed neutropenia, suggesting strong hematological toxicity; 13.40% of patients developed grade 3-4 diarrhea after using abemaciclib plus Ful500. For second-line endocrine therapy in HR+/HER2- advanced/metastatic breast cancer, CDK4/6i is a better choice than mTORi, PI3Ki, HDACi, and Ful; it shows good PFS and OS outcomes and a low probability for serious adverse events.>.

Primary outcome analysis of the phase 3 SONIA trial (BOOG 2017-03) on selecting the optimal position of cyclin-dependent kinases 4 and 6 (CDK4/6) inhibitors for patients with hormone receptor-positive (HR+), HER2-negative (HER2-) advanced breast cancer (ABC).

LBA1000 Background: The phase-3, randomized, investigator-initiated, nationwide SONIA trial is evaluating the efficacy, safety and cost-effectiveness of CDK4/6i added to either first- or second-line endocrine therapy (ET) in patients with HR+, HER2- ABC who have received no prior therapy for ABC. The addition of CDK4/6i to ET improves progression-free (PFS) and overall survival (OS) in HR+, HER2- ABC, as initial treatment (first-line) and after prior endocrine monotherapy (second-line). Most international guidelines advice first-line use, despite prolonged toxicity and a steep increase in costs compared to use in second-line. Evidence of superiority of first-line use over second-line based on a head-to-head comparison is lacking. Methods: Pre- and postmenopausal women (N=1050), who received no prior therapy for ABC, with measurable or evaluable disease and WHO performance status 0-2 were enrolled in 74 Dutch hospitals. (Neo)adjuvant therapy was allowed (disease-free interval after non-steroidal aromatase inhibitor (NSAI) &gt;12 months). Patients were randomized 1:1 to receive strategy A (first-line treatment with an NSAI + CDK4/6i, followed on progression by fulvestrant (F)) or strategy B (first-line treatment with an NSAI, followed on progression by F + CDK4/6i). Choice between one of the available CDK4/6i (abemaciclib, palbociclib, ribociclib) was a stratification factor and left to the discretion of the treating physician. The primary endpoint is time from randomization to second objective disease progression, as assessed by local investigators, or death (PFS2). Secondary endpoints include OS, safety, quality of life, and cost-effectiveness. Results: After a median follow-up of 37.3 months (data cut-off 1 December 2022), median PFS2 was 31.0 months in strategy A versus 26.8 months in strategy B (hazard ratio 0.87; 95% confidence interval, 0.74 to 1.03; P=0.10). The treatment effect was consistent across the levels of pre-defined subgroups. The safety profile was characteristic for ET + CDK4/6i. Median time on CDK4/6i was 24.64 months in strategy A and 8.08 months in strategy B (Δ 16.56 months). The number of grade ≥3 adverse events was 2782 for strategy A and 1620 for strategy B. Conclusions: First-line use of CDK4/6i + ET does not provide statistically significant, nor clinically meaningful PFS benefit compared to second-line use in women with HR+, HER2- ABC. Use in first-line prolongs the time on CDK4/6i by 16.56 months and increases toxicity and costs. Second-line use may thus be a preferred option for the majority of patients. (Funded by The Netherlands Organisation for Health Research and Development and Dutch Health Insurers; ClinicalTrials.gov number, NCT03425838). Clinical trial information: NCT03425838 .

Second-line endocrine therapy (ET) with or without palbociclib (P) maintenance in patients (pts) with hormone receptor-positive (HR[+])/human epidermal growth factor receptor 2-negative (HER2[-]) advanced breast cancer (ABC): PALMIRA trial.

1001 Background: Cyclin-dependent kinases 4 and 6 inhibitors (CDK4/6i) in combination with ET has become a standard first-line treatment for pts with endocrine-sensitive, HR[+]/HER2[-] ABC. The optimal treatment after progression on a CDK4/6i remains unknown. This study aims to determine if P maintenance with an alternative ET improves the antitumor activity of second-line treatment in this patient population. Methods: A total of 198 pts with HR[+]/HER2[-] ABC who had disease progression to first-line P plus ET (aromatase inhibitor or fulvestrant) were included. Pts were eligible if they had clinical benefit to the first-line treatment defined as response or stable disease ≥24 weeks, or who had progressed on a P-based regimen in the adjuvant setting with disease progression after at least 12 months of treatment but no more than 12 months following P treatment completion. Pts were randomly assigned (2:1 ratio) to receive P plus second-line ET (letrozole or fulvestrant, based on prior ET) or second-line ET alone. Stratification factors were prior ET and the presence of visceral involvement. Primary endpoint was investigator-assessed progression-free survival (PFS) determined by RECIST v.1.1. Secondary endpoints included overall response rate (ORR), clinical benefit rate (CBR), overall survival, and safety. The 2-sided log-rank test (α = 0.05) had an 80% power to detect a hazard ratio ≤0.59 in favor of P maintenance. Results: Between April 2019 and October 2022, 136 and 62 pts were randomized to receive P+ET and ET, respectively. Pts characteristics were well balanced. Median age was 59 years (range: 33-85), 61.1% were ECOG 0, 61.1% had visceral disease, and 89.9% received aromatase inhibitor + P as first-line treatment for metastatic disease. At median follow-up of 8.7 months and 155 PFS events, median investigator-assessed PFS was 4.2 months (95% CI 3.5–5.8) in the P+ET vs. 3.6 months (95% CI 2.7–4.2) in the ET arm (hazard ratio 0.8, 95% CI 0.6–1.1, p=0.206). This result was consistent across all stratification subgroups. 6-month PFS rate was 40.9% and 28.6% for P+ET and ET, respectively. Among 138 pts with measurable disease, no significant differences were observed in ORR (6.4% vs. 2.3%) or CBR (33.0% vs. 29.5%) for P+ET and ET, respectively. Grade 3-4 adverse events were higher in pts treated with P+ET (45.2% vs. 8.3%) and no new safety signals were identified. No treatment-related deaths were reported. Conclusions: For HR[+]/HER2[-] ABC pts, maintaining P with a second-line ET beyond progression on prior P-based therapy did not significantly improve PFS compared with second-line ET alone. Planned biomarker analysis may help identify which pts are more likely to benefit from this therapeutic approach. Clinical trial information: NCT03809988 .

Impact of COVID-19 pandemic on the treatment of prostate cancer in the Brazilian public health system.

e17106 Background: COVID-19 pandemic reached Brazil in the beginning of 2020 causing a profound impact in economic and social activities, up to the end of 2021. In Brazil, there is universal access to the public health system (BPHS-SUS); however, during the pandemic public resources were directed mainly to the management of COVID-19 infected patients. We evaluated the impact of the 2020/2021 pandemic on the treatment of prostate cancer in the BPHS-SUS. Methods: we compared data regarding the number of radical prostatectomies, radiotherapy treatments, and hormonal and chemotherapy treatments administered in the time frame from March 1st, 2020 (when lockdown measures were initially adopted in Brazil) to February 29th, 2022, with that of the two most recent pre-pandemic years (March 1st, 2018, to February 28th, 2020). A large proprietary healthcare data science platform offered by TECHTRIALSÒ was surveyed. Results: in the two pandemic years, 15,196 radical prostatectomies were performed in the BPHS, with a cost of U$ 14,271,297; there was a 23.3% reduction in the number of surgeries compared with the two pre-pandemic years (19,818 radical prostatectomies, with a cost of U$ 18,056,470). In the pandemic, 34,982 men were treated with radiation therapy, with a cost of U$ 39,616,736; this meant a 18.7% reduction in the number of patients treated with radiation therapy as compared with the two pre-pandemic years (43,013 men, with a cost of U$ 44,148,190). Regarding hormonal treatments, numbers were similar: 116,490 men were treated during the pandemic (cost of U$ 74,834,615); in the pre-pandemic timeframe, 115,949 patients received hormonal therapy (cost of U$ 75,179,674). As to chemotherapy for hormone-resistant disease, in the pandemic 14,946 men were treated (cost of U$ 23,402,947) compared with 12,695 men treated in the two pre-pandemic years (cost of U$ 19,239,099). Conclusions: there was a significant reduction in the number of radical prostatectomies and of radiation therapy treatments during the pandemic years in the BPHS-SUS. Abrupt reductions of potentially curative therapies will probably affect stage migration, costs to the public system and patients’ survival in the ensuing years. The number of systemic therapies (first- and second-line hormonal therapies, and chemotherapies) were slightly increased, probably reflecting the BPHS-SUS policy of maintaining systemic treatments active during the pandemic.

Clinicopathological characteristics, evolution, treatment patterns and outcomes of hormone-receptor-positive/HER2-low-positive metastatic breast cancer: A retrospective analysis.

e13058 Background: HER2-low positivity is more prevalent in breast cancers with positive hormone receptor (HR). Patients with HR-positive and low HER2 expression may have different prognosis and characteristics. Nevertheless, research focusing on HR-positive/HER2-low-positive breast cancer remains scarce. Methods: This study included 458 patients with HR-positive/HER2-negative metastatic breast cancer (HR+/HER2- MBC) who received first- or second-line endocrine therapy at the Fudan University Shanghai Cancer Center (FUSCC) between July 2010 and October 2022. Results: Clinicopathological characteristics, HER2 expression in primary and metastatic lesions, treatment patterns, and clinical outcomes of various therapies were compared between the HER2-low-positive and HER2-zero groups. 54.37% (249/458) of the HR+/HER2- MBC patients were HER2-low-positive. Comparable clinicopathological characteristics were observed in the HER2-low-positive and HER2-zero groups. PFS of first- and second-line endocrine treatment was comparable for HER2-low-positive and HER2-zero patients. When taking chemotherapy, the HER2-low-positive group had a shorter PFS than the HER2-zero group (median PFS: 8.64 vs. 9.03 months, p = 0.03). 41.79% (28/67) of HER2-zero primary tumors increased their HER2 score on biopsy, while 41.67% (35/84) of HER2-low-positive tumors became HER2-zero. Patients with an elevated HER2 IHC score from the primary tumor to the metastatic tumor had a longer PFS than those with constant HER2-low-positive status (median PFS: 11.99 months vs. 8.84 months, p = 0.02). Conclusions: HR-positive MBC patients with HER2-low and HER2-zero expression responded similarly to endocrine therapy. But HER2-low-positivity in HR-positive MBC may reduce chemotherapeutic effectiveness and HER2 heterogeneity should be taken into consideration.

Phase II trial of fulvestrant plus enzalutamide in ER+/HER2− advanced breast cancer

This clinical trial combined fulvestrant with the anti-androgen enzalutamide in women with metastatic ER+/HER2− breast cancer (BC). Eligible patients were women with ECOG 0–2, ER+/HER2− measurable or evaluable metastatic BC. Prior fulvestrant was allowed. Fulvestrant was administered at 500 mg IM on days 1, 15, 29, and every 4 weeks thereafter. Enzalutamide was given at 160 mg po daily. Fresh tumor biopsies were required at study entry and after 4 weeks of treatment. The primary efficacy endpoint of the trial was the clinical benefit rate at 24 weeks (CBR24). The median age was 61 years (46–87); PS 1 (0–1); median of 4 prior non-hormonal and 3 prior hormonal therapies for metastatic disease. Twelve had prior fulvestrant, and 91% had visceral disease. CBR24 was 25% (7/28 evaluable). Median progression-free survival (PFS) was 8 weeks (95% CI: 2–52). Adverse events were as expected for hormonal therapy. Significant (p < 0.1) univariate relationships existed between PFS and ER%, AR%, and PIK3CA and/or PTEN mutations. Baseline levels of phospho-proteins in the mTOR pathway were more highly expressed in biopsies of patients with shorter PFS. Fulvestrant plus enzalutamide had manageable side effects. The primary endpoint of CBR24 was 25% in heavily pretreated metastatic ER+/HER2− BC. Short PFS was associated with activation of the mTOR pathway, and PIK3CA and/or PTEN mutations were associated with an increased hazard of progression. Thus, a combination of fulvestrant or other SERD plus AKT/PI3K/mTOR inhibitor with or without AR inhibition warrants investigation in second-line endocrine therapy of metastatic ER+ BC.

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 P5-02-27: Serum thymidine kinase activity as a prognostic marker in women with metastatic breast cancer treated with two different schedules of palbociclib plus second-line endocrine therapy within the CCTG MA38 trial

Abstract Background: Thymidine kinase-1 is a cell proliferation marker downstream of the CDK4/6 pathway, whose activity can be measured in serum to reflect tumor proliferation. The CDK4/6 inhibitor palbociclib (P) is approved for the treatment of patients (pts) with hormone receptor positive metastatic breast cancer (MBC) in first or second line endocrine-based treatment settings. Approximately 10-15% of pts exhibit de novo resistance to P, with circulating levels of thymidine kinase activity (TKa) previously shown as a potential marker of early treatment resistance. Therapeutic strategies to address primary resistance to P are currently lacking. Little is known of the clinical efficacy of alternative dosing schedules of P, and its effect on TKa. Here we report serum TKa measured at different timepoints from samples collected within the MA38 (NCT02630693) study. Methods: MA38 is an open label randomised Phase 2 trial comparing two different schedules of P plus second-line ET in pts with ER-positive, HER2-negative MBC. Pts were assigned to receive physician’s choice ET plus either standard P dosing (125mg daily for 21 days on a 28-day cycle), or 100mg daily continuously. Serum samples were collected at baseline (BL; n=135), at 12 weeks (W12; n=122) and 24 weeks (W24; n=95). TKa was measured with DiviTum®, a refined ELISA-based assay (lower limit of detection [LLOD] = 100 DuA). Kaplan-Meier method estimated BL, W12 and W24 (95% CI) median PFS (mPFS; from randomization until progression by RECIST criteria or death) and overall survival (OS; from randomization until death from any cause) in groups of patients defined by dichotomizing TKa as “high” or “low” at the median. Results: MA38 enrolled 180 pts from December 2015 and February 2017 across Canada. Median follow up was 19 months. Overall, the median age was 60, and 90% of pts were post-menopausal. All pts had estrogen receptor-positive disease, and 64% had visceral metastases. On study, 56% received fulvestrant with P, 34% aromatase inhibitor and 10% tamoxifen. TKa was successfully measured in 100% of samples. Median TKa (mTKa) at BL was 234 DuA (IQR 138.5 - 438). BL TKa was not associated with clinical or pathological characteristics. TKa was prognostic at BL with mPFS of 5.5 months (mo) in pts with high TKa vs 16.3 mo with low TKa (HR=2.43; 95% CI, 1.6-3.7; p&amp;lt; 0.001). Similar results were obtained employing other previously reported cut off values. At multivariate analysis, BL TKa was independent from other prognostic factors including age, ECOG status and presence of visceral metastases (adjusted HR= 2.34; 95%CI 1.5- 3.6; p &amp;lt; 0.001). In terms of OS, BL TKa was an independent prognostic factor (adjusted HR=2.0; 95% CI, 1.1-3.7; p=0.02). At 12 mo, OS rate was 68% in pts with high BL TKa vs 92% in low TKa. Both for PFS and OS, no interaction between BL TKa and study arm was observed. At W12 mTKa was 129.5 DuA (IQR 100 - 219.8) and below LLOD (IQR 100 - 180) at W24. At these timepoints, landmark analyses showed no significant difference in PFS according to TKa. However, at W12 high TKa was significantly associated with worse OS (HR 2.0; 95%CI 1.0- 4.0; p=0.03), with a similar trend at W24 (HR 2.5; 95%CI 0.9-6.4; p=0.06). Conclusions: Baseline TKa is a reliable prognostic marker of both PFS and OS in pts treated with P and ET, further substantiating previous data. Monitoring TKa during treatment may provide important clinical information. A significant relationship between TKa and assigned treatment arm was not observed, suggesting TKa is not influenced by P treatment dose or intensity. These data confirm the role of baseline TKa as a new marker for patient stratification, and supports further investigation for the assessment of the clinical utility of TKa as a monitoring biomarker in the advanced setting. Citation Format: Amelia McCartney, Chiara Biagioni, Bingshu Chen, Lois Shepherd, Karen Gelmon, Anil A. Joy, Wendy Parulekar, Mattias Bergqvist, Ilenia Migliaccio, Angela Leo, Matteo Benelli, Emanuela Risi, Erica Moretti, Luca Livraghi, Laura Biganzoli, Luca Malorni. Serum thymidine kinase activity as a prognostic marker in women with metastatic breast cancer treated with two different schedules of palbociclib plus second-line endocrine therapy within the CCTG MA38 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 P5-02-27.

Abstract P5-02-05: Detection of high-risk patients resistant to CDK4/6 inhibitors with hormone receptor-positive HER2-negative breast cancer in Japan

Abstract (Background) Cyclin-dependent kinase 4 and 6 inhibitors (CDK4/6i) improve the prognosis of hormone receptor-positive HER2-negative breast cancer (HR+/HER2- BC) by approximately 5 years. However, some patients show resistance to CDK4/6i and have poor prognosis. Thus, predicting resistance in patients is important. Although PAM50 is a strong tool for predicting late recurrence risk in HR+/HER2- BC by analyzing gene expression signatures, it is not always available. The non-luminal disease score (NOLUS), developed as an approximate formula for PAM50, is a pathology-based subtyping assay used to predict non-luminal disease using immunohistochemical analysis (Pascual et al. Front Oncol, 2021). (Materials &amp; Methods) This multicenter, retrospective observational study was approved by the central ethics committee of Gifu University. From December 2017 to December 2021, real-world data of patients with metastatic HR+/HER2- BC who received CDK4/6i therapy were collected from 11 institutes in Japan. Data were obtained for patients who received CDK4/6i, such as palbociclib (PAL) or abemaciclib (ABE), as the first- or second-line endocrine therapy. The association between the efficacy of CDK4/6i and NOLUS was investigated by evaluating pathological and clinical data, including progression-free survival (PFS) and overall survival (OS). Pathological data, including the expression levels of ER, PgR, HER2, and Ki67, were evaluated according to the ASCO/CAP guidelines by experienced pathologists in each institute using either primary or metastatic tumors. PFS was defined as the period from the 1) starting date of combination therapy to progressive disease (PD); 2) the starting date of combination therapy to PD when CDK4/6i was interrupted due to adverse events or patients’ preference; and 3) the starting date of endocrine monotherapy to PD when CDK4/6i was added. NOLUS was calculated using the formula: NOLUS (0-100) = -0.45*ER% − 0.28*PR% + 0.27*Ki67% + 73, and the patients were divided into two groups, NOLUS(+) [≥ 51.38, non-luminal disease] and NOLUS(−) [&amp;lt; 51.38, luminal disease]. The expression levels of ER, PgR, HER2, and Ki67 in each group were compared using Wilcoxon rank-sum and Fisher’s exact tests. Next, prognosis, including survival rate, PFS, and OS, was evaluated with a 95% confidence interval (CI) using the Kaplan–Meier method with the log-rank test. Statistical significance was set at p &amp;lt; 0.05. (Results) Of the 300 patients, 28 (9.3%) were NOLUS(+) and 272 (90.7%) were NOLUS(−). The expression rates (%) in NOLUS(+) and NOLUS(−) were, respectively, 28.2 ± 19.4 and 89.0 ± 11.3 for ER (p &amp;lt; 0.001); 6.3 ± 15.9 and 44.3 ± 37.9 for PgR (p &amp;lt; 0.001); and 42.5 ± 23.8 and 26.9 ± 19.1 for Ki67 (p &amp;lt; 0.001). The expressions of HER2 (score 0, 1, 2, and ISH-negative, 3) were 42.9%, 28.6%, 28.6%, and 0% for NOLUS(+); and 30.8%, 51.7%, 17.5%, and 0.4% for NOLUS(−) (p = 0.086). There were apparent statistical differences in prognosis between the NOLUS(+) and NOLUS(−) groups. PFSs for 6M and 1y were 71.4% and 30.5% for NOLUS(+), and 85.2% and 66.6% for NOLUS(−) (HR, 3.15; 95%CI: 2.02-4.93; p &amp;lt; 0.001). OS for 6M and 1y were 92.6% and 92.6% for NOLUS(+), and 97.7% and 93.8% for NOLUS(−) (HR, 3.01; 95%CI: 1.48-6.09, p = 0.001). NOLUS(−) patients showed statistically better PFS with first-line therapy than with second-line therapy. However, NOLUS(+) patients showed no prognostic difference between the first and second therapeutic lines, suggesting CDK4/6i inefficacy. (Conclusion) CDK4/6i efficacy and prognosis were significantly different between NOLUS(+) and NOLUS(−) patients. This feasible method can predict patients with CDK4/6i-resistance and help select a better therapeutic approach to overcome resistance. Citation Format: Manabu Futamura, Takahiro Nakayama, Tersuhiro Yoshinami, Chiya Oshiro, Mikiya Ishihara, Midori Morita, Akira Watanabe, Azusa Taniguchi, Masami Tsukabe, Masafumi Shimoda, Kanae Mitta, Yoko Chihara, Hiroyuki Yasojima, Yoshimi Ouchi, Yoshihisa Tokumaru, Takuma Ishihara, Norikazu Masuda. Detection of high-risk patients resistant to CDK4/6 inhibitors with hormone receptor-positive HER2-negative breast cancer in Japan [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 P5-02-05.

Health-related quality of life and estimation of the minimally important difference in the Functional Assessment of Cancer Therapy-Endocrine Symptom score in postmenopausal ER+/HER2- metastatic breast cancer with low sensitivity to endocrine therapy.

The HORSE-BC study previously demonstrated that second-line endocrine therapy (ET) for patients with acquired endocrine-resistant metastatic breast cancer (MBC) still provided a clinically meaningful benefit. Herein, we investigated the health-related quality of life (HRQOL) in the HORSE-BC study. Patients with acquired endocrine-resistant MBC who were scheduled for second-line ET were recruited. The HRQOL was assessed at baseline, and 1 and 3 months after second-line ET initiation. To investigate the minimally important difference (MID) in the Functional Assessment of Cancer Therapy-Endocrine Symptoms (FACT-ES), we evaluated the means and standard deviations for the distribution-based method, and differences in the change in HRQOL for the anchor-based method. We also investigated the association between FACT-ES total scores and clinical benefit. Overall, 56 patients were enrolled. Of these, 47 were analyzed. When defined as 1/3 standard deviation estimates based on the distribution method, the calculated MID was 5.9. The MIDs of the FACT-ES total scores based on the anchor method were 7.7 for decline and 4.1 for improvement. The MID decline proportions were 6.1% and 14.7% lower in patients who experienced clinical benefits than in those who did not at 1 and 3 months, respectively. The ratios of MID improvement in patients who experienced clinical benefits were 18.3% and 3.2% higher, respectively; the mean change in the FACT-ES total score from baseline improved in patients who experienced clinical benefits. Maintaining the HRQOL as determined by FACT-ES may be associated with clinical benefits in patients with acquired endocrine-resistant MBC treated with ET.

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.

Multisite Radiotherapy Combined With Tislelizumab for Metastatic Castration-Resistant Prostate Cancer With Second-Line and Above Therapy Failure: Study Protocol for an Open-Label, Single-Arm, Phase Ib/II Study.

BackgroundTislelizumab combined with radiotherapy as a salvage treatment for patients with end-stage metastatic castration-resistant prostate cancer (mCRPC) is not reported. This study aimed to describe a protocol to evaluate the safety and efficacy of multisite radiotherapy combined with tislelizumab as a salvage therapy for mCRPC in patients who had at least one second-line treatment failure.MethodsThe study included patients with mCRPC who had at least one lesion suitable for radiotherapy and failed androgen deprivation therapy (ADT), followed by at least one novel second-line endocrine therapy. All patients received tislelizumab monotherapy induction therapy for two cycles, then combined with multisite radiotherapy for one cycle, followed by tislelizumab maintenance therapy, until either disease progressed or the patient developed unacceptable toxicity. Radiation methods and lesions were individually selected according to the specified protocol. Primary endpoints included safety and objective response rate. Secondary endpoints included prostate-specific antigen (PSA) response rate, disease control rate, overall survival, radiographic progression-free survival (rPFS), and biochemical progression-free survival (bPFS). Furthermore, the exploratory endpoints included the identification of the predictive biomarkers and exploration of the correlation between biomarkers and the tumor response to the combined regimen.DiscussionThis study included three treatment stages to evaluate the efficacy of immunotherapy and the combination of immunotherapy and radiotherapy for patients with mCRPC who have had at least second-line treatment failure. Additionally, radiation-related and immune-related early and late toxicities were determined, respectively. Furthermore, the study also aimed to identify the predictive biomarkers associated with immunotherapy for treating mCRPC.Trial Registration https://www.chictr.org.cn/showproj.aspx?proj=126359, identifier ChiCTR2100046212.

Abstract IA015: Exploring how competition can be leveraged to improve adaptive therapy in metastatic prostate cancer

Abstract Prostate cancer remains the most prevalent cancer in men in the US. While continuous first-line hormone treatment at maximum tolerable dose is the standard of care, continuous treatment often selects for the resistant phenotypes resulting in castration resistant disease. Second-line hormone therapy options, such as abiraterone acetate (AA), have been proven effective for metastatic castration resistant prostate cancer (mCRPC). Adaptive AA, whereby treatment is cycled on and off using patient-specific treatment triggers, has been shown to be effective at reducing toxicity and prolonging time to progression. It is hypothesized that cycling through treatment allows sensitive cells to competitively suppress resistant cells, thereby increasing the amount of time that treatment is effective. It has been proposed that there exists a subset of patients for which this competition can be enhanced through slight modifications to adaptive AA. Here, we investigate this by calibrating a simple mathematical model to longitudinal prostate-specific antigen data from 16 mCRPC patients undergoing adaptive AA. Model parameters are used to simulate modified adaptive therapy and compare against conventional adaptive therapy. Model simulations show that modified adaptive therapy can extend time to progression, while reducing the cumulative dose patients receive. This is a promising first step in improving patient care, particularly in those patients who do not respond well to conventional adaptive therapy. Citation Format: Renee Brady-Nicholls, Heiko Enderling. Exploring how competition can be leveraged to improve adaptive therapy in metastatic prostate cancer [abstract]. In: Proceedings of the AACR Special Conference on the Evolutionary Dynamics in Carcinogenesis and Response to Therapy; 2022 Mar 14-17. Philadelphia (PA): AACR; Cancer Res 2022;82(10 Suppl):Abstract nr IA015.

Abstract P1-19-01: Palbociclib plus endocrine therapy significantly enhances overall survival of HR+/HER2- metastatic breast cancer patients compared to endocrine therapy alone - A large institutional study

Abstract PURPOSE: Cyclin-dependent kinase 4/6 inhibitor (CDKi) therapy combined with endocrinetherapy is considered standard of care for patients with advanced hormone receptor (HR)-positive, HER2-negative breast cancer (BC). The Breast Medical Oncology Database at MDAnderson Cancer Center (MDACC) was analyzed to assess effectiveness of CDKi+palbociclib. PATIENTS AND METHODS: From a total of 5402 advanced HR+ HER2- BC patients referred toMDACC between 1997 and 2020, we identified eligible patients who received palbociclib incombination with first- (n=778) and second-line (n=410) endocrine therapy. We furtheridentified “control” patients who received endocrine therapy alone in the first- (n=2452) andsecond-line (n=1183) setting. We conducted a propensity score matching analysis to balancethe baseline demographic and clinical characteristics between the palbociclib treated andcontrol cohorts to assess the effect of palbociclib treatment on progression-free survival (PFS)and overall survival (OS). Stratified log-rank test was used to assess the effect of palbociclib inthe matched cohorts. RESULTS: For the propensity-matched cohort in the first-line setting (n=708), the palbociclibgroup had significantly longer median PFS (17.4 vs. 11.1 months; p&amp;lt;0.0001) compared tocontrols. Median OS (44.3 vs. 40.2 months; p =1) did not show any survival benefit in the firstline setting. However, in the second-line setting, with 380 propensity-matched cohort, thepalbociclib group had significantly longer PFS (10 vs 5 months, p&amp;lt;0.0001) as well as OS (33 vs 24months; p &amp;lt; 0.022), compared to controls.2. CONCLUSION: In this single center analysis, of a large cohort of metastatic HR+ HER2- BCpatients, palbociclib in combination with endocrine therapy was associated with improved PFSin both first- and second-line settings and OS in the second-line setting compared withendocrine therapy alone cohort.3 Citation Format: Akshara Singareeka Raghavendra, Min Jin Ha, Nicole M. Kettner, Senthil Damodaran, Rachel Layman, Kelly K Hunt, Yu Shen, Debu Tripathy, Khandan Keyomarsi. Palbociclib plus endocrine therapy significantly enhances overall survival of HR+/HER2- metastatic breast cancer patients compared to endocrine therapy alone - A large institutional study [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P1-19-01.

Metastatic Lobular Carcinoma of the Male Breast Masquerading as a Pancreatic Head Mass, a Diagnostic Dilemma—Rare Case and Literature Review

AbstractMale breast cancer comprises of 1% of all and invasive lobular carcinomas (ILC) are even rarer in males. ILC are known to have unusual metastatic sites. We report a case of a 51-year-old male diagnosed with breast cancer, who presented with a recurrent chest wall nodule and icterus after 24 months of disease-free interval. On further investigations, he was found to have pancreatic head mass associated with conjugated hyperbilirubinemia suggestive of obstructive jaundice and a left parasternal soft tissue recurrence. A self-expandable metallic stent was inserted for recurrent cholangitis. Biopsy from the chest wall nodule was recurrence of ILC and pancreatic head mass was suspected to be either a second primary or an isolated pancreatic head metastasis of ILC on imaging. In either case surgical resection if operable and localized was planned. However, on staging laparoscopy, the patient was found to have mild ascites and multiple peritoneal nodules, which on biopsy proved to be metastases from ILC. Patient was treated with second-line hormonal therapy with luteinizing hormone-releasing hormone agonist and an aromatase inhibitor. ILC may present with unusual sites of metastasis leading to diagnostic dilemma. A high index of suspicion of metastases and appropriate biopsies can help one embark upon the most appropriate plan.

Tumor board presentation of a woman with metastatic, hormone receptor‐positive, mismatch repair‐deficient endometrial cancer

Tumor board presentation of a woman with metastatic, hormone receptor‐positive, mismatch repair‐deficient endometrial cancer