Advanced Breast Cancer Setting Research Articles

CDK4/6 Inhibitors—Overcoming Endocrine Resistance Is the Standard in Patients with Hormone Receptor-Positive Breast Cancer

Tamoxifen and aromatase inhibitors can be considered as some of the first targeted therapies. For the past 30 years, they were the endocrine treatment standard in the advanced and early breast cancer setting. CDK4/6 inhibitors, however, are the first substances in almost two decades to broadly improve the therapeutic landscape of hormone receptor-positive breast cancer patients for the upcoming years. This review is designed to discuss the recent history, current role, future directions and opportunities of this substance class. The CDK4/6 inhibitors abemaciclib, dalpiciclib, palbociclib and ribociclib have all demonstrated a statistically significant improvement in progression-free survival in advanced disease. However, to date, abemaciclib and ribociclib are the only CDK4/6 inhibitors to have shown an improvement in overall survival in patients with metastatic breast cancer. Moreover, abemaciclib is the first CDK4/6 inhibitor to also reduce the risk of recurrence in those with early-stage disease. Further CDK inhibitors, treatment combinations with other drugs and different therapy sequences are in development. Achieving significant improvements in survival rates in the advanced and early breast cancer treatment setting, CDK4/6 inhibitors have set a new standard of care for patients with advanced breast cancer. It remains important to better understand resistance mechanisms to be able to develop novel substances and treatment sequences.

Implementation of CDK4/6 Inhibitors and its Influence on the Treatment Landscape of Advanced Breast Cancer Patients - Data from the Real-World Registry PRAEGNANT.

Background Comprehensive data from prospective clinical trials have led to a high level of evidence establishing CDK4/6 inhibitors in combination with endocrine treatment (CDK4/6i + ET) as a standard for the treatment of HER2-negative, hormone receptor-positive (HER2− HR+) breast cancer patients in the first-line advanced therapy setting. Data on patient populations that have been treated in the real-world setting may provide an insight into changes of patient characteristics and prognosis over time. Methods The data were extracted from the prospective real-world registry PRAEGNANT (NCT02338167). Patients had to have HER2− HR+ advanced breast cancer in the first-line metastatic setting. The chosen therapies were described as well as progression-free survival (PFS) and overall survival (OS) in relation to the given therapies and time periods during which they were indicated. Results CDK4/6 inhibitors have been rapidly implemented since their introduction in November 2016. In recent years (2018 – 2022), about 70 – 80% of the patient population have been treated with CDK4/6 inhibitors, while endocrine monotherapy was given to about 10% and chemotherapy to about 15% of all patients. The prognosis was worst in patients treated with chemotherapy. Recently, mainly patients with a good prognosis are being treated with endocrine monotherapy, and patients who are treated with chemotherapy have an unfavorable prognosis. The PFS and OS of patients treated with CDK4/6i + ET have remained similar over time despite changes in patient characteristics. Conclusion A treatment with CDK4/6i + ET has rapidly become the therapy standard for patients in the first-line advanced breast cancer setting. After the implementation of CDK4/6i + ET, endocrine monotherapy is only given to patients with a very favorable prognosis, while chemotherapy is provided to patients with a rather unfavorable prognosis. These changes in patient characteristics did not seem to influence the prognosis of patients treated with CDK4/6i + ET.

Abstract P1-18-05: Early changes in circulating tumor DNA and its effect on clinical outcomes in patients with advanced breast cancer receiving the CDK4/6 inhibitor palbociclib: Genotyping results from POLARIS

Abstract Background: POLARIS is a prospective, real-world study of palbociclib in patients with hormone receptor-positive (HR+)/human epidermal growth factor receptor 2-negative (HER2–) advanced breast cancer (ABC) in the United States and Canada. These analyses evaluated the difference in tumor mutation profiles of patients receiving palbociclib in the first line versus second line or greater and examined the applicability of circulating tumor DNA (ctDNA) monitoring in a real-world setting. Methods: The clinical database cut-off date was March 16, 2021. Patients in the biomarker analysis group provided consent for serial blood sample collections, received ≥1 dose of initial palbociclib combination treatment, and had ≥1 ctDNA measurement available. The Guardant360 platform with somatic single-nucleotide variants in complete or critical exons of 73 genes was used. The association between early changes in ctDNA mutation allele fractions at Cycle 2 Day 1 (C2D1) and disease progression at Week 24 was evaluated using univariate and multivariable logistic regression analysis adjusting for line of therapy. Results: Among patients with HR+/HER2– ABC (N=347), 93.9% (n=326) had ctDNA measured at baseline, of which 85.9% (n=280) had ≥1 ctDNA alteration detected; 66.6% of patients received palbociclib treatment in the first line and 33.4% as second line or greater ABC setting. The frequencies of gene mutations at baseline were generally higher in patients receiving palbociclib as a second-line or greater therapy compared to those who received it as first-line therapy, particularly for ESR1 mutations (30% vs 15%) and FGFR1 mutations (13% vs 9%). With a median (range) follow-up duration of 18.5 (0.1-46.3) months, patients with total ctDNA increase at C2D1 (log ratio change >0) were 3.74 times more likely to have disease progression at Week 24 (odds ratio, 3.74 [95% CI, 1.71-8.17]; P=0.001) compared with those without change or with a decrease in ctDNA at C2D1 (log ratio change ≤0). The observed significant association remained after adjusting for line of therapy in the multivariable regression analysis (odds ratio, 2.62 [95% CI, 1.14-6.04]; P=0.023). Conclusions: Among patients with HR+/HER2- ABC receiving palbociclib, early changes in ctDNA mutations were significantly associated with disease progression. Further studies are needed to confirm these findings and to evaluate the clinical utility of ctDNA-guided “adaptive” early therapeutic interventions to improve outcomes in patients with metastatic breast cancer. Pfizer; NCT03280303 Citation Format: Debu Tripathy, Zhe Zhang, Joanne L. Blum, Meghan S. Karuturi, Steven L. McCune, Bijoy Telivala, Shailendra Lakhanpal, Kamal Patel, Richard C. Frank, Kit Lu, Chetan Deshpande, Yao Wang, Yuan Liu, Aditya Bardia. Early changes in circulating tumor DNA and its effect on clinical outcomes in patients with advanced breast cancer receiving the CDK4/6 inhibitor palbociclib: Genotyping results from POLARIS [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 P1-18-05.

Best of ASCO 2021: new data from triple-negative breast cancer

SummaryThis year’s ASCO Annual Meeting has been a showcase for the overwhelming success of novel, targeted therapies, particularly in a tumor entity that has – until recently – been felt to be only treatable with chemotherapy. New data are extremely encouraging, but also highlight the need for target identification beyond the classical clinicopathological factors. Both, the Olympia and the Neotala study have been performed in BRCA-mutated tumors, and their results clearly point to the necessity to offer germline testing to HER2-negative high risk early breast cancer. In addition, GeparNuevo once more highlights the fact that immunotherapy is here to stay, not only in the advanced breast cancer setting, but also in early stage breast cancer. The side effect profile is acceptable, and long-term outcome a real improvement to conventional chemotherapy.

Prognostic Factors for Overall Survival in Patients with Hormone Receptor-Positive Advanced Breast Cancer: Analyses From PALOMA-3.

BackgroundThis analysis investigated whether baseline characteristics affect the survival benefit derived from palbociclib‐fulvestrant and the optimal timing of cyclin‐dependent kinase 4/6 inhibitor therapy for advanced breast cancer (ABC) in patients from PALOMA‐3.Patients and MethodsIn total, 521 patients were randomized 2:1 to receive palbociclib (125 mg/day, 3/1 schedule)–fulvestrant (500 mg, intramuscular injection, on days 1 and 15 of cycle 1, and then day 1 of each subsequent cycle) or matching placebo‐fulvestrant. Median overall survival (OS) and progression‐free survival were estimated using the Kaplan‐Meier method.ResultsMultivariable analysis identified endocrine sensitivity, nonvisceral disease, no prior chemotherapy for ABC, and Eastern Cooperative Oncology Group performance status (ECOG PS) of 0 as significant prognostic factors for OS. Patients without chemotherapy for ABC had fewer prior lines of treatment in any setting and in the ABC setting versus patients with prior chemotherapy for ABC (two or fewer prior systemic therapies: 69% vs. 42%; no more than one prior line for ABC: 82% vs. 33%, respectively). Median OS was prolonged with palbociclib‐fulvestrant in patients without prior chemotherapy for ABC (39.7 vs. 29.5 months; hazard ratio, 0.75; 95% confidence interval [CI]: 0.56–1.01) and was similar in patients with prior chemotherapy for ABC (25.6 vs. 26.2 months; hazard ratio, 0.91 [95% CI: 0.63–1.32]) versus placebo‐fulvestrant.ConclusionPrognostic factors for OS included endocrine sensitivity, nonvisceral disease, ECOG PS of 0, and no prior chemotherapy for ABC. Exploratory analyses suggest improved OS with palbociclib‐fulvestrant versus placebo‐fulvestrant in patients with no prior chemotherapy for ABC, prior endocrine sensitivity, and fewer prior regimens of systemic therapy. (Clinical trial identification number: NCT01942135).Implications for PracticePrognostic factors for overall survival in HR+/HER2− advanced breast cancer (ABC) include the absence of prior chemotherapy in the advanced setting, endocrine sensitivity, nonvisceral disease, and an ECOG performance status of 0. Improved overall survival benefit was observed with palbociclib‐fulvestrant versus placebo‐fulvestrant in patients (regardless of menopausal status or visceral involvement) with no prior chemotherapy for ABC, with prior endocrine sensitivity, and fewer prior regimens of systemic therapy. Progression‐free survival was prolonged with palbociclib across subgroups (regardless of chemotherapy exposure in ABC). These exploratory findings suggest that patients may receive greater clinical benefit from palbociclib‐fulvestrant if they receive the combination before chemotherapy in the advanced setting.

Resumption of Trastuzumab in Patients With Disease Recurrence After (Neo-) Adjuvant Anti-HER2-therapy in Patients With HER2-positive Breast Cancer.

HER2-positive breast cancers eventually relapse in about one third of patients. Is anti-HER2-directed therapy with Herceptin® (trastuzumab) effective in re-treatment? Between 2008 and 2018, 216 patients with recurrent HER2-positive breast cancer (BC) were re-treated with Herceptin (HER) during first-line therapy. This study assessed the effectiveness and tolerability of re-treatment with HER. After approval from Ethical committee, the NIS was conducted according to German Drug Act. Re-treatment with HER was documented at routine visits starting with a basic observational period of maximum 12 months and a follow-up period of maximum additional four years. HER2-positive BC relapsed after a median of 36.5 months (mos). Patients were re-treated with HER +/- chemotherapy +/- endocrine therapy. HER-containing regimens resulted in median progression-free survival (mPFS) of 12.7 (95%CI=10.5-14.8) mos and overall survival (OS-2) of 31.6 mos (95%CI=28.8-38.4) since recurrence diagnosis. Differentiation of recurrence types (local, visceral, non-visceral) unfolded worst prognosis for patients with visceral metastases. Cardiac monitoring within this non-interventional study (NIS) did not result in new safety concerns. Re-therapy with HER in the first-line setting of advanced HER2-positive breast cancer is effective and without unexpected or intensified adverse events.

Patients' and Clinicians' Perceptions of Clinician-Expressed Empathy in Advanced Cancer Consultations and Associations with Patient Outcomes.

Background: Empathy is a cornerstone of effective communication. However, clinicians' and patients' perceptions of clinician-expressed empathy might differ. The independent perceptions of patients and clinicians on clinician-expressed empathy in advanced cancer consultations and the associations of these perceptions with patient outcomes are unknown.Objective: We assessed (1) patients' and clinicians' independent perceptions of clinician-(self-)expressed empathy in advanced cancer consultations and (2) the associations between these perceptions and affective patient outcomes.Methods: This observational study included data from 41 consultations in the advanced breast cancer setting. Postconsultation, patients' and clinicians' perceptions of clinician-expressed empathy were assessed, as well as patients' (1) pre–post anxiety, (2) post-anxiety, (3) emotional well-being, and (4) satisfaction. Multilevel regression analyses were run to draw conclusions.Results: Patients perceived higher levels of empathy than clinicians, without a significant relationship between the two (mean [M] = 85.47, standard deviation [SD] = 14.00 vs. M = 61.88, SD = 15.30, 0–100 scale; β = 0.14, p < 0.138, 95% confidence interval [CI] = −0.04 to 0.32). Higher patient-perceived empathy was associated with decreased anxiety [(1) β = −0.67, p = 0.039, 95% CI = −1.30 to −0.03; (2) β = −0.15, p = 0.042, 95% CI = −0.30 to −0.01], higher satisfaction (β = 0.05, p < 0.001, 95% CI = 0.03 to 0.08), and lower emotional distress (β = −0.32, p < 0.001, 95% CI = −0.48 to −0.16). There were no associations with clinicians' perceptions [(1) β = −0.34, p = 0.307, 95% CI = −1.00 to 0.31; (2) β = −0.02, p = 0.824, 95% CI = −0.17 to 0.14; (3) β < 0.01, p = 0.918, 95% CI = −0.03 to 0.02; (4) β = 0.08, p = 0.335, 95% CI = −0.08 to 0.25].Conclusions: Patients' and clinicians' empathy perceptions differed. In improving patient outcomes, the focus should be on patients' perceptions of clinician-expressed empathy. Future research could focus on ways to elicit patients' perceptions of empathy with the higher aim of improving patient outcomes.

Abstract P2-20-01: Impact of neratinib on development and progression of central nervous system (CNS) metastases in patients with HER2-positive metastatic breast cancer (MBC): Findings from the NALA, NEfERT-T, and TBCRC 022 trials

Abstract Background: The development of metastatic disease in the CNS presents a considerable challenge in the management of patients with MBC as a result of the lack of evidence-based treatment options currently available. Up to 50% of patients with HER2+ MBC develop CNS metastases. A (non-significant) reduction in the cumulative incidence of CNS recurrences was seen in the randomized phase 3 ExteNET trial of neratinib as extended adjuvant treatment of patients with early-stage HER2+ breast cancer following adjuvant trastuzumab-based therapy (Martin et al. Lancet Oncol 2017). Here we review data from the following three trials of neratinib in the metastatic setting: the Phase 3 NALA trial (ClinicalTrials.gov: NCT01808573; Saura et al. ASCO 2019), the Phase 2 NEfERT-T trial (NCT00915018; Awada et al. JAMA Oncol 2016); and the TBCRC 022 trial (NCT01494662; Freedman et al. J Clin Oncol 2019), which suggest activity for neratinib in patients with MBC and CNS metastases. Methods: Patients in NALA (who had received at least 2 lines of HER2-directed therapy for MBC) were randomized 1:1 to neratinib (N; 240 mg qd po) + capecitabine (C; 750 mg/m2 bid po) or lapatinib (L; 1250 mg qd po) + C (1000 mg/m2 bid po). In the NEfERT-T trial, previously untreated patients with recurrent and/or MBC were randomized 1:1 to N (240 mg qd po) or trastuzumab (T; 4 mg/kg then 2 mg/kg weekly), each combined with paclitaxel (P; 80 mg/m2 on days 1, 8, and 15 every 28 days). In TBCRC 022, patients with measurable, progressive HER2+ brain metastases received N (240 mg qd po) + C (750 mg/m2 qd po). The co-primary endpoints in NALA were centrally assessed progression-free survival (PFS) and overall survival (OS); time to intervention for symptomatic metastatic CNS disease was a secondary endpoint. PFS was the primary endpoint in NEfERT-T; frequency of and time to symptomatic and/or progressive CNS lesions was a secondary endpoint. The primary endpoint in TBCRC 022 was composite CNS objective response rate (ORR), requiring a reduction of ≥50% in the sum of target CNS lesion volumes without progression of non-target lesions, new lesions, escalating steroids, progressive neurologic signs or symptoms, or non-CNS progression. Results: CNS outcomes in NALA, NEfERT-T, and TBCRC 022 are summarized in the Table. In NALA, significantly fewer N+C vs L+C-treated patients required intervention for symptomatic CNS metastases. In NEfERT-T, the frequency of symptomatic or progressive CNS recurrences was significantly reduced and the time to onset of CNS progression significantly delayed in the N+P group vs the T+P group. In TBCRC 022, almost half of L-naive patients had a partial response using composite criteria. Table. Overall/CNS outcomes in NALA, NEfERT-T, and TBCRC 022NALANEfERT-TTBCRC 022N+CL+CN+PT+PL-naive N+CL-treated N+CNo. of patients3073142422373712ORR, %332775781443Composite CNS ORR, %aN/AN/AN/AN/A4933CBR, %45*368885N/AN/APFSHR (p-value)0.76 (0.0059)1.02 (0.89)N/AMedian, months8.8b6.6b12.912.95.53.1OSHR (p-value)0.88 (0.2086)1.05 (0.77)N/AMedian, months24.0b22.2bNENE13.315.1Intervention for CNS disease, overall cumulative incidence, %22.8*29.2N/AN/AN/AN/AProgressive CNS disease, cumulative incidence, %c11.213.910.1**20.2N/AN/A*p&amp;lt;0.05 for N+C vs L+C. **p=0.002 for N+P vs T+P. aDefined as a reduction of ≥50% in the sum of target CNS lesion volumes without progression of non-target lesions, new lesions, escalating steroids, progressive neurologic signs or symptoms, or non-CNS progression. bRestricted mean values. cOverall cumulative index in NALA; 2-year cumulative index in NEfERT-T. CBR = clinical benefit rate; N/A = not applicable. NE = not estimable.Conclusions: Neratinib has demonstrated activity against CNS brain metastasis in the setting of advanced and metastatic breast cancer and may also limit the development of new CNS metastases in the adjuvant setting. A pooled analysis of data from NALA and NEfERT-T, which will enable subgroup analyses to be performed, is underway and will be presented at the meeting. Citation Format: Ahmad H Awada, Adam M Brufsky, Cristina Saura, Rachel A Freedman, Nancy U Lin, Judith Bebchuk, Feng Xu, Sara Hurvitz. Impact of neratinib on development and progression of central nervous system (CNS) metastases in patients with HER2-positive metastatic breast cancer (MBC): Findings from the NALA, NEfERT-T, and TBCRC 022 trials [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 P2-20-01.

Abstract PD3-10: Higher serum PD-L1 predicts for increased overall survival to lapatinib vs trastuzumab in the phase 3 CCTG MA.31 trial

Abstract Background: In the CCTG (Canadian Clinical Trials Group) MA.31 randomized phase 3 trial, the trastuzumab-taxane combination led to longer PFS than lapatinib-taxane in HER2-positive metastatic breast cancer (MBC). We previously reported the prognostic utility of pretreatment serum PD-L1 in the trastuzumab arm of MA.31 (ASCO 2018, #1031), and here we evaluate serum PD-L1 in the lapatinib arm, and in the whole trial. Higher serum PD-L1 has been reported to be associated with reduced response to treatment with the immune checkpoint inhibitors in melanoma and lung cancer. Methods: MA.31 accrued 652 centrally and/or locally-identified HER2-positivepatients; 186 in the trastuzumab arm, and 202 in the lapatinib armhad pretreatment serum available. TheELLA immunoassay platform (ProteinSimple, San Jose, CA) was used to quantitate serum PD-L1. Step-wise forward Cox multivariate analysis was used for PFS and OS, and testing for treatment-biomarker interaction was based on the local partial-likelihood method (Liu Y, Jiang W, and Chen BE, Statistics in Medicine 34, 3516-3530, 2015). Results: In the total study population, pretreatment serum PD-L1 concentration had a median of 86.2 pg/ml, and 25% and 75% interquartiles of 64.1 and 134.3 pg/ml, respectively. In univariate analysis in the whole trial, and within both treatment arms, serum PD-L1 was not a significant biomarker for PFS. For OS, higher serum PD-L1 (as a continuous variable) was significant for shorter OS within the trastuzumab arm (HR=3.84, p=0.04), but was not associated with OS in the lapatinib arm (p=0.37). In the whole trial, in multivariate analysis for OS [15 covariates included: age, race, ECOG status, anthracyclines, other chemo, endocrine, radio, other prior adjuvant therapy, disease status, ER status, PR status, Ki67 (log transformed), CK5, EGFR, treatment arm, and serum PD-L1 (with median cut point)], serum PD-L1 remained a significant independent covariate (HR= 2.27, p= 0.001 (Table).There was significant interaction between treatment arm and continuous serum PD-L1 (Bootstrap method, p=0.0025); above 214.2 pg/ml serum PD-L1 (89% percentile), higher pretreatment serum PD-L1 was associated with a shorter OS to trastuzumab treatment, but longer OS to lapatinib treatment. Conclusions: In the CCTG MA.31 trial, serum PD-L1 was a significant predictive factor: higher pretreatment serum PD-L1 was associated with a shorter OS to trastuzumab treatment, but longer OS to lapatinib treatment. Immune evasion may decrease the effectiveness of trastuzumab therapy. Further evaluation of elevated serum PD-L1 in the advanced breast cancer setting is warranted to identify HER2-positive MBC patients who may benefit from novel immune-targeted therapies in addition to trastuzumab. Multivariate Analysis (whole trial): Significant Independent CovariatesCovariateP-ValueHRLower 95% CIHigher 95% CISerum PD-L1 (pretreatment) (&amp;gt;median vs &amp;lt;median)0.0012.271.403.68EGFR Status (continuous IHC score)0.0031.0121.0041.019Other Chemotherapy (yes vs no)0.0081.911.193.07Treatment Arm (trastuzumab vs. lapatinib)0.0100.530.330.86ECOG Performance Status (0 vs 1 or 2)0.0250.590.370.94Ki67 (log)0.0461.451.0062.081 Citation Format: Moku PR, Shepherd LE, Ali SM, Leitzel K, Parulekar WE, Zhu L, Virk S, Nomikos D, Aparicio S, Gelmon KA, Drabick JJ, Cream L, Halstead SE, Umstead T, Mckeone D, Maddukuri A, Polimera HV, Ali A, Poulose J, Pancholy N, Spiegel H, Nagabhairu V, Chen BE, Lipton A. Higher serum PD-L1 predicts for increased overall survival to lapatinib vs trastuzumab in the phase 3 CCTG MA.31 trial [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 PD3-10.

Abstract P6-18-05: First-line ribociclib + endocrine therapy in hormone receptor-positive, HER2-negative advanced breast cancer: A pooled efficacy analysis

Abstract Background: In three separate Phase III randomized, placebo-controlled trials, ribociclib (RIB; cyclin-dependent kinase 4/6 inhibitor) + various endocrine therapy (ET) partners prolonged progression-free survival (PFS) vs placebo (PBO) + ET in patients (pts) with hormone receptor-positive (HR+), HER2-negative (HER2–) advanced breast cancer (ABC). Here we further evaluate the efficacy of RIB-based regimens of interest (i.e. with a non-steroidal aromatase inhibitor [NSAI] or fulvestrant [FUL]) in pts who were ET-naïve in the ABC setting, using pooled data from three Phase III trials: MONALEESA (ML)-2 (NCT01958021; all pts), ML-3 (NCT02422615; no prior ET for ABC subgroup only), and ML-7 (NCT02278120; RIB + NSAI subgroup only). Methods: Postmenopausal pts with no prior ET for ABC received RIB (600 mg/day; 3-weeks-on/1-week-off) or PBO + either letrozole (2.5 mg/day) in ML-2 or FUL (500 mg every 28 days, with an additional dose on Day 15 of Cycle 1) in ML-3. In ML-7, premenopausal pts with no prior ET and ≤1 line of chemotherapy for ABC received RIB or PBO + goserelin (3.6 mg every 28 days) + NSAI (anastrozole [1 mg/day]/letrozole [2.5 mg/day]). The primary endpoint of all three trials was locally assessed PFS. Secondary endpoints included overall response rate (ORR), clinical benefit rate (CBR), and duration of response (DoR; ML-3 and -7). DoR was an exploratory endpoint in ML-2. Results: Data were pooled for 820 pts treated with RIB + ET (ML-2: n=334; ML-3: n=238; ML-7: n=248) and 710 pts treated with PBO + ET (ML-2: n=334; ML-3: n=129; ML-7: n=247). As of the data cutoffs (ML-2: January 2, 2017; ML-3: November 3, 2017; ML-7: August 20, 2017), in the RIB + ET vs PBO + ET arms, 385 (47%) vs 234 (33%) pts remained on-treatment; the most common reason for discontinuation was disease progression (n=292 [36%] vs n=391 [55%]). In this pooled analysis, median PFS was prolonged for RIB + ET vs PBO + ET, with a hazard ratio of 0.570 (95% confidence interval [CI] 0.491–0.662); median PFS was 25.3 months (95% CI 23.9–29.6) vs 15.6 months (95% CI 14.4–16.9), respectively. Consistent PFS benefit for RIB + ET vs PBO + ET was observed across pt subgroups, including ECOG performance status, age, race, or presence/absence of liver and/or lung metastases or bone-only disease. Among all pts in the pooled analysis, the ORR was 41% for RIB + ET vs 28% for PBO + ET and the CBR was 79% vs 70%, respectively. In pts with measurable disease at baseline (RIB + ET: n=639; PBO + ET: n=542), the ORR was 51% for RIB + ET vs 37% for PBO + ET and the CBR was 79% vs 68%, respectively. In the RIB + ET vs PBO + ET arms, the median DoR was 26.7 months vs 20.0 months. A decrease in best percentage change from baseline in the sum of longest diameters per RECIST was observed in 86% of pts receiving RIB + ET vs 73% of pts receiving PBO + ET. Conclusions: RIB in combination with various ET partners demonstrates improved clinical outcomes vs PBO + ET across a broad population of pts with HR+, HER2– ABC. These data provide further support for the use of RIB-based combinations in pre- and postmenopausal pts with HR+, HER2– ABC who have received no prior ET for advanced disease. Citation Format: Tripathy D, Hortobagyi G, Chan A, Im S-A, Chia S, Yardley D, Esteva FJ, Hurvitz S, Kong O, Bao W, Rodriguez Lorenc K, Diaz-Padilla I, Slamon DJ. First-line ribociclib + endocrine therapy in hormone receptor-positive, HER2-negative advanced breast cancer: A pooled efficacy analysis [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 P6-18-05.

Abstract P6-18-03: Biomarker analysis of CDK 4/6 and endocrine pathways in hormone-receptor positive (HR+) advanced breast cancer (ABC) bone only disease patients: A joint analysis of PALOMA-2 and PALOMA-3 studies

Abstract Background: Palbociclib (PAL) in combination with endocrine therapy (ET) is a preferred treatment option for untreated and previously treated patients with hormone receptor–positive (HR+), human epidermal growth factor receptor 2 (HER2)–negative ABC. Patients with bone only disease could derive prolong disease control with single agent ET. Further understanding the predictive markers for sensitivity to ET alone and P+ET in both endocrine sensitive and resistant settings could help guide clinical treatment sequencing decision. We performed biomarker (BM) analysis of baseline tumor tissues in both PALOMA-2 (P2) and PALOMA-3 (P3) in bone only (BO) vs non-bone (NBO) only patients. Methods: Postmenopausal women (N=666) with no prior systemic therapy for ER+/HER2-ABC were randomized 2:1 to receive PAL+LET or matching placebo (PBO)+LET in P2. In P3 women (N=521) who progressed on prior endocrine therapy were randomized 2:1 to receive PAL+ FUL vs matching PBO+FUL. All pts including those with BO disease had to consent to provide tumor tissues to participate the current study. EdgeSeq Oncology Biomarker Panel (HTG Molecular Diagnostics; Tucson, AZ) was used for mRNA profiling. Cox regression analysis was used to evaluate the association of BO disease with treatment effect as well as the association of gene expression with treatment effect in BO vs NBO pts. Results: Treatment effect in the BM population from each study was consistent with that observed in the respective ITT population. In ITT population, BO disease was reported in 151 (23%) pts of P2 with mPFS 36.2mo PAL+LET arm (n=103) vs 11.2mo LET arm (n=48), HR=0.40 (0.26-0.62) and in 124 (24%) pts of P3 with mPFS 14.3mo PAL+FUL arm (n=86) vs 9.2mo FUL arm (n=38), HR=0.64(0.38-1.06). BO disease was reported in 107 (24%) pts in P2 and 81 (27%) pts in P3 BM population. In P2, longer mPFS was seen with PAL+ LET vs PBO+LET in BO vs NBO disease (30.6 mo vs 11.2 mo; HR=0.42 (0.25-0.69) in BO pts and 22.1 mo vs 13.8 mo HR=0.67 (0.52-0.88) in NBO pts) although the interaction effect was not statistically significant. Similar results were also observed in P3 with longer mPFS in PAL+FUL vs PBO+FUL in BO vs NBO disease (16.6 mo vs 11.2 mo HR=0.79 (0.40-1.56) in BO pts and 11.1mo vs 3.5 mo HR=0.47 (0.34-0.66) in NBO pts) with insignificant interaction effect. In both studies, BO pts had higher incidence of luminal A disease (BO vs NBO: P2=62% vs 47%; P3=54% vs 40%) and lower rate of luminal B disease (P2=19% vs 33%; P3: 26% vs 33%). In both studies, baseline ESR1, Cyclin E and CDK 4 gene expression level were comparable between BO vs NBO pts. Elevated CDK4 gene expression level was associated with resistance to LET in P2 and lower Cyclin E gene expression predicts the effect of PAL in P3. Conclusion: mPFS was significantly prolonged in BO pts with the addition of PAL to ET. BO disease was more frequently associated with luminal A subtype in ABC setting. CDK4 expression level was similar to NBO disease pts but associated with resistance to single agent LET. Citation Format: Finn RS, Turner NC, Liu Y, Rugo HS, Loibl S, Diéras V, Slamon DJ, André F, Gelmon K, DeMichele A, Loi S, Zhang Z, Giorgetti C, Gauthier E, Huang Bartlett C, Cristofanilli M. Biomarker analysis of CDK 4/6 and endocrine pathways in hormone-receptor positive (HR+) advanced breast cancer (ABC) bone only disease patients: A joint analysis of PALOMA-2 and PALOMA-3 studies [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 P6-18-03.

Abstract P2-07-05: A clinical calculator to predict disease outcomes in women with hormone receptor-positive advanced stage breast cancer treated with first-line endocrine therapy

Abstract Purpose: Endocrine based therapy is an effective strategy to manage hormone receptor-positive, human epidermal growth factor receptor 2-negative (HR+/HER2-) advanced breast cancer (ABC). However, nearly all patients exhibit/develop either de novo or acquired resistance. While prognostic biomarkers of endocrine responsiveness are well established for the adjuvant treatment in ER+ breast cancer, less is known regarding prognostic and predictive biomarkers of response in the first line ABC setting. We sought to develop a clinical calculator based on clinical criteria for predicting progression-free survival (PFS) and overall survival (OS) of women with HR+/HER2- ABC who will be receiving endocrine monotherapy as first-line treatment for ABC. Methods: The development of the clinical calculator will be based on data from modern clinical trials in women with HR+/HER2- ABC. The studies to be included in the final analyses are given in Table 1. The control arm data from trials1-6 will form the training dataset (N = 1,223) and be used to construct the clinical prediction models. Variables considered include age, race, ECOG status, disease measurability, body mass index, disease-free interval, number of metastatic sites, locations of metastatic sites, prior endocrine therapy, and prior chemotherapy. Missing values will be imputed using single imputation with all variables included in the imputation model. For continuous variables, restricted cubic splines will be used to determine if non-linear effects may be more appropriate. The Lasso regression will be used as a variable selection technique to reduce the dimensionality of covariates; initially all pairwise interactions will be included in the model. Following Lasso regression, the multivariable Cox proportional hazards models will be constructed for PFS and OS including only variables retained in Lasso. The final model will be internally validated for discrimination and calibration using 10-fold cross-validation. External validation will be performed using control arm data from EGF 30008 (N = 536). Results: To date, control arm data from four trials (trials 1-4) have been received. The preliminary results presented here are based on pooled data from C40503 and LEA, for which data elements have been harmonized. Models for predicting PFS and OS have good calibration and are associated with bias-corrected C-indices of 0.61 and 0.65, respectively. These models will be updated using pooled data from trials 1-6. Conclusions: Our preliminary data demonstrate that clinical calculators based on baseline clinical factors can provide accurate prediction of PFS and OS in patients with HR+/HER2- ABC treated with first-line ET. If validated, these tools may be used for risk stratification in future clinical trials and to identify patients who may require more or less aggressive therapy. Table 1:Studies to be includedTrial NumberTrial NameTrial PISample Size in Control Arm1C40503Maura Dickler152 (letrozole)2LEAMiguel Martin179 (letrozole)3FACTJonas Bergh188 (anastrozole)4FALCONJohn Robertson194 (anastrozole)5S0226Rita Mehta345 (anastrozole)6MONARCH 3Matthew Goetz165 (nonsteroidal AI)7EGF 30008Stephen Johnston536 (letrozole) Citation Format: Polley M-YC, Dickler MN, Johnston S, Goetz MP, de la Haba J, Loibl S, Mehta RS, Bergh J, Roberston J, Barlow W, Liu H, Tenner K, Martin M. A clinical calculator to predict disease outcomes in women with hormone receptor-positive advanced stage breast cancer treated with first-line 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 P2-07-05.

Targeted Therapy for Premenopausal Women with HR+, HER2− Advanced Breast Cancer: Focus on Special Considerations and Latest Advances

The incidence of advanced breast cancer in premenopausal women is increasing, and breast cancer in younger women is often more aggressive and has a worse prognosis compared with breast cancer in older women. Premenopausal women with hormone receptor-positive (HR+) breast cancer are frequently under-represented in clinical trials, and treatment strategies in the premenopausal setting are usually extrapolated from data from postmenopausal patients, with the addition of ovarian function suppression to endocrine therapy in HR+ disease. However, the underlying biology of breast cancer in premenopausal women can be different from postmenopausal women, and treatment strategies should ideally be specifically tested in premenopausal patients. Recent phase III trials have now investigated cyclin-dependent kinase 4/6 (CDK4/6) inhibitors in premenopausal patients with HR+, HER2- advanced breast cancer: Palbociclib and abemaciclib have been tested in a subset of premenopausal patients in the PALOMA-3 and MONARCH-2 studies, and ribociclib has been tested in the phase III MONALEESA-7 trial, which was entirely dedicated to premenopausal women. This comprehensive review summarizes the differences in the biology of HR+, HER2- breast cancer in the premenopausal population compared with the postmenopausal population; discusses special considerations for treatment of premenopausal women; and reviews the evidence from clinical trials investigating endocrine therapy, other targeted treatments, and ovarian function suppression in the HR+, HER2- advanced breast cancer setting. Clin Cancer Res; 24(21); 5206-18. ©2018 AACR.

Abstract IA31: What limits the response of breast cancer to immunotherapy?

Abstract Checkpoint blockade has been evaluated successfully in the classically immunogenic solid tumor types such as melanoma and renal cell carcinoma, as well as in hematologic malignancies. While a large degree of T-cell infiltrate has been observed in primary breast cancers, particularly triple-negative and Her2-positive subtypes, efficacy with checkpoint blockade as monotherapy has been modest so far in studies in advanced disease. Given that higher levels of T-cell infiltrate have been associated with improved prognoses and response to cytotoxic chemotherapy, my lab has hypothesized that these T cells would have functional characteristics that would be important in immunosurveillance of breast cancer. We have characterized these T cells using methods such as multiplex immunohistochemistry, bulk gene expression, and flow cytometry, as well as single-cell transcriptomic sequencing in order to better characterize these T cells. We have also observed lower levels of immune infiltrate in samples from metastatic breast cancer lesions, suggesting that the primary disease setting may be the most amenable to checkpoint inhibitor approaches. Data currently support that line of therapy in the advanced breast cancer setting; tumor burden and T-cell infiltrate predict for higher response rates to PD-1 blockade as monotherapy. Finally, given that most patients with advanced breast cancer have a “noninflamed” tumor microenvironment, my lab has been evaluating how therapeutics can modulate the immune microenvironment. Certain agents such as MEK inhibitors as well as combination targeted therapies can potentially increase tumor immunogenicity as well as synergize well with immunotherapies. These combinatorial approaches may serve to increase the response rate of immunotherapy in breast cancer patients as well as prolong duration of response in patients treated with new therapeutic agents. Citation Format: Sherene Loi. What limits the response of breast cancer to immunotherapy? [abstract]. In: Proceedings of the AACR Special Conference: Advances in Breast Cancer Research; 2017 Oct 7-10; Hollywood, CA. Philadelphia (PA): AACR; Mol Cancer Res 2018;16(8_Suppl):Abstract nr IA31.

SREBP1, targeted by miR-18a-5p, modulates epithelial-mesenchymal transition in breast cancer via forming a co-repressor complex with Snail and HDAC1/2

The progression of localized breast cancer to distant metastasis results in a poor prognosis and a high mortality rate. In this study, the contributions of miRNAs to tumor progression and the regulatory mechanisms leading to their expression alterations were investigated. Using highly lung-metastatic sub-lines from parental breast cancer cells, miRNA expression profiling revealed that the miR-17-92 cluster is significantly downregulated and the miR-18a-5p is the most evidently decreased. Ectopic expression and inhibition of miR-18a-5p demonstrated its capacity in suppressing migration and invasion of breast cancer cells. Further research identified sterol regulatory element binding transcription protein 1 (SREBP1), the master transcription factor that controls lipid metabolism, as a candidate target of miR-18a-5p. SREBP1 is overexpressed and strongly associated with worse clinical outcomes in breast cancer. Functionally SREBP1 promotes growth and metastasis of breast cancer both in vitro and in vivo. To unravel the underlying mechanism of SREBP1-mediated metastasis, mRNA profiling and subsequent gene set enrichment analyses (GSEA) were performed and SREBP1 was demonstrated to be significantly associated with epithelial-mesenchymal transition (EMT). Furthermore, SREBP1-mediated repression of E-cadherin was found to be deacetylation dependent and was augmented by recruiting Snail/HDAC1/2 repressor complex. In the light of these data, we propose that reduced expression of miR-18a-5p and concomitant overexpression of SREBP1 lead to induction of EMT states that in turn, promote breast cancer progression and metastasis. Taken together, our study reveals the crucial role of miR-18a-5p and SREBP1 in the EMT and metastasis, thus providing promising drug targets for tailored therapy in the advanced breast cancer setting.

Clinical considerations of the role of palbociclib in the management of advanced breast cancer patients with and without visceral metastases

BackgroundThis report assesses the efficacy and safety of palbociclib plus endocrine therapy (ET) in women with hormone receptor-positive, human epidermal growth factor receptor 2-negative advanced breast cancer (ABC) with or without visceral metastases. Patients and methodsPre- and postmenopausal women with disease progression following prior ET (PALOMA-3; N=521) and postmenopausal women untreated for ABC (PALOMA-2; N=666) were randomized 2:1 to ET (fulvestrant or letrozole, respectively) plus palbociclib or placebo. Progression-free survival (PFS), safety, and patient-reported quality of life (QoL) were evaluated by prior treatment and visceral involvement. ResultsVisceral metastases incidence was higher in patients with prior resistance to ET (58.3%, PALOMA-3) than in patients naive to ET in the ABC setting (48.6%, PALOMA-2). In patients with prior resistance to ET and visceral metastases, median PFS (mPFS) was 9.2months with palbociclib plus fulvestrant versus 3.4months with placebo plus fulvestrant [hazard ratio (HR), 0.47; 95% confidence interval (CI), 0.35–0.61], and objective response rate (ORR) was 28.0% versus 6.7%, respectively. In patients with nonvisceral metastases, mPFS was 16.6 versus 7.3months, HR 0.53; 95% CI 0.36–0.77. In patients with visceral disease and naive to ET in the advanced disease setting, mPFS was 19.3months with palbociclib plus letrozole versus 12.9months with placebo plus letrozole (HR 0.63; 95% CI 0.47–0.85); ORR was 55.1% versus 40.0%; in patients with nonvisceral disease, mPFS was not reached with palbociclib plus letrozole versus 16.8months with placebo plus letrozole (HR 0.50; 95% CI 0.36–0.70). In patients with prior resistance to ET with visceral metastases, palbociclib plus fulvestrant significantly delayed deterioration of QoL versus placebo plus fulvestrant, whereas patient-reported QoL was maintained with palbociclib plus letrozole in patients naive to endocrine-based therapy for ABC. ConclusionsPalbociclib plus ET prolonged mPFS in patients with visceral metastases, increased ORRs, and in patients previously treated for ABC, delayed QoL deterioration, presenting a standard treatment option among patients with visceral metastases amenable to endocrine-based therapy. Clinical trial registrationNCT01942135, NCT01740427

Abstract P5-21-24: Retrospective assessment of treatment patterns and outcomes associated with palbociclib plus letrozole for postmenopausal women with HR+/HER2– advanced breast cancer enrolled in an early access program

Abstract Background: The objective of this study was to evaluate treatment patterns and clinical outcomes among patients who received palbociclib in combination with letrozole (P+L) for the treatment of HR+/HER2–advanced breast cancer (ABC) as part of an Expanded Access Program (EAP) in the United States. Methods: Data were obtained by a retrospective chart review of patients previously enrolled in the EAP. Complete data from time of initial diagnosis of ABC until the date of chart abstraction (end of follow-up), including the post-EAP period, were obtained. Clinical outcomes assessed included clinical benefit rate (CBR), defined as complete response, partial response, or stable disease for ≥24 weeks from P + L initiation, progression free survival (PFS) and overall survival (OS). Survival outcomes were assessed using the Kaplan-Meier statistical analysis. Results: Data from 126 patients were included in this analysis. Median age was 62.5 years at EAP enrollment, and a majority of patients were Caucasian (83%). Approximately 25% of patients had de novo metastatic disease. A majority of patients had a performance status of ECOG 0 (56%) or 1 (37%) at EAP enrollment. Visceral disease was present in 71% of patients and 16% had bone-only disease. The majority of patients in this cohort from the EAP were heavily pre-treated, having had up to 5 prior lines of therapy in the metastatic setting prior to initiating P + L therapy; nearly 59% received 3+ prior lines before initiating P + L. Only 11% of patients received P + L as their initial regimen for MBC. At the time of the last available record, 12 patients were still on P + L therapy, an average of 21 months after the start of the EAP program. Nearly 80% of patients had prior AI exposure and 69% had prior chemotherapy. CBR was 33% for the overall sample of patients treated with P + L and 22% in those with 3+ prior lines of treatment. Patients with prior AI exposure in the ABC setting (n=100) had a CBR of 27% while those without prior AI exposure had CBR of 58%. Patients with prior chemotherapy (n=87) had a CBR of 28% and those without prior chemotherapy had CBR of 46%. For the entire cohort, 6- and 12-month PFS rates were 40% and 25% respectively; 12- and 24-month OS rates were 66% and 44%, respectively. Patients receiving 3+ lines of prior therapy had 6- and 12-month PFS rates of 28% and 19%, respectively, and 12- and 24-month OS rates of 59% and 34% respectively. Conclusions: Our results suggest that the majority of patients enrolled in the EAP program derived benefit from receiving treatment with P + L despite multiple prior lines of treatment and prior endocrine-based therapy, including prior AI. These findings further demonstrate the benefit of treatment with palbociclib combination therapy in HR+/HER2– MBC. Citation Format: Brufsky A, Davis K, Mitra D, Nagar S, McRoy L, Cotter M, Stearns V. Retrospective assessment of treatment patterns and outcomes associated with palbociclib plus letrozole for postmenopausal women with HR+/HER2– advanced breast cancer enrolled in an early access program [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 P5-21-24.

Abstract P5-21-03: Palbociclib (PAL) + letrozole (LET) as first-line therapy in estrogen receptor–positive (ER+)/human epidermal growth factor receptor 2–negative (HER2−) advanced breast cancer (ABC): Efficacy and safety updates with longer follow-up across patient subgroups

Abstract BACKGROUND: Endocrine therapy (ET) has been the primary first-line (1L) therapy for ER+ ABC. In the PALOMA-2 study (NCT01740427), PAL (P)+LET (L) significantly prolonged progression-free survival (PFS; HR=0.58, P&amp;lt;.001) after a median 23 mo follow-up (FU) (Finn et al. NEJM 2016). Here we report more mature PFS overall and in subgroups, with (w/) longer FU. The study is ongoing for overall survival FU. METHODS: Postmenopausal pts w/ ER+/HER2- ABC and no prior systemic therapy in the ABC setting were randomized 2:1 to P (125 mg/d) + L (2.5 mg QD) or placebo (PBO) + L. Key endpoints: investigator-assessed PFS and safety. Median PFS (mPFS) was estimated (intent-to-treat population). RESULTS: 666 pts (444, P+L; 222, PBO+L) were enrolled. Arms were well balanced: visceral (48%)/nonvisceral (52%) disease and prior ET (56%)/no prior ET (44%). After a median FU of 38 mo w/ P+L and 37 mo w/ PBO+L, mPFS was 27.6 and 14.5 mo, respectively, in the overall population (HR=0.56, P&amp;lt;.0001; Table). TABLE. mPFS overall and by relevant subgroupsP+LPBO+LP+L vs PBO+LmPFS, mo (95% CI)mPFS, mo (95% CI)HR (95% CI)P* Overall27.6 (22.4–30.3)14.5 (12.3–17.1)0.56 (0.46–0.69)&amp;lt;.0001 Measurable disease23.7 (19.3–27.6)14.5 (12.3–18.5)0.63 (0.50–0.79)&amp;lt;.0001 Nonmeasurable disease36.2 (27.6?NE)16.5 (8.3–19.6)0.39 (0.25–0.60)&amp;lt;.0001 Visceral19.3 (16.4–24.2)12.3 (8.4–16.4)0.62 (0.47–0.81)&amp;lt;.0005 Nonvisceral35.9 (27.7–NE)17.0 (13.8–24.8)0.50 (0.37–0.67)&amp;lt;.0001 Bone only†36.2 (27.6–NE)11.2 (8.2–22.0)0.41 (0.26–0.63)&amp;lt;.0001 Not bone only24.2 (19.4–27.7)14.5 (12.9–18.5)0.62 (0.50–0.78)&amp;lt;.0001 De novo metastatic27.9 (22.1–33.4)22.0 (13.9–27.4)0.61 (0.44–0.85)&amp;lt;.005 Prior ET24.2 (18.8–27.6)11.2 (8.4–14.5)0.54 (0.42–0.71)&amp;lt;.0001 No prior ET30.3 (24.5–35.7)21.9 (15.9–27.4)0.59 (0.43–0.80)&amp;lt;.0005 Nonvisceral36.2 (27.9–NE)27.6 (19.1–35.6)0.59 (0.38–0.92)&amp;lt;.01 Visceral23.7 (16.8–30.3)13.9 (10.2–22.2)0.55 (0.36–0.85)&amp;lt;.005 Disease sites130.4 (24.8–NE)16.5 (11.0–22.1)0.52 (0.36–0.75)&amp;lt;.0005228.1 (19.4–NE)16.3 (11.0–27.4)0.57 (0.37–0.89)&amp;lt;.01323.7 (19.2–27.6)13.8 (8.8–17.0)0.61 (0.46–0.82)&amp;lt;.0005NE=not estimable. *Not adjusted for multiple analyses; 1-sided P values. †Per tumor site. All subgroups benefited from addition of P to L. Notably, pts w/ low disease burden (bone only, nonvisceral disease, few disease sites) derived significant PFS benefit, including those w/ both nonvisceral disease and no prior ET (mPFS, 36.2 vs 27.6 mo; HR=0.59, P&amp;lt;.01). Importantly, median time from randomization to start of 2nd subsequent systemic anticancer therapy was 39 vs 29 mo for P+L vs PBO+L (HR=0.72, P&amp;lt;.005). There were no new safety signals w/ longer FU. CONCLUSIONS: This is the longest FU of a phase 3 study of a cyclin-dependent kinase 4/6 inhibitor for ABC. P+L continues to consistently improve PFS vs PBO+L across all subgroups while toxicity remains manageable; notably P+L delays time to starting 2nd subsequent anticancer therapies by 10 mo. Pts w/ low disease burden or sensitivity to ET alone had PFS &amp;gt;3 y (significant vs PBO+L), demonstrating the clinical benefit of P+ET. These data confirm P+L should be a 1L therapy option for pts w/ HR+/HER2- ABC. Funding: Pfizer Citation Format: Rugo HS, Finn RS, Dieras V, Ettl J, Lipatov O, Joy A, Harbeck N, Castrellon A, Lu DR, Mori A, Gauthier ER, Huang C, Gelmon KA, Slamon DJ. Palbociclib (PAL) + letrozole (LET) as first-line therapy in estrogen receptor–positive (ER+)/human epidermal growth factor receptor 2–negative (HER2−) advanced breast cancer (ABC): Efficacy and safety updates with longer follow-up across patient subgroups [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 P5-21-03.

The role of abemaciclib in treatment of advanced breast cancer.

Until recently, the mainstay of treatment in the majority of hormone receptor (HR)-positive, human epidermal growth factor 2 receptor (HER2)-negative advanced breast cancer (ABC) has consisted of single-agent endocrine therapy (ET). However, as understanding of endocrine resistance has grown, newer targeted agents have come to the fore. Inhibition of cyclin-dependent kinase complexes 4 and 6 (CDK4/6) combined with ET has shown significant activity in HR+ HER2− ABC, with impressive results in terms of progression-free survival (PFS) when compared with ET alone. This review summarizes the seminal findings pertaining to CDK4/6 inhibition in this population, specifically focusing on abemaciclib, contrasted with palbociclib and ribociclib. Potential directions for future studies are discussed, as a way of addressing outstanding issues such as establishing optimal treatment sequencing and agent combinations, appropriate patient selection to derive maximal benefits, predictive biomarkers and the employment of CDK4/6 inhibition beyond the ABC setting.

PAM50 Provides Prognostic Information When Applied to the Lymph Node Metastases of Advanced Breast Cancer Patients.

Purpose: Transcriptional pathway activity and the molecular subtypes of breast cancer metastases have been shown to significantly influence patient postrelapse survival. Here, we further determine the relevance of clinically employed gene signatures in the advanced breast cancer (ABC) setting.Experimental Design: Sufficient RNA for expression profiling was obtained from distant metastatic or inoperable loco-regional relapse tissue by fine-needle aspiration from 109 patients of the Swedish TEX clinical trial. Gene signatures (GGI, 70 gene, recurrence score, cell-cycle score, risk of recurrence score, and PAM50) were applied to all metastases, and their relationship to long- (5-year) and short-term (1.5-year) postrelapse survival at all and locoregional lymph nodes (n = 40) versus other metastatic sites (n = 69) combined was assessed using Kaplan-Meier and/or multivariate Cox regression analyses.Results: The majority of metastases were classified into intermediate or high-risk groups by all signatures, and a significant association was found between metastatic signature subgroups and primary tumor estrogen receptor status and histologic grade (P < 0.05). When considering all sites of metastasis, only PAM50 was statistically significant in Kaplan-Meier analysis (Log-rank P = 0.008 and 0.008 for long- and short-term postrelapse breast cancer-specific survival, respectively). This significance remained in both uni- and multivariate models when restricting analyses to lymph node metastases only, and a similar trend was observed in other metastatic sites combined, but did not reach formal significance.Conclusions: Our findings are the first to demonstrate that the PAM50 signature can provide prognostic information from the lymph node metastases of ABC patients. Clin Cancer Res; 23(23); 7225-31. ©2017 AACR.