2nd Line Endocrine Therapy Research Articles

Real-world treatment outcomes in patients with HR+ HER2- advanced breast cancer treated with CDK4/6 inhibitors and endocrine therapy.

1067 Background: The addition of cyclin-dependent kinases 4 and 6 inhibitors (CDK4/6i) to endocrine therapy (ET) improves progression-free (PFS) and overall survival (OS) in hormone receptor-positive, HER2-negative advanced breast cancer (HR+/HER2- ABC) in 1st and 2nd line setting. The international guidelines advise using 1st line CDK4/6i; however, its superiority over 2nd line use is debatable. Methods: We retrospectively analyzed clinical data of HR+/HER2- ABC pts administered palbociclib (PAL), ribociclib (RIB) or abemaciclib (ABM) added to either 1st or 2nd line ET. Results: A total of 1511 pts (PAL=507; RIB=724; ABM=280) from 11 cancer Polish centers treated between Sep 2017 and Dec 2023. Median follow-up was 29.6 (95%CI 28.2 to 30.9) months (m). Mean age was 62.6±11.9, 58.9±12.2 and 61.4±10.8 years in PAL, RIB and ABM, respectively. 815 patients (53.9%) had visceral and 1109 (73.4%) bone metastases. 1254 pts (83%) received 1st line CDK4/6i, in 841 (67%) combined with aromatase inhibitor (AI) and in 413 (33%) with fulvestrant (FUL). Second-line CDK4/6i was used in 257 pts (17%); 59 (23%) and 198 (67%) with AI and FUL, respectively. There was no difference in PFS, PFS2, and OS between three CDK4/6i in combination with AIs in 1st and 2nd line setting. Median PFS (95%CI) for 1st line AI with PAL, RIB, ABM were 29.0 (21.6-37.0), 32.0 (24.5-36.9), not reached (N/R) (21.9-N/R) m; PFS2: 37.0 (28.8-N/R), 33.0 (29.5-40.2), N/R (28.9-N/R); OS: 48.9 (42.9-N/R), 48.6 (41.9-N/R), N/R (36.7-N/R). Median PFS (95%CI) for 2nd line AI with PAL, RIB, ABM were 11.9 (9.49-N/R), 10.8 (8.27-N/R), 11.0 (6.43-N/R); PFS2: 22.7 (16.8-N/R), 32.3 (24.9-N/R), 31.0 (13.2-N/R); OS: 27.4 (24.4-N/R), 36.7 (30.1-N/R), 45.5 (29.0-N/R) (no statistical significance). In contrast, RIB+FUL was superior to PAL+FUL and ABM+FUL in both lines (Table). The safety profile was concordant with the reported data for ET + CDK4/6i. Conclusions: Identifying predictive factors of response is essential for the rational use of CDK4/6i and ET in HR+/HER2- ABC. [Table: see text]

Palbociclib (P) plus tamoxifen (TAM) ± goserelin in women with hormone receptor-positive (HR+)/HER2-negative (HER2−) advanced breast cancer (ABC): Primary results of NCCH1607/PATHWAY, an Asian international double-blind randomized phase 3 trial.

LBA1068 Background: In Asian countries, BC incidence rates are rising, with a higher proportion of pre/perimenopausal (pre/peri-M) patients (pts). Data on treatment options for pre/peri-M pts are limited. Adding P to endocrine therapy (ET), such as aromatase inhibitor or fulvestrant, has improved progression-free survival (PFS) in phase 3 studies. However, the efficacy and safety of P in combination with TAM are still unclear in pts with HR+/HER2− ABC regardless of M status. This combination was investigated in PATHWAY (NCT03423199): a double-blind randomized phase 3 trial conducted in Japan, Korea, Taiwan and Singapore. The study was conducted as a Clinical Research Collaboration with the National Cancer Center Hospital being the regulatory sponsor and Pfizer providing drug and financial support. Methods: Women with HR+/HER2− ABC were randomly assigned 1:1 to receive either P (125 mg once daily, days 1-21 of a 28-day cycle) or placebo in combination with TAM (20 mg once daily, continuously) as 1st or 2nd line treatment for ABC. Pre/peri-M women received concurrent ovarian function suppression with goserelin. Pts were stratified by 1st vs 2nd line ET and M status. The primary endpoint was PFS as assessed by investigators. Secondary endpoints include overall survival (OS), objective response, safety, and patient-reported outcomes. Results: A total of 184 pts were assigned to P + TAM (91 pts) and placebo + TAM (93 pts). At data cutoff date (Sep 15, 2022), 138 PFS events had occurred. Median follow-up was 40.9 months for censored pts. Median PFS was 24.4 months (95% CI: 13.1, 32.4) with P + TAM and 11.1 months (95% CI: 7.4, 14.6) with placebo + TAM (hazard ratio [HR]: 0.602 [95% CI: 0.428, 0.848], 1-sided p-value from stratified log rank test: 0.002). The HRs for PFS of the subgroups by stratification factors were as follows: for pts with 1st line ET (HR: 0.521 [95% CI: 0.332, 0.817]) or with 2nd line ET (HR: 0.707 [95% CI: 0.421, 1.189]), and for pre/peri-M pts (HR: 0.378 [95% CI: 0.192, 0.742]) or post-M pts (HR: 0.677 [95% CI: 0.456, 1.005]). While OS data were still immature, the primary analysis showed a 27% reduction in overall risk of death (median OS: not reached in both arms, HR: 0.73 [95% CI: 0.442, 1.207]). 93.4% of pts with P + TAM vs. 20.4% of pts with placebo + TAM had grade (G) ≥3 treatment-emergent adverse events (TEAEs). The most frequently observed G ≥3 TEAE was neutropenia (89.0% in P + TAM arm and 1.1% in placebo + TAM arm). There were no G5 TEAEs in either arm. Conclusions: The study achieved its primary endpoint, demonstrating a significant and clinically meaningful improvement in PFS for P + TAM compared with placebo + TAM for pts with HR+/HER2− ABC. Early OS data with P+TAM is encouraging. TEAEs were generally consistent with the known safety profile of P and ET. Clinical trial information: NCT03423199 .

EPIK-B5: A phase III, randomized study of alpelisib (ALP) plus fulvestrant (FUL) in patients with hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-), PIK3CA-mutated advanced breast cancer (ABC) progressing on/after an aromatase inhibitor (AI) with a cyclin-dependent kinase 4/6 inhibitor (CDK4/6i).

TPS1109 Background: Endocrine therapy (ET) + CDK4/6i is standard of care for HR+, HER2− ABC; however, CDK4/6i resistance, in which the phosphatidylinositol-3-kinase (PI3K) pathway has a key role, remains challenging. Progression-free survival (PFS) for ≥ 2nd-line ET monotherapy post CDK4/6i is poor; prognosis may be worse in patients with a PI3KCA mutation. ALP (PI3K-α selective inhibitor and degrader) + FUL is approved by the European Medicines Agency (EMA) for HR+, HER2–, PIK3CA-mutated ABC after ET monotherapy. Outside the EMA, ALP + FUL approval includes post-CDK4/6i use. ALP + FUL has shown clinical activity and consistent safety in a small subpopulation in SOLAR-1 with prior CDK4/6i treatment (n = 9) and in BYLieve Cohort A (CDK4/6i + AI as immediate prior treatment; n = 121). The EPIK-B5 study aims to confirm the efficacy and safety of ALP + FUL in a larger population with HR+, HER2–, PIK3CA-mutated ABC with prior CDK4/6i + AI treatment. Methods: EPIK-B5 is a Phase III, randomized (1:1), double-blind, placebo-controlled study assessing the efficacy and safety of ALP (300 mg/d orally starting Cycle 1 Day 1 [C1D1]) + FUL (500 mg intramuscularly on C1D1 and C1D15, and D1 of subsequent cycles) in patients (N ≈ 234) with HR+, HER2–, PIK3CA-mutated ABC progressing on/after CDK4/6i + AI. Patients randomized to placebo + FUL can cross over to ALP + FUL after progression. Randomization is stratified by presence of lung and/or liver metastasis and prior CDK4/6i setting. Adult men or postmenopausal women with confirmed HR+, HER2–, PIK3CA-mutated ABC and ≥ 1 measurable lesion are eligible. The primary endpoint is PFS per blinded independent review committee assessment. Secondary endpoints include overall survival, overall response and clinical benefit rates, duration of and time to response, PFS by PIK3CA-mutation status in circulating tumor DNA, PFS on next-line treatment, time to definitive deterioration of ECOG status, quality of life (QoL), and safety and tolerability. Exploratory endpoints include biomarker analyses, additional QoL endpoints, and time to subsequent chemotherapy. Recruitment is ongoing, with enrollment planned over 2 years in 18 countries; completion of primary data collection is anticipated in 2026. Clinical trial information: NCT05038735; EUDRACT2021-001966-39.

Abstract P2-11-06: Assessment of ESR1 genomic aberrations and their role in endocrine therapy resistance in breast cancer

Abstract Background: Endocrine therapy (ET) is an effective treatment of estrogen receptor positive (ER+) breast cancer (BC). However, not all ER+ cancers respond to ET and many eventually acquire resistance. Genomic aberrations in ESR1 have been reported to play a role in resistance to treatment. ESR1 mutations (ESRMs), reported in 10-50% of metastatic or recurrent BCs treated with aromatase inhibitors (AIs), can lead to constitutive activation and reduced sensitivity to ET. The incidence and clinical implications of ESR1 amplification (ESRA) is not well-established. A variety of structural rearrangements involving ESR1 have been reported in primary BCs, with some more strongly associated with tamoxifen and AI resistance. This study aimed to establish a rapid, reliable and cost-effective method to screen and monitor ESR1 genomic aberrations in clinical BC tissue samples and relate these to the 1st line and subsequent ETs patients received. Patients: • Cohort A - 20 post-menopausal women (PMW) with ER+ BC who had acquired resistance to AIs and received subsequent lines of ET. Previous NGS data were available for these patients. • Cohort (B) - 425 ER+ BC patients, with paired matched tissue samples from the primary and progressive/recurrent cancer on 1st line ET; sites included local recurrence (25%), nodal recurrence (29%), distant recurrence (3%) and primary progression on neoadjuvant ET (44%). Median follow-up 10 years. All patients received 2nd line ET, 14% developed a further recurrence on 2nd line ET. Methods: ESRMs were assessed by allele-specific real-time quantitative (rt-qPCR) and digital droplet PCR (ddPCR) assays, a novel fluorometric in situ mutation detection (ISMD) approaches and AmpliSeq targeted sequencing. ESRA and ESR1 fusions were detected by targeted sequencing and validated using FISH and custom ligation assays for commonly-reported fusion proteins (currently ESR1-e6>YAP1 and ESR1-e6>PCDH11X), respectively. Results: Results from ddPCR and ISMD were consistent with NGS findings in cohort A. There was expansion of D538G mutant clones with acquired resistance in 5/20 patients (25%). ESR1 copy number gain was seen in 11/20 patients (55%) in resistant samples. Gene amplification was confirmed by FISH in 6, corresponding to those with the highest gain from the NGS data. In cohort B, recurrent/resistant samples (including 2nd recurrences) with matched primaries are currently being screened for ESR1 genomic aberrations using all methods allowing for a comprehensive comparison. This will allow full characterisation of mutations, copy number changes and gene fusions in the largest cohort of ET resistant cancers to date. Results will be interpreted in the context of 1st line ET (51% Tamoxifen, 34% non-steroidal AI, 8% exemestane, 7% other ET) and 2nd line ET in the 14% of patients who developed a 2nd recurrence. ESR1 genomic aberrations have been identified in 38% of samples to date, with specific aberrations associated with particular ETs. Discussion: • A reliable, robust and cost-effective methodology for the detection and quantitation of ESR1 aberrations in clinical BC samples has been developed and compared with NGS and targeted sequencing approaches. • This method would allow rapid screening for key aberrations with the potential to inform selection of 2nd line therapy. • Multiplexing of fluorometric assays may enable in situ clonality analysis that allows visualisation of multiple genomic driver aberrations simultaneously. • In the largest cohort of patients with resistance to ET to date, there is a high incidence of ESR1 genomic aberrations. These are associated with specific ETs. Analysis between these changes and response, disease-free and overall breast cancer-specific survival on 2nd line ET is currently ongoing. Citation Format: Carlos Martinez-Perez, Charlene Kay, James Meehan, Mark Gray, Rebecca Swan, Lorna Renshaw, Jane Keys, Andrew H Sims, Olga Oikonomidou, J Michael Dixon, Arran K Turnbull. Assessment of ESR1 genomic aberrations and their role in endocrine therapy resistance in breast cancer [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P2-11-06.

Abstract P6-04-03: In-depth genomic analysis of acquired resistance to multiple sequential lines of endocrine therapy in breast cancer

Abstract Background: 80% of all breast cancers (BCs) are ER+. Not all respond to endocrine therapy (ET) and many eventually develop resistance. An in-depth genomic analysis of cancers that acquired resistance (aR) to multiple sequential lines of ET after an initial period of response has been performed. Patients: A unique cohort of tissues from 20 post-menopausal women with ER+ BC was collected. All patients initially responded to neoadjuvant ET; 19/20 received an aromatase inhibitor (AI): letrozole (LET) (n=18) or anastrozole (AN) (n=1), 1 patient received fulvestrant followed by adjuvant tamoxifen (TAM) (mean treatment duration 22 months, range 4-67) before developing resistance. Patients were then treated by surgery or 2nd line ET. Overall, 13/20 received 2nd line ET either AN (n=1), TAM (n=10) or exemestane (EX) (n=1); 6 went on to receive 3rd line ET with EX (n=5) or LET (n=1). Methods: Serial RNA & DNA from 3-5 cancer samples per patient (89 samples) had Ribo0-RNAseq and DNA exome sequencing. Somatic mutations and copy number alterations (CNA) were determined. Fisher’s exact test was used to compare mutation frequencies (MFs). Differential gene expression analysis was performed using two-class unpaired Significance Analysis of Microarrays (SAM). Results: Mutations: Comparisons of MFs between all sensitive vs resistant tumours identified mutations in SAAL1 and SLC9A9 as being enriched in sensitive tumours while mutations in GATA3 and ZFPM2 were enriched across tumours with acquired resistance to ET. Only KMT2C was identified as enriched in resistant tumours when comparing sensitive to only those that acquired resistance to 1st line LET. When comparing sensitive tumours to only those that had acquired resistance to multiple lines of ET (LET and TAM +/- AN and EX), sensitives were significantly enriched for mutations in CCDC141 and SLC9A9 and multi-drug resistant (MDR) tumours were significantly enriched for mutations in 11 genes including ESR1 and GATA3, and genes involved in cell adhesion (CDH1, FLG, FLG2 and FREM2). ESR1 mutations were identified in 6/20 patients; 5 patients had D538G mutations, 2 appeared during resistance to 1st line LET and 3 in MDR tumours. 1 patient had an ESR1 frame-shift mutation which appeared during resistance to 1st line LET. GATA3 was mutated in 7/20 patients, of which 4 had mutations in all samples including baseline, 2 had mutations uniquely present in MDR tumours and 1 had mutations that appeared during resistance to 1st line LET. CNA: No significant gains or losses were identified when comparing sensitive tumours to those resistant to 1st line LET alone, but significant gains were identified across multiple chromosomes in MDR tumours. Gain of ESR1 was seen in 8/20 patients; in 3 patients there was ESR1 gain at diagnosis which persisted through initial response and subsequent aR. 5 patients developed ESR1 gain during MDR but not during initial resistant to 1st line LET. Gene Expression: Analysis comparing sensitive and MDR tumours identified 82 differentially expressed genes (FDR=0). MDR tumours had higher proliferation and higher expression of transcriptional regulators including FOS and FOSB, histone cluster genes and genes involved in oxidative phosphorylation. MDR tumours also had higher expressions of GATA3 induced genes. Discussion: In contrast to 1st line ET resistance, aR to multiple lines was characterised by significant gains across multiple chromosomes including ESR1 gain in a quarter of tumours. MDR tumours were also characterised by enrichment of mutations in particular genes including ESR1 (D538G in particular) which occurs in one-third of patients with aR. GATA3 is expressed in >90% of BCs, is reported to be mutated in up to 10% of all BCs may be integral to the functions of ESR1; mutations in GATA3 were enriched in MDR tumours and may highlight a new area of ET resistance. Citation Format: Arran K Turnbull, Youli Xa, Carlos Martinez-Perez, Olga Oikonomidou, James Meehan, Mark Gray, Lisa A Carey, Charles M Perou, J Michael Dixon. In-depth genomic analysis of acquired resistance to multiple sequential lines of endocrine therapy in breast cancer [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P6-04-03.

Abstract P5-04-14: Tracking ESR1 mutation clonal evolution in breast cancer using in situ mutation detection

Abstract Background: Approximately 70% of breast cancers (BCs) are estrogen receptor positive (ER+). Not all ER+ cancers respond to endocrine therapy (ET) and many eventually develop acquired resistance. Next-generation sequencing (NGS) has shown ESR1 mutations (ESRMs) are present in 10-50% of recurrent/metastatic cancers treated with aromatase inhibitors (AIs). Many of these mutations are located in the ligand-binding domain of ER, so they can lead to constitutive activation. This suggests ESRMs are a major mechanism of acquired resistance to endocrine therapy (ET) and numerous studies have shown a link between ESRMs and reduced sensitivity to 2nd line ET. The aim of this project was to investigate the incidence and clonal evolution of common ESRMs in BCs resistant to multiple sequential ETs using NGS, as well as novel PCR and in situ mutation detection methods. Methods: We have optimised an allele-specific real-time PCR (rtPCR) assay and an in situ mutation detection method (ER-ISMD) for the assessment of ESRMs. Both have been designed to identify a missense gain-of-function D538G mutation with a single nucleotide-resolution in formalin-fixed paraffin-embedded (FFPE) BC tissues. Two unique cohorts have been studied: (A) 20 post-menopausal women (PMW) with ER+ BC who acquired resistance to letrozole and were treated with up to 4 subsequent lines of ET. Serial RNA and DNA from 3-5 cancer samples per patient (58 samples from 20 patients) were analysed by Ribo0-RNAseq, DNA exome sequencing, rtPCR and ER-ISMD. (B) 150 PMW with ER+ BC who developed local (n=79), lymph node (n=59) or distant (n=12) recurrences on 1st line adjuvant letrozole, anastrozole or tamoxifen. Of these, 48 patients developed subsequent recurrences on 2nd line ET. Tissue samples from each recurrence and matched primary BC were collected. Results: In cohort A, 5/20 patients (20%) had expansion of a D538G ESR1 mutation clone at time of resistance 1st line ET (3:letrozole, 1:anastrozole, 1:tamoxifen). The mutant allele frequency (MAF) increased further in the 4 BCs treated with 2nd line ET (2:tamoxifen, 2:exemestane) and further still in the 1 BC who received 3rd line exemestane. 0/6 patients with ESRM responded to subsequent ET. Allele-specific rtPCR and ER-ISMD have been used to validate these findings and also identified low frequency ESRM clones in the sequential samples prior to the development of clinical resistance, that were not reported by NGS. Both methods have also been applied to screen tissues from patients in cohort B, where ESRMs have also been identified in recurrent samples. Complete analysis is currently ongoing. Conclusions: · ESRMs develop and expand in some BCs as a mechanism for acquired resistance to ET and are associated with a lack of response to subsequent standard ETs. · Allele-specific rtPCR can detect ESRMs and is more cost-effective and easier to use than NGS for ER mutation analysis. · Some ESRMs predate clinical resistance. · ER-ISMD is a novel approach that allows for identification and visualisation of the distribution of mutant clones in morphologically intact FFPE tissue. · ER-ISMD has the potential to become a clinically useful tool to help direct the use of 2nd line ET in routine care. Citation Format: Martinez-Perez C, Turnbull AK, Tanioka M, Fernando A, Renshaw L, Keys J, Wheless A, Garrett A, Parker J, He X, Sims AH, Carey LA, Perou CM, Dixon JM. Tracking ESR1 mutation clonal evolution in breast cancer using in situ mutation detection [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P5-04-14.

Abstract P4-13-13: Meta-analyses of visceral versus non-visceral metastases treated by AI & SERD agents as 2nd line endocrine therapy (ET) for HR+ breast cancer (BC)

Abstract There is a prevailing belief that ET for HR+ advanced BC is not as effective in patients with visceral metastases (VM) compared to non-visceral metastases (nVM), particularly with later lines of ET. Recently fulvestrant 500mg (Ful 500), has been reported to have greater efficacy in nVM compared to i) VM treated by Ful 500 but also compared to ii) nVM treated by Ful 250 (2nd line) and iii) nVM treated by aromatase inhibitor (AI), anastrozole (1st Line) – implying both site and agent related efficacy. Absence of significant overall survival (OS) difference in PALOMA 3 (2nd line) has increased the debate regarding when to add CDK 4/6is to ET, especially given the OS advantage for Ful 500 monotherapy in the 1st & 2nd line settings. Patients & Methods: Anonymised, individual patient level data was obtained from randomised controlled trials (RCTs) involving AI & SERD used as mono-theraphy in 2nd or 3rd Line setting in known HR+ BC. All the trials were Phase 3 double-blind, placebo RCTs. All were rigorously assessed for clinical benefit (CB), progression free survival (PFS), duration of CB (DoCB) and OS. Details of the studies, types of ET and patient numbers are shown in the Table. Results: Outcome data is presented for each study and then summarised under AI, SERD (Ful 250 or 500) and 'all Ets combined'. Odds ratios (Ors) & hazard ratios (HRs) for VM versus nVM by endocrine agents are shown in the Table. AgentStudyTotal Pats.HR+ Pats.CBRPFSOSDoCBAI(n)(n)OR (95%Cis)HR (95%Cis)HR (95%Cis)HR (95%Cis)Exe00202301831.181.441.271.50Exe00211931681.151.951.832.12AnaEFECT3403360.941.521.201.10AnaSOFEA2492491.291.181.051.41subtotal7636871.11 (0.84-1.48)1.47*** (1.22-1.79)1.21* (1.01-1.45)1.43** (1.10-1.86)SERDFul 25000202191601.791.701.401.23Ful 25000212041771.281.811.322.06Ful 250EFECT3513450.791.401.311.03Ful 250SOFEA2312310.701.171.242.22Ful 250CONFIRM1521521.131.071.510.84Subtotal9268341.05 (0.75-1.45)1.39*** (1.16-1.67)1.34*** (1.14-1.57)1.36 (0.93-1.98)SERDFul 500CONFIRM1441442.24 (1.12-4.48)1.30 (0.90-1.87)1.33 (1.14-1.57)0.97 (0.55-1.66)All ETsTotal183316651.13 (0.92-1.39)1.42*** (1.26-1.59)1.28*** (1.14-1.44)1.35** (1.09-1.66) [Pats=Patients; (n)=number; CBR-Clinical Benefit Rate; p-values p<0.05*, p<0.01**, p<0.001***] Median PFS (months) for nVM for AI, SERD250, SERD500 & ‘all Ets combined’ were 5.4, 5.5, 11.0 & 5.5 respectively: for VM they were 2.9, 3.5, 5.5 & 3.2 respectively. Median OS (months) for nVM for AI, SERD250, SERD500 & ‘all Ets combined’ was 24.2, 26.0, 35.4 & 25.4 respectively: for VM the figures were 22.8, 20.8, 26.4 & 22.0 respectively.Conclusions:1) In the 2nd line HR+ setting AI & Ful 250 both significantly increased PFS & OS in nVM versus VM. Longer PFS appears due to longer duration of control (DoCB) than increasing the number of patients responding (CBR). 2) Median OS for nVM ranged from 24 – 35 months versus 20.8-26.4 months for VM: for the majority of patients the 2nd line ET setting is not ‘immediately life threating’ and ET is therefore an option to consider. 3) These data on site of disease (nVM vs VM) contribute to the selection of which patients should receive endocrine mono- and which endocrine combination therapy (ie plus mTORi or CDK4/6i) in the second line setting. Citation Format: Robertson JFR, Di Leo A, Johnston S, Chia S, Bliss J, Bradbury I, Campbell C. Meta-analyses of visceral versus non-visceral metastases treated by AI & SERD agents as 2nd line endocrine therapy (ET) for HR+ breast cancer (BC) [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P4-13-13.

Abstract OT3-02-02: PATHWAY: Asian, multicenter, phase 3 trial of tamoxifen with or without palbociclib ± goserelin in women with hormone receptor-positive, HER2-negative advanced or metastatic breast cancer

Abstract BACKGROUND: The incidence rates of breast cancer (BC) in Asian counties have been rising rapidly. The age-specific female BC incidence rates peak before menopause (around 40-50 years of age) in Asia, however treatment options for pre/perimenopausal patients are limited. Palbociclib (P) is an oral novel cyclin-dependent kinase 4/6 (CDK4/6) inhibitor. The addition of P to endocrine therapy (ET) such as aromatase inhibitor or fulvestrant has been demonstrated improved progression-free survival (PFS) in phase 3 studies PALOMA-2 and PALOMA-3. This study is designed to evaluate efficacy and safety of P plus tamoxifen (TAM) in patients with hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative advanced or metastatic BC regardless of menopausal status. This study is conducted as a Clinical Research Collaboration by National Cancer Center Hospital with research funding from Pfizer. TRIAL DESIGN: PATHWAY/NCCH1607 is a double-blind, placebo-controlled, randomized, phase 3 study. Patients will be randomized 1:1 to receive either P (125 mg once daily, days1-21 of a 28-day cycle) or placebo in combination with TAM (20 mg once daily, continuously). Pre/perimenopausal women should receive concurrent ovarian function suppression with goserelin. Randomization will be stratified by prior ET for advanced/metastatic BC (1st line ET vs. 2nd line ET) and menopausal status (pre/perimenopausal vs. postmenopausal). KEY ELIGIBILITY CRITERIA: Eligible patients include women of any menopausal status with HR-positive, HER2-negative advanced or metastatic BC; candidates to receive TAM as 1st line or 2nd line ET for advanced/metastatic disease; ≥18 years of age; measurable or non-measurable disease (RECIST v.1.1); ECOG performance status 0-1; adequate organ function; have not received treatment with TAM (except for patients who have had more than 12 months from completion of adjuvant therapy with TAM); and have not received any CDK4/6 or phosphoinositide 3-kinase (PI3K) - mammalian target of rapamycin (mTOR) inhibitors. SPECIFIC AIMS: The primary endpoint is PFS as assessed by the investigator. Secondary endpoints include overall survival (OS), 1, 2, and 3-year survival probabilities, objective response (OR), duration of response, clinical benefit rate (CBR), pharmacokinetics, safety, and patient-reported outcomes. STATISTICAL METHODS: The sample size was determined to detect a 38% reduction in the hazard of disease progression or death in P plus TAM arm with a 1-sided significance level of 2.5% and power of 80%. A stratified log rank test will be used to compare PFS between the 2 treatment arms. PRESENT ACCRUAL AND TARGET ACCRUAL: Target accrual of 180 patients will be enrolled within 23 sites among Japan, Korea, Taiwan, and Singapore. As of June 2018, 46 patients have been enrolled. CONTACT INFORMATION: This trial is registered at ClinicalTrials.gov NCT03423199 and UMIN000030816. For more information, email NCCH1607_office@ml.res.ncc.go.jp Citation Format: Noguchi E, Hata T, Nakamura K, Kuchiba A, Hayashi M, Hamada A, Yonemori K, Sohn J, Lu Y-S, Yap Y-S, Fujiwara Y, Tamura K. PATHWAY: Asian, multicenter, phase 3 trial of tamoxifen with or without palbociclib ± goserelin in women with hormone receptor-positive, HER2-negative advanced or metastatic breast cancer [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr OT3-02-02.

Abstract P4-13-09: Sequential second line endocrine therapy is still an effective strategy for postmenopausal ER+ and HER2- advanced breast cancer with low sensitivity to initial endocrine therapy

Abstract Background:It is unclear how to define responsiveness to endocrine therapy (ET) during the clinical course of advanced breast cancer (ABC), especially in evaluation of the effect of sequential ET. Objective:The goal of the study was to evaluate the efficacy of second line treatment of physician's choice (2nd-line TPC) for estrogen receptor-positive (ER+) and HER2-negative postmenopausal ABC with very low or low sensitivity to initial ET. Methods:A multicenter prospective observational cohort study was performed for 2nd-line TPCs. ABC with low sensitivity to initial ET was defined as recurrence within 5 years (yrs) during adjuvant ET or progression within 9 months (mo.) of initial ET. Similarly, ABC with very low sensitivity to initial ET was defined as recurrence within 2 yrs during adjuvant ET or progression within 3 mo. of initial ET. The expected clinical benefit rate (CBR: defined as patients who achieved CR, PR or SD for 24 weeks) was 50%. The null hypothesis of a CBR of 30% was tested with a one-sided α of 5%. 90% confidence intervals (CIs) were calculated for hypothesis tests. Results: A total of 56 patients (pts) were enrolled, but 7 were ineligible and one discontinued before starting the protocol treatment. The median age was 66 yrs (range: 41-88) and the median BMI was 23.4 kg/m2 (16.4-31.9). All pts were ER+ and 80% were PgR+. Most of pts had a baseline PS of 0 or 1, 90% had invasive ductal carcinoma, and 10% had invasive lobular carcinoma. Postoperative recurrence was detected in 84% and these pts had a median duration of adjuvant ET of 30.5 mo. (5.3-58.9). De novo stage IV ABC was present in 16%, with a median duration of first-line ET of 5 mo. (2.3-10.8). Adjuvant chemotherapy including anthracycline- and/or a taxane-containing regimen was administered in 58% (29/49). As adjuvant ET before initial recurrence, 34 pts received non-steroidal aromatase inhibitors (AIs) (88.0%), 1 received a steroidal AI (2.3%), and 3 received a selective estrogen receptor modulator (SERM). As first line ET in de novo stage IV, 7 pts (14%) were treated with AIs or a SERM (1 case). 2nd-line TPCs were also used, with 40 pts receiving fulvestrant (82%), 5 receiving SERMs (10%), 3 receiving a mTOR inhibitor plus a steroidal AI (6%), and one patient receiving an AI alone. The overall CBR was 44.9% (90% CI: 34.6-57.6, p=0.009), and CBR was similar across following subgroups (PgR+: n=39, 51.3%, 90% CI: 39.6-65.2, p=0.0016; very low sensitivity group: n=17, 58.8%, 90% CI: 42.0-78.8, p=0.003; non-visceral metastases: n=25, 40%, 90% CI; 34.1-65.9, p=0.0175). However, there were not statistically significant CBR in PgR- (n=10, 20.0%, 90% CI; 8.73-50.7, p=0.617), fulvestrant subgroup (n=40, 40.0 %, 90% CI; 29.2-54.2, p=0.063), low sensitive group (n=32, 37.5%, 90% CI; 26.0-53.6, p=0.1326), and visceral metastases (n=24, 48%, 90%CI; 28.2-60.3 p=0.072). The median PFS was 7.1 mo. (95% CI: 5.6-10.6). Conclusion:This study shows that 2nd line ETs was effective and might be a valid option in the sequence of treatments for postmenopausal women with ABC with low sensitivity to initial ET. It was suggested that PgR and visceral metastasis were significant predictive factors for CBR. Citation Format: Araki K, Fujisawa T, Sakamaki K, Kikawa Y, Iwamoto T, Sangai T, Shien T, Takao S, Nishimura R, Takahashi M, Aihara T, Mukai H, Taira N. Sequential second line endocrine therapy is still an effective strategy for postmenopausal ER+ and HER2- advanced breast cancer with low sensitivity to initial endocrine therapy [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P4-13-09.

Abstract P4-03-01: Causes of endocrine therapy resistance: An in-depth genomic analysis of resistant multidrug ER+ breast cancers

Abstract Background: 70% of all breast cancers (BCs) are ER+. Not all ER+ cancers respond to endocrine therapy (ET) and many eventually develop resistance. The aim was to perform in-depth genomic analysis of both primary resistant BCs, that do not respond to ET, and cancers which progress (>40% increase in size) after an initial response as they acquire resistance (AQR) to ET. Methods: A unique series of 48 post-menopausal women with ER+ BC received neoadjuvant ET using letrozole (L) or anastrozole (A) (mean treatment duration 17 months, range 3-67). 13/48 received up to 4 lines of ET. 12/48 responded to A or L, 16/48 had primary resistance and 20/48 had AQR. Of 20 with AQR, 13 had 2nd line ET with A or tamoxifen (T). 6 had 3rd line ET with exemestane (E) and 1 had 4th line megestrol acetate (MA). Serial RNA & DNA from 3-5 cancer samples/patient (226 samples) had Ribo0-RNAseq, DNA exome sequencing and somatic mutation detection using UNCeqR. We have data so far on 29 patients: 5 responders, 4 with primary resistance and 20 AQR, the full cohort will be complete shortly. Results: ESR1 Mutations (ESRM): 1/5 responders had an ESRM (E380Q) at diagnosis. This clone disappeared with response to L. 5/20 patients with AQR (25%) had clonal expansion of an ESRM during 1st line ET (L:4, A:1). 4 had a chr6:152419926[lowbar]A:G (D538G) ESRM and 1 had a novel ESRM. Of the 5 with ESRM acquired during 1st line ET, the mutant allele fraction (MAF) increased further in the 4 who had 2nd ET (3:T, 1:E) and increased further for the 2 who had 3rd line E. ESR1 Amplification (ESRA): 5 patients developed ESRA. 3/5 developed ESRA on 2nd or 3rd line E that was not present on AQR to 1st line L or A and 2nd line T. The other 2 developed ESRA on L. 2/5 with ESRA had concomitant CYP19A1 amplification. One patient with ESRA that developed on 3rd line E subsequently responded to MA. No patients with primary resistance to 1st line ET had an ESRM or ESRA. PIK3CA mutations (PIK3M): 5/20 with AQR had PIK3M (25%). 3/7 had PIK3M at diagnosis and in 3 MAF increased between 1st and 2nd line ET. 2/7 developed PIK3M when resistant to 2nd line ET, 1 of the 2 had ESRA. 2 patients responsive to L had PIK3M at diagnosis and MAF decreased with therapy. Other Mutations: Unique mutations with limited commonality developed and new clones expanded in the remaining cancers during primary and acquired resistance. Clonality analysis of AQR samples to different ETs showed proliferation of specific clones, characterised by novel sets of mutations, which typically became the dominant clone at the time of resistance to a particular agent. Summary: 13/20 with acquired resistance had ESRM, ESRA, or PIK3M in resistant tumours: 1 had all 3, 2 ERSM + ESRA, 1 ERSA + PIK3CA, 4 ESRM only, 2 ESRA only and 3 had PIK3M only. Conclusions: • Endocrine resistance is complex • ESRM or ESRA is uncommon at diagnosis and does not explain primary ET resistance • ESRM (in particular the D538G mutation) occurs in one-third of patients with acquired resistance. 2nd line ET results in clonal selection and expansion of ESRM cells. Assessing recurrences for ESRM by in situ detection has clinical utility • ESRA is only seen in heavily ET-pre-treated tumours, with its significance being unknown. Citation Format: Dixon JM, Turnbull AK, Tanioka M, Wheless A, Garrett A, Martinez-Perez C, Parker J, He X, Sims AH, Thomas JS, Carey LA, Perou CM. Causes of endocrine therapy resistance: An in-depth genomic analysis of resistant multidrug ER+ breast cancers [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P4-03-01.

Efficacy of docetaxel chemotherapy in metastatic prostate cancer (mPC) patients (pts) experiencing early castration resistance (CR).

5075 Background: mPC pts experiencing a short period of sensitivity to initial androgen deprivation therapy (ADT) have an unfavourable prognosis and lower probability of response to 2nd-line endocrine therapy suggestive of androgen receptor (AR) pathway-independent mechanisms of resistance. Recent studies have shown that docetaxel may kill PC cells through AR targeting. We thus investigated whether docetaxel may have efficacy in pts with early CR. Methods: Two independent prospective databases (Institut Gustave Roussy and Institut Jean Godinot) of mCRPC pts were analyzed. Early CR was defined as progression within the first year of ADT. The primary endpoint was time to progression (TTP) on docetaxel. Secondary criteria were clinical benefit (decrease in 2 points on a 0-to-10-pain-scale or in dose or type of pain medication), PSA response (decrease > 50% in PSA serum level) and overall survival (OS). Pts with early CR were compared to pts with sensitivity to initial ADT > 1 year (t-test for quantitative data, χ-2 test or Fischer’s exact test for qualitative data, Logrank test for TTP and OS). Results: 188 pts were selected for analysis. A higher frequency of unfavourable prognostic factors in pts with early CR as compared with others pts was observed with a median PSA serum level of 81 ng/dl (4-8000) vs 35 ng/dl (4-4260) (p=5.10-5), presence of visceral metastasis in 11% vs 2% of pts (p=0.01) and Gleason score ≥ 8 in 63% vs 41% of pts respectively (p=0.001). Clinical benefit and PSA response on docetaxel were observed in 84% vs 89% of pts (p=0.45) and 67% vs 81% of pts (p=0.10) respectively. Median TTP was 6.1 months (95%CI=6-7.5) vs 7.8 months (95%CI=7-8.3) (p=0.04). Median OS was 22.4 months (95%CI=17.1–28.6) vs 36.1 months (95%CI=26.3–42.4) (p=0.002). Conclusions: mPC pts experiencing early CR have more unfavourable baseline prognostic factors, shorter TTP on docetaxel and shorter OS as compared with pts experiencing time to CR > 1 year. However, similar clinical and biological benefits from docetaxel chemotherapy were observed in this subset of pts. Since they have lower probability of response to second-line endocrine therapy, docetaxel appears as the best option after progression on initial ADT.

Abstract P2-14-04: A Phase Ib Dose Escalation Trial of RO4929097 (a γ-secretase inhibitor) in Combination with Exemestane in Patients with ER + Metastatic Breast Cancer.

Abstract Background: RO4929097 is a potent and oral selective inhibitor of γ-secretase (GSI), producing inhibitory activity of Notch 1–4 signaling in tumor cells. Preclinical studies have demonstrated synergism of GSIs in combination with endocrine therapy, in ERα-positive xenografts. This suggests that optimal treatment of ER+ BC would benefit from an antiestrogen and GSI combination. Materials and Methods: To explore the safety, tolerability and preliminary antitumor activity of Exemestane (25 mg/d) with R04929097 combination, we conducted a Phase Ib trial in patients with ER+/ HER2− MBC, whose disease relapsed during treatment with or within 6 months of discontinuation of an adjuvant nonsteroidal aromatase inhibitor or Tamoxifen, or whose MBC progressed during treatment with 1st or 2nd line endocrine therapy. Goserelin (3.6 mg q28 days Sub-Q) was given to all premenopausal patients. R04929097 was administered orally daily for 3 consecutive days, followed by 4 days off on a 21 day cycle. Doses of R04929097 were escalated on a standard 3+3 design over 5 doses (20, 30, 45, 90, and 140 mg). Patients were fully evaluated for dose limiting toxicity (DLT) for 3 weeks. Patients were treated until disease progression or occurrence of unacceptable toxicity. Results: A total of 15 patients were enrolled. Median age was 56; average number of chemotherapies received in the adjuvant or metastatic setting was 3.3. Eleven patients had received adjuvant endocrine therapy. One patient received this as 1st line endocrine therapy, eleven patients received this study as 2nd line endocrine therapy; and three patients received this study as 3rd line endocrine therapy in the metastatic setting. Of the 14 patients evaluable, 1 had a partial response, 6 had stable disease, and 7 had progressive disease. All patients have discontinued the study at this time, 11 due to progression, 2 due to toxicity, and 1 withdrew after beginning protocol therapy. Twenty percent of patients had stable disease for six months or greater. Of the patients with stable disease for six months, one patient progressed at 9 months and 2 patients progressed at 10 months. The most common toxicities were nausea (73.3%), anorexia (60%), hyperglycemia (53.3%), hypophosphatemia (46.7%), fatigue (66.7%), and cough (33.0%). Grade 3 toxicities were uncommon and included hypophosphatemia (13.0%) and rash (6.3%). There were no grade 4 toxicities. Rash was the only DLT and was seen at 140 mg. Conclusion: The combination of R04929097 and Exemestane was overall well tolerated, but MTD was not determined as access to drug ended. Further studies with GSIs in combination with endocrine therapy are warranted on the basis of a favorable safety profile and preliminary evidence of stable disease seen in patients with ER+ MBC refractory to previous endocrine therapies. PK, PD and biomarker analysis is ongoing. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P2-14-04.

P53 overexpression is a significant factor in predicting resistance to 3rd generation aromatase inhibitors (AIs) in hormone-sensitive recurrent or advanced breast cancer

715 Background: HER-2 positivity is an appropriate predictive factor for the resistance to tamoxifen. However our knowledge of which factors indicate the resistance to 3rd AIs in recurrent or advanced breast cancer is insufficient. In our study, we assessed the correlations between the efficacy (response rate, time to progression) of 3rd AIs and clinicopathological factors to determine the appropriate predictive factor for the resistance to 3rd AIs. Methods: We investigated the disease courses and clinicopathological factors in seventy-nine recurrent or advanced patients (pts) treated with 3rd AIs in our hospital between February 1996 and December 2004. Sixty-three of the 79 pts treated with 3rd AIs as 1st line or 2nd line endocrine therapy (Anastrozole: 47cases, Exemestane: 15, Letrozole: 1) were eligible for this retrospective study. All pts were postmenopausal with positive ER and/or PgR tumors. Forty cases were treated as 1st line endocrine therapy, and 23 cases as 2nd line therapy. Forty-eight pts ha...

New aromatase inhibitors (Ais) as 1st-line endocrine therapy (ET) in metastatic breast cancer (MBC): A pooled analysis of 3238 women from 8 phase III trials

602 Background: Some of the new non-steroidal AIs (anastrozole and letrozole) have been registred for the treatment of first line ET for MBC. We previously presented the results of a pooled analysis of AIs in 2nd line ET for MBC (Carlini P, ASCO 2004). In order to assess the benefit in TTP and ORR of all AIs when compared to tamoxifen, we performed a pooled analysis including all phase-III trials with new AIs (letrozole, anastrozole, fadrazole, formestane, exemestane) as 1st-line ET for MBC. Methods: Entry criteria: published/presented phase-III studies evaluating AIs as 1st-line ET in MBC. Randomized phase-II trials were ruled out. Time to progression (TTP) and overall response rate (ORR) were our end-points. Event-based relative risk ratio (RR) and 95% confidence intervals (CI) were derived. Combined effect estimation was computed with a fixed-effect model. An heterogeneity test was applied as well. Results: Eight trials were eligible (3238 pts). Significant benefit in favour of AIs versus tamoxifen were seen in TTP (RR 0.83, 95% CI 0.76–0.90, p<0.001), although significant heterogeneity (p<0.00001). When considering only trials with non-steroidal AIs (6 studies, 2458 pts), a significant benefit in favour of AIs versus tamoxifen were seen in TTP (RR 0.80, 95% CI 0.73–0.89, p<0.001), although significant heterogeneity (p<0.0001). Significant benefit in favour of AIs versus tamoxifen were seen in ORR (RR 1.18, 95% CI 1.06–1.31, p=0.002), although significant heterogeneity (p<0.011). When considering only trials with non-steroidal AIs (6 studies, 2458 pts), a significant benefit in favour of AIs versus tamoxifen were seen in ORR (RR 1.19, 95% CI 1.06–1.36, p=0.005), although significant heterogeneity (p=0.04). Conclusions: When all subgroups were analyzed for TTP and ORR, significant differences were found. AIs in 1st-line ET for MBC seem to add a significant benefit versus tamoxifen. The significant heterogeneity of all outcomes requires a careful evaluation of these results No significant financial relationships to disclose.

New aromatase inhibitors (AIs) as 2nd-line endocrine therapy (ET) in metastatic breast cancer (MBC): A comprehensive review of 5832 women from 14 phase III trials

629 Background: New AIs have been developed in controlled clinical trials after tamoxifen failure in MBC. A meta-analysis of the three FDA/EMEA-approved AIs revealed that they conferred a significant survival benefit when compared with megestrol (M) (Messori, Anticancer-Drugs 2000). We performed a comprehensive review (Simes, Stat Med 1987) including phase-III trials with new AIs (2nd generation - formestane, fadrozole - and 3rd generation - letrozole, anastrozole, vorozole, exemestane) approved or not by FDA-EMEA as 2nd-line ET for MBC pts between 1996 and 2003. Methods:Published or presented trials had to met the following criteria: phase-III studies evaluating AIs as 2nd-line ET in MBC. No phase-II trials were gathered. Letters/editorials, comparative trials of 3rd-generation vs 3rd-generation AIs or given as adjuvant/neoadjuvant ET were ruled-out. Overall response rate (ORR) and time to progression (TTP) were our end-points; survival was excluded because of lack of data. For this analysis, ratios (HR and RR) and 95% confidence intervals (CI) were derived. Results: Fourteen trials were eligible (5832 pts). No significant differences were seen in the whole group of 9 trials comparing AIs vs M (3908 pts, ORR-RR 1.07, 95% CI 0.88–1.30; TTP-HR 1.00, 95% CI 0.89–1.12), in the 6 trials including non-steroidal AIs vs M (2415 pts, ORR-RR 1.10, 95% CI 0.84–1.46; TTP-HR 0.95, 95% CI 0,85–1.07), in the 3 studies comprehending steroidal AIs vs M (1493 pts, ORR-RR 1.08, 95% CI 0.61–1.94; TTP-HR 1.08, 95% CI 0.61–1.94), in 3 trials comparing 3rd generation AIs (letrozole and vorozole) vs 1st and 2nd generation AIs (aminiglutethimide and fadrazole) (1073 pts, ORR-RR 1.50, 95% CI 0.78–2.88; TTP-HR 1.18, 95% CI 0.66–2.13), and finally in 2 only studies comparing the new AI anastrozole vs the steroidal antiestrogen fulvestrant (851 pts, ORR-HR 0.86, 95% CI 0.14–1.79; TTP-HR 0.77, 95% CI 0.07–9.01). Conclusions: When all subgroups were analyzed for ORR and TTP, no significant differences were found. AIs in 2nd-line ET for MBC pts did not seem to add any significant benefit to standard comparator arm in terms of ORR and TTP. No significant financial relationships to disclose.