HER2-negative Advanced Breast Cancer Research Articles

Radiosensitizing Effects of CDK4/6 Inhibitors in Hormone Receptor-Positive and HER2-Negative Breast Cancer are through Downregulating DNA Repair Mechanism and NF-κB-Signaling Pathway

CDK4/6 inhibitors combined with endocrine therapy are demonstrated to prolong survival for hormone receptor (HR)-positive and HER2-negative advanced breast cancer. We sought to assess whether cyclin-dependent kinases 4 and 6 (CDK4/6) inhibitors can enhance the radiosensitivity and their underlying mechanisms in this subtype of breast cancer through both in vitro and in vivo approaches. We used MCF-7 and T-47D (HR-positive and HER2-negative) breast cancer cell lines, and different doses of CDK4/6 inhibitors (ribociclib and palbociclib) and radiotherapy (RT) to assess the biological functions and mechanisms through in vitro study. The radiation enhancing effect was assessed by clonogenic assay, numbers of the DNA damage response-related molecules, γH2AX and 53BP1, were assessed by immunofluorescence. The p-ERK, c-Myc, and DNA-double strand break (DNA-DSB)-related molecules, p-DNA-PKcs, and p-ATM, were assessed by western blotting. We used NF-κB p65 Transcription Factor Assay Kit to evaluate the transcriptional activity of NF-κB. We evaluated the antitumor effect of combined RT (2 Gy every other day for total 6 Gy) and ribociclib through the MCF-7 orthotopic xenograft model. The synergistic effects of combining RT with different concentrations of ribociclib and palbociclib pretreatment were demonstrated by colonogenic assay. We revealed that CDK4/6 inhibitors synergistically increased the numbers of RT-induced γH2AX and 53BP1, downregulated the expression of p-DNA-PKcs and p-ATM activated by RT, and diminished the expression of RT-triggering p-ERK expression, and NF-κB activation and its down-streaming gene, c-Myc. When compared with control, ribociclib, and RT group, combined ribociclib and RT significantly shrunk the tumor growth of MCF-7 cell xenograft tumors, and downregulated the immunohistochemical expression of p-ERK, p-NF-κB p65, and c-Myc than control group. Our results demonstrated that combining CDK4/6 inhibitors enhanced the radiosensitivity in HR-positive and HER2-negative breast cancer cells, and conceivably radioenhancing mechanisms of CDK4/6 inhibitors are at least through lessening DNA-DSB repairing processes and weakening the activation of ERK signaling and NF-κB signaling by RT.

The Treatment Landscape of Elderly Patients with Hormone Receptor-Positive Her2 Negative Advanced Breast Cancer: Current Perspectives and Future Directions.

Breast cancer (BC) in elderly women is an increasing health issue due to demographic changes. BC tends to present later and may receive less than standard treatment options. More often, BC in elderly patients is endocrine-positive (HR+). The treatment of elderly patients with metastatic BC (mBC) represents a therapeutic challenge. In recent years, the treatment landscape of patients that are HR+/Her2-negative has changed due to the introduction in clinical practice of new targeted drugs, which have improved patient outcomes. Elderly patients are a small percentage of all patients enrolled in clinical trials and, to date, there are no standardized guidelines that define the best treatment option for this patient population. This can lead to undertreatment or overtreatment, impacting patient morbidity and mortality. Geriatric Assessment tools to tailor the treatment in elderly patients are underused because they are long and difficult to apply in a busy routine clinical practice. For all these reasons, there is an urgent need to produce data about the best treatment for elderly patients with HR+ mBC. Herein, we report data from randomized clinical trials and real-world evidence on the therapeutic options for HR+ Her2-negative mBC elderly patients and explore future treatment directions.

Fulvestrant plus vandetanib versus placebo for the treatment of patients with metastatic breast cancer resistant to aromatase inhibitor therapy (FURVA): a multicentre, Phase 2, randomised controlled trial

BackgroundFURVA, a randomised, double-blind Phase II trial, investigated whether the addition of vandetanib to fulvestrant improved progression-free survival (PFS) in patients with an aromatase inhibitor(AI)-resistant advanced breast cancer.MethodsPostmenopausal women with oestrogen receptor-positive (ER+ve)/HER2-negative advanced breast cancer, who experienced disease progression on an AI, were randomised (1:1) to fulvestrant 500 mg (Q28) with vandetanib 300 mg od (f + v) or placebo (f + p) until disease progression or discontinuation. The primary endpoint was PFS; secondary endpoints included overall survival (OS) and the influence of REarranged during Transfection (RET) signalling on outcomes.ResultsIn total, 165 participants were randomised to f + v (n = 80) or f + p (n = 85). Median PFS was 5.5 months (m) for f + v compared to 5.5 m for f + p (hazard ratio (HR) 0.88; 95% CI: 0.62–1.23; P = 0.22). Unexpectedly, high total RET expression was associated with a PFS advantage of 8.87 m vs 3.94 with low RET (HR 0.493: 95% CI 0.32–0.77; P = 0.002) independent of the treatment arm, supported by an OS advantage 21.95 m vs 18.04 (HR 0.584; 95% CI 0.34–1.00; P = 0.051) in the high-RET group.ConclusionThe addition of vandetanib to fulvestrant does not improve PFS. However, high total RET expression was associated with improved PFS, suggesting RET may have a prognostic role in patients treated with fulvestrant.Clinical trial registrationClinicalTrials.gov, NCT02530411.

Treatment strategies for patients with resistant advanced breast cancer to CDK4/6 inhibitors

CDK4/6 inhibitors have become the standard of care for HR-positive, HER2-negative advanced breast cancer. However, there is still a lack of standard recommendations for the subsequent treatment of patients with CDK4/6 inhibitor resistance, especially those with primary resistance or rapid progression. Currently, appropriate treatment strategies included re-challenge of CDK4/6 inhibitors, combination with PI3K/AKT/mTOR inhibitors, new antibody drug conjugate (ADC), novel endocrine therapy drugs, and chemotherapy. In addition, many new targeted drugs and new combination treatment strategies are also being explored. In the future, precise treatment strategies based on biomarkers should be established, as well as the optimal sequence of use of different therapies.

Stratified endocrine therapy for advanced breast cancer: stratification guided, combination preferred

The endocrine therapy of hormone receptor (HR)-positive human epidermal growth factor receptor 2 (HER2)-negative breast cancer has stepped into an era of targeted combination therapy. Many targeted agents, led by cyclin-dependent kinase 4/6 inhibitor (CDK4/6i), have provided abundant treatment options for patients with HR-positive HER2-negative advanced breast cancer. To meet the needs of clinical practice in China and standardize the administration of targeted agents, the stratified endocrine strategy for advanced breast cancer has been proposed by Chinese Society of Clinical Oncology (CSCO) Breast Cancer guidelines based on medicine evidence and drug accessibility, offering scientific and organized decision-making guidance for clinical oncologists.

CDK4/6 inhibitors, PI3K/mTOR inhibitors, and HDAC inhibitors as second-line treatments for hormone receptor-positive, HER2-negative advanced breast cancer: a network meta-analysis

BackgroundThis study sought to compare the benefits and safety of agents including Cyclin-dependent kinase 4/6 (CDK4/6) inhibitors, phosphoinositide 3-kinase (PI3K)/mammalian target of rapamycin (mTOR) inhibitors, and histone deacetylase (HDAC) inhibitors as second-line treatments for these patients by conducting a comprehensive systematic review and network meta-analysis.MethodsThe Medline, Embase and Cochrane Library databases were searched for randomized trials comparing CDK4/6 inhibitors, PI3K/mTOR inhibitors, or HDAC inhibitors vs. placebo with the addition of exemestane or fulvestrant as second-line treatments in patients with HR + advanced breast cancer up to December 16, 2021. Outcomes of interest were progression-free survival (PFS), overall response rate (ORR), overall survival (OS), clinical benefit rate (CBR), and grade 3–4 adverse drug events (ADEs). The present study was conducted according to the Cochrane Collaboration and PRISMA statements. The overall effect was pooled using the random effects model.ResultsSeventeen studies with a total of 9,100 participants were included in the current study. Compared with placebo plus fulvestrant, PFS was significantly improved by CDK4/6 inhibitor plus fulvestrant, mTOR inhibitor plus fulvestrant, mTOR inhibitor plus exemestane, and PI3K inhibitor plus fulvestrant, but not HDAC inhibitor plus exemestane. While mTOR inhibitor plus exemestane was the best regimen (SUCRA value 89.5%), the mTOR inhibitor plus exemestane regimen induced more severe adverse events (SAEs) than the HDAC inhibitor plus exemestane regimen [OR, 95% CI: 2.40 (1.40–4.10)].ConclusionmTOR inhibitor and CDK4/6 inhibitor-based regimens demonstrated superior clinical efficacy and comparable safety profiles as second-line treatment in patients with HR-positive, HER2-negative advanced breast cancer.

Systemic Therapy for Metastatic Triple Negative Breast Cancer: Current Treatments and Future Directions.

Until recently, despite its heterogenous biology, metastatic triple negative breast cancer (TNBC) was treated as a single entity, with successive lines of palliative chemotherapy being the only systemic option. Significant gene expression studies have demonstrated the diversity of TNBC, but effective differential targeting of the four main (Basal-like 1 and 2, mesenchymal and luminal androgen receptor) molecular sub-types has largely eluded researchers. The introduction of immunotherapy, currently useful only for patients with PD-L1 positive cancers, led to the stratification of first-line therapy using this immunohistochemical biomarker. Germline BRCA gene mutations can also be targeted with PARP inhibitors in both the adjuvant and metastatic settings. In contrast, the benefit of the anti-Trop-2 antibody-drug conjugate (ADC) Sacituzumab govitecan (SG) does not appear confined to patients with tumours expressing high levels of Trop-2, leading to its potential utility for any patient with an estrogen receptor (ER)-negative, HER2-negative advanced breast cancer (ABC). Most recently, low levels of HER2 expression, detected in up to 60% of TNBC, predicts benefit from the potent HER2-directed antibody-drug conjugate trastuzumab deruxtecan (T-DXd), defining an additional treatment option for this sub-group. Regrettably, despite recent advances, the median survival of TNBC continues to lag far behind the approximately 5 years now expected for patients with ER-positive or HER2-positive breast cancers. We review the data supporting immunotherapy, ADCs, and targeted agents in subgroups of patients with TNBC, and current clinical trials that may pave the way to further advances in this challenging disease.

Detection of high-risk patients resistant to CDK4/6 inhibitors with hormone receptor-positive HER2-negative advanced and metastatic breast cancer in Japan (KBCSG-TR-1316)

BackgroundCyclin-dependent kinase 4/6 inhibitors (CDK4/6i) improve the prognosis of hormone receptor-positive HER2-negative advanced/metastatic breast cancer (HR+/HER2− mBC). However, some cancers show resistance to CDK4/6i and have a poor prognosis. The non-luminal disease score (NOLUS) was developed to predict non-luminal disease using immunohistochemical analysis.MethodsThe association between the efficacy of CDK4/6i and NOLUS was investigated by evaluating pathological and clinical data, including real-world progression-free survival (rw-PFS) and overall survival (OS). Real-world data of patients with HR+/HER2− mBC who received CDK4/6i therapy [palbociclib or abemaciclib] as first- or second-line endocrine treatments was obtained. NOLUS was calculated using the formula: NOLUS (0–100) = − 0.45 × estrogen receptor (ER) (%) − 0.28 × progesterone receptor (PR) (%) + 0.27 × Ki67(%) + 73, and the patients were divided into two groups: NOLUS-positive (≥ 51.38) and NOLUS-negative (< 51.38).ResultsOf the 300 patients, 28 (9.3%) were NOLUS-positive, and 272 (90.7%) were NOLUS-negative. The expression rates (%) of ER and PgR in NOLUS-positive patients were lower than those in NOLUS-negative patients (p < 0.001). Ki67 expression was higher in NOLUS-positive patients. There were statistically significant differences in prognosis (rw-PFS and OS) between the two groups. Moreover, NOLUS-negative patients showed statistically better rw-PFS with first-line therapy than second-line therapy. However, NOLUS-positive patients showed poor prognoses with both the first and second therapeutic lines, suggesting CDK4/6i inefficacy for NOLUS-positive patients.ConclusionsThe efficacy and prognosis of CDK4/6i significantly differed between the NOLUS-positive and NOLUS-negative patients. This feasible method can predict patients with HR+/HER2− mBC resistant to CDK4/6i and help select a better therapeutic approach to overcome resistance.

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

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

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 .

Dalpiciclib in advanced breast cancer.

Hormone receptor-positive, HER2-negative advanced breast cancer is largely not curable. Anti-oestrogen agents improve the prognosis of patients with hormone receptor-positive, HER2-negative advanced breast cancer, but resistance eventually occurs. Targeting cyclin-dependent kinase 4 (CDK4) and CDK6 increases endocrine therapy efficacy, leading to the approval of CDK4/6 inhibitors palbociclib, ribociclib, and abemaciclib in the this treatment setting. 1 Spring LM Wander SA Andre F et al. Cyclin-dependent kinase 4 and 6 inhibitors for hormone receptor-positive breast cancer: past, present, and future. Lancet. 2020; 395: 817-827 Summary Full Text Full Text PDF PubMed Scopus (180) Google Scholar Dalpiciclib plus letrozole or anastrozole versus placebo plus letrozole or anastrozole as first-line treatment in patients with hormone receptor-positive, HER2-negative advanced breast cancer (DAWNA-2): a multicentre, randomised, double-blind, placebo-controlled, phase 3 trialOur findings suggest that dalpiciclib plus letrozole or anastrozole could be a novel standard first-line treatment for patients with hormone receptor-positive, HER2-negative advanced breast cancer, and is an alternative option to the current treatment landscape. Full-Text PDF

Phase II study of pembrolizumab plus mifepristone in patients with advanced HER2-negative breast cancer.

1095 Background: Metastatic breast cancer is incurable, and novel treatment (tx) strategies are needed. Single agent immune checkpoint inhibitor (ICI) tx has limited efficacy; combination approaches may yield better results. Multiple mechanisms of glucocorticoid-induced immunosuppression have been proposed, including the suppression of the cytotoxic Th1 cytokine response via glucocorticoid receptor (GR) activation. We hypothesize that pretreatment with a GR antagonist shifts the cytotoxic immune response toward Th1, thus enhancing response to ICIs. We present the safety and efficacy of the combination of pembrolizumab and mifepristone in advanced HER2-negative breast cancer. Methods: This (NCT03225547) was a phase II non-randomized study of pembrolizumab and mifepristone in patients (pts) with advanced HER2-negative breast cancer. Pts with prior ICI tx were excluded. Pts received mifepristone 300mg daily and pembrolizumab 200mg every 3 weeks; mifepristone was started 7 days prior to pembrolizumab. The primary endpoint was objective response rate (ORR). Secondary endpoints included progression-free survival (PFS), overall survival (OS), disease control rate (DCR), and safety and tolerability. Results: 18 patients were enrolled from March 2018 – November 2020; 10 patients with TNBC (cohort 1) and 8 patients with HR+ BC (cohort 2). Mean age was 53 yrs (range 33-74) and 33% of patients were self-reported Black. In cohort 1, 50% of patients were tx naive in this advanced setting, and 90% of patients had &lt; 2 prior lines of tx. In cohort 2, 25% of patients had not received prior chemo in the metastatic setting. The overall ORR was 6%. One pt with TNBC had a complete response (CR). She received 36 cycles of tx; tx was discontinued due to mucositis and rash, and she remains in CR at &gt;48 mos from start of tx. No patients in cohort 2 had a partial or complete response. The most common treatment-related adverse events were rash (61%), thyroid abnormality (17%), and pruritis (17%). 45% of patients experienced a grade 3 or 4 adverse event; all except one (hypokalemia) were due to rash. Rash was described as maculopapular dermatitis. The DCR at 18 weeks was 33.3% in the overall population; it was 44.4% in cohort 1 and 16.7% in cohort 2. Overall median PFS was 1.9 months [95% CI 1.8 – 3.6]. Overall median OS was 12.9 months [95% CI 5.8 – 23.0]. Conclusions: While this regimen demonstrated efficacy in a small subset of patients, including one pt with long-term CR, given the non-randomized design, we cannot determine if mifepristone enhanced the efficacy of ICI. In addition, a higher than anticipated rate of skin toxicity, possibly related to mifepristone enhancing the activity of ICI, was observed in the study, leading to early closure. While the benefit/risk analysis of this combination does not support further evaluation, additional investigation of alternative chemotherapy-free, immunomodulatory strategies is warranted. Clinical trial information: NCT03225547 .

A prospective, single-arm, single-center, exploratory clinical study of anlotinib combined with irinotecan in second-line and above treatment of HER-2–negative advanced breast cancer.

e13114 Background: The group of HER2-negative accounts for 70-80% of breast cancer and effective treatments for heavily pretreated patients with HER2-negative metastatic breast cancer are urgently needed. Irinotecan is a semi-synthetic water-soluble camptothecin derivative which can be used as a chemotherapeutic agent for HER2-negative breast cancer after failure of anthracycline and taxanes treatments. Anlotinib is a novel multitarget tyrosine kinase inhibitor targeting VEGFR, PDGFR, FGFR, and c-Kit. This study aimed to evaluate the efficacy and safety of irinotecan combined with anlotinib in second-line and above treatment of HER-2 negative advanced breast cancer. (ChiCTR2000037448) Methods: This open-label, single-arm, phase II study enrolled women aged 18 years and older with HER2-negative breast cancer who underwent ≥1 line chemotherapy, All patients were treated with irinotecan (60mg/m2, administered intravenously on Days 1 and 8 of each 21 day cycle) and anlotinib (12mg, qd, administered orally on Days 1-14 of each 21 day cycle). The primary endpoint was objective response rate (ORR). Secondary endpoints were progression-free survival (PFS), disease control rate (DCR), overall survival (OS) and safety. Results: From November 2020 to November 2022, 14 patients were enrolled in this study. Median follow-up was 10.8 months (95% CI 4.3-17.3). Median PFS was 5.9 months (95% CI 2.0-9.8). Of all the patients whose efficacy could be evaluated (13/14), no patient achieved complete response (CR); 3(23.07%) and 8(61.54%) patients got partial response (PR) and stable disease (SD), respectively. ORR was 23.1% (95% CI 5.0-53.8) and DCR was 84.6% (95% CI 54.6-98.1). OS has not reached. The major treatment-related adverse events (incidence≥10%) were fatigue (42.86%), hypertension (42.86%), neutropenia (28.57%), hand foot syndrome (21.43%) and myelosuppression (14.29%). There is no grade 3/4 adverse events occurred.28.57% (4/14) of patients had dose reductions. Conclusions: The combination of irinotecan and anlotinib showed better treatment response and tolerable toxicity in the treatment of second-line and above patients with HER2-negative metastatic breast cancer. Further studies enrolling more patients are still needed. Clinical trial information: ChiCTR2000037448 .

Exploratory biomarker analysis of acelERA breast cancer (BC): Phase II study of giredestrant vs. physician’s choice of endocrine therapy (PCET) for previously treated, estrogen receptor-positive, HER2-negative advanced BC (ER+, HER2– aBC).

1069 Background: ET is the mainstay treatment of ER+ aBC. Giredestrant is a highly potent, nonsteroidal, oral selective ER antagonist and degrader (PO SERD) that achieves robust ER occupancy. acelERA BC (NCT04576455) is a Phase II, randomized, open-label study that evaluated giredestrant vs. PCET in the second- or third-line ER+, HER2– aBC setting. The study did not reach statistical significance for the primary endpoint of investigator-assessed progression-free survival, although giredestrant demonstrated a more pronounced effect in patients (pts) with ESR1-mutated ( ESR1m) tumors. We present an exploratory biomarker analysis. Methods: Pts (N = 303) were post- or pre-/perimenopausal women, and men, with ER+, HER2– aBC who had received 1–2 prior lines of systemic therapy for aBC. Randomization was 1:1 to giredestrant (30 mg PO daily) or PCET (fulvestrant/aromatase inhibitor). Baseline plasma circulating tumor (ct)DNA (n = 232) was evaluated with the FoundationOne Liquid CDx (n = 229) or PredicineCARE (n = 3) assays; ESR1 and other gene mutations in ctDNA were defined as variants with known or likely impact on protein function. Gene expression and PAM50 molecular subtype were assessed by RNAseq from tumor tissue (n = 184) which, based on collection date relative to aBC, was defined as representing early BC (eBC, n = 67), first line (1L, n = 64), or post-1L (n = 46). ER pathway activity was quantified by expression of a predefined set of 38 ER-induced or -repressed genes. Results: The majority of tumors were of the Luminal A (51%) and Luminal B (43%) PAM50 subtypes. Post-1L ESR1m tumors (n = 17) were significantly enriched for Luminal B (64%) compared with eBC (39%), 1L (44%), and post-1L tumors with no ESR1m detected ( ESR1nmd; n = 29; 45%) (p &lt; 0.001). Post-1L ESR1nmd tumors, but not ESR1m tumors, had significantly lower ER pathway activity compared with eBC or 1L tumors (p = 0.0001, 0.001). Within the post-1L subgroup, those with ESR1m had a distinct ctDNA mutational profile with more GATA3 (n = 29) and fewer CHEK2 mutations (n = 0) than ESR1nmd (n = 3 and n = 11, respectively). Tumor ER pathway activity and ESR1 expression in tumor tissue, as well as pre-treatment ctDNA composite tumor fraction and ESR1 variant allele frequency, were significantly correlated with best overall response to single-agent ET (partial response vs. progressive disease; p &lt; 0.001, p = 0.022, p = 0.001, and 0.045, respectively). Conclusions: These data show that tumor response to single-agent ET is correlated with baseline ctDNA features and with tumor ER pathway activity. Interestingly, ER pathway activity was significantly lower in late-line tumors, except in ESR1m tumors. Overall, these results support the continued investigation of improved and personalized treatment options for pts with ER+, HER2– aBC. Clinical trial information: NCT04576455 .

Comparative overall survival of patients in trials of CKD4/6 inhibitors in combination with endocrine therapy in advanced breast cancer.

1056 Background: CDK4/6i and endocrine therapy (ET) are an international gold standard therapy in estrogen receptor (ER) positive and HER2-negative advanced breast cancer (aBC). Individual trials of abemaciclib, palbociclib and ribociclib show similar impact on progression-free survival yet differing statistical significance for OS. A robust comparative evaluation of the efficacy, safety, and tolerability of the three drugs is warranted. Methods: We searched PubMed, ASCO, ESMO and SABCS proceedings to identify phase 3 randomized clinical trials reporting OS of CDK4/6i in combination with ET in ER-positive aBC in first or second line. A network meta-analysis using WinBUGS was performed to evaluate comparative efficacy, based on the ET partner, in the absence of direct comparisons. Trial level data on common and serious adverse events (AE) were extracted for each drug. The odds ratio (OR) for each AE was calculated comparing each CDK4/6i to the respective endocrine therapy backbone (aromatase inhibitor (AI) or fulvestrant) alone. Results: Seven studies comprising 4087 patients met the inclusion criteria. Median follow up was 70.2 months. Four studies paired a CDK4/6i with an AI or tamoxifen, 3 studies were paired with fulvestrant. There were no statistically significant differences in OS between any of the CDK4/6i with any ET backbone. Compared to palbociclib, ribociclib and abemaciclib showed significantly lower grade 1-2 fatigue/asthenia (ribociclib OR 0.69 [95% CI 0.58, 0.83]; abemaciclib OR 0.6 [95% CI 0.49, 0.74]) and abemaciclib showed significantly lower grade 1-2 alopecia (abemaciclib 0.76 [95% CI 0.6, 0.97]). Compared to palbociclib, ribociclib and abemaciclib showed significantly higher GI toxicity (ribociclib any grade vomiting OR 1.71 [95% CI 1.36, 2.15]; abemaciclib any grade vomiting OR 2.1 [95% CI 1.61, 2.62], any grade diarrhea 13.2 [95% CI 10.31, 16.78]). Treatment discontinuation was highest with abemaciclib. Conclusions: In this network meta-analysis, there was no statistically significant difference in OS between CDK4/6i despite differences in individual trials. Real-world data analyses may help to identify if a there is a meaningful inter-drug difference in efficacy. Significant differences between CDK4/6i are observed for safety and tolerability outcomes. [Table: see text]

Effect of high immune-related gene expression on resistance to CDK4/6 inhibitors in advanced breast cancer.

e13063 Background: Treatment for estrogen receptor-positive (ER+)/HER2-negative advanced breast cancer (ABC) has undergone a revolution with the approval of cyclin-dependent kinase 4/6 inhibitors (CDK4/6i). Biomarkers of treatment resistance are limited, though growing evidence points towards antitumor immune response as a key factor. We aimed to investigate immune-mediated resistance to CDK4/6i. Methods: Gene expression (GE) was analyzed in 63 FFPE tumors from 55 patients with ER+/HER2- BC (34 primary, 21 metastatic (M1) and 8 paired biopsies) treated with CDK4/6i. Breast Cancer 360 panel (nCounter NanoString Technologies) including intrinsic subtyping (IS). Patients were stratified into good/poor response (GR/PR), based on data from pivotal studies considering both hormone sensitivity and progression-free survival (PFS): 66,5% were GR and 37,5% PR. Multiple T-testing was used to assess GE differences and Kaplan Meier methods and Cox regression models for survival. Results: Thirty-six patients (65.5%) received CDK4/6i in first line. 16 deaths were notified at the time of the analysis. Most tumors were luminal A or B (n = 23;36.5%), 11.1% HER2-enriched (n = 7) and 3.2% Basal-like (n = 2). 54.9% patients had visceral M1 before CDK4/6i. In first line, patients with luminal A, followed by luminal B tumours showed longer PFS compared to HER2-enriched (p = 0.02). The presence of visceral M1 and PR to CDK4/6i were associated with significantly shorter PFS and overall survival (OS) (p &lt; 0.05), remaining as independent predictors after adjustment by the standard clinico-pathological variables. To investigate other factors driving resistance to CDK4/6i, GE differences between response groups was compared. Increased GE of several immune-related features was associated with PR using the M1 samples, including macrophages, PDL2, IFN-gamma and inflammatory-chemokines; (log2C (-0.9)-(-1.2); p-value &lt; 0.05); while only few characteristics were significative using primary biopsies (Homologous recombination deficiency, log2FC -1.01, p = 0.02; Likelihood test for model comparison: p-value &lt; 0.001). High GE of macrophages signature was associated with worse OS (HR: 3.14; CI 1.3-7.6, p = 0.03), and progesterone receptor with better OS (HR:0.78; CI95%0.64-0.95, p = 0.04). Other genes related to immunity/inflammation ( CD68, CD163, CCR1 or CDC25B), were also associated with worse OS (HR 1.8-6.1; p-value &lt; 0.05), further pointing towards immune response as a key determinant of CDK4/6i efficacy. Conclusions: Our study suggests a key role of tumor immunity in resistance to CDK4/6i, with an additional association of macrophages with worse outcome. The correlation of poor response to CDK4/6i with worse survival suggests its utility as a surrogate biomarker. Further investigation of the use of immunotherapeutic agents in this setting is deserved to improve CDK4/6i response.

Feasibility of treatment with another CDK4/6 inhibitor after severe ribociclib liver toxicity.

e13067 Background: Ribociclib is, for now, the only CDK4/6 inhibitor having demonstrated a statistically significant increase of overall survival in first-line in hormone receptor-positive, HER2-negative advanced breast cancer. One of the limiting toxicities of ribociclib is the occurrence of grade III/IV hepatobiliary toxicity in approximately 5% of patients. It contraindicates the reintroduction of the drug. Therapeutic options after this type of adverse event are challenging because there are very limited data regarding cross reactivity in risk for hepatic injury between ribociclib, palbociclib or abemaciclib. Methods: We describe a cohort of 28 patients who presented with grade III and/or IV ribociclib-induced hepatitis and who subsequently received another CDK4/6 inhibitor. Cases were collected from the French pharmacovigilance database and additional cases were obtained through institutional databases. Data were retrospectively obtained from patients’ reports. Results: Twenty-eight patients, from 11 centers, presented a grade III (71%, 20 patients) or a grade IV (29%, 8 patients) transaminase elevation with ribociclib. Median transaminase elevation was 12.3 x ULN (upper limit normal) for AST and 15.2 x ULN for ALT. This toxicity occurred within the first 6 months of treatment for all patients except one. Ribociclib was associated with letrozole in 21 patients, fulvestrant in 5 patients and anastrozole or exemestane in 2 patients. No acute liver failure occurred. All patients switched to another CDK4/6 inhibitor (23 patients - 82% - palbociclib and 5 - 18% - abemaciclib) without significant reoccurrence of liver toxicities. Four patients (14%) presented a transient grade 1 or 2 hepatic toxicity (all of them with palbociclib), 20 patients (71%) received the second CDK4/6 inhibitor at full dose. The median follow-up was 16 months. Conclusions: Treatment with palbociclib or abemaciclib after grade III or IV transaminase elevation due to ribociclib is feasible and none of the patients in this cohort exhibited reoccurrence of significant liver toxicity afterwards. Ribociclib liver toxicity occurs mainly during the first 6 months of treatment and takes several months to recover. [Table: see text]

Primary efficacy analyses of NeoRHEA, neoadjuvant biomarker research study of palbociclib combined with endocrine therapy in estrogen receptor positive/HER2 negative breast cancer.

522 Background: CDK4/6 inhibitors (CDK4/6i) and endocrine therapy (ET) are standard of care in the treatment of estrogen receptor (ER) positive, HER2-negative (ER+/HER2-) advanced breast cancer (BC). We tested palbociclib + ET as neoadjuvant therapy to identify baseline biomarkers of no response. Methods: NeoRHEA (NCT03065621) was a phase II, single arm trial evaluating 4 months of neoadjuvant palbociclib and ET in pre- or post-menopausal women with ER+/HER2- early BC. The primary objective was to identify biomarkers of no response by locally-assessed ultrasound (US) using RNA-seq on baseline (pretreatment) tumor biopsies. No response to treatment was defined as stable or progressive disease (SD or PD) at post-treatment US based on WHO criteria. Secondary endpoints included residual cancer burden (RCB) of 3 and absence of complete cell cycle arrest (CCCA) defined as Ki67 by immunohistochemistry (IHC) &gt; 2.7% at surgery. We evaluated baseline clinicopathological characteristics, RNA-seq derived PAM50 subtypes and mRNA expression of ESR1, Ki67, CCNE1, RB1 and CDK6 single genes according to US response and CCCA. We also performed gene set enrichment analysis (GSEA) for 50 gene sets related to cancer hallmarks according to US response and CCCA. Results: 73 of 100 patients enrolled had baseline frozen tumors with enough cellularity and successful RNA-sequencing performed. Among the 73 patients, 70% were post-menopausal, 84% had cT2 and 70% cN0 tumors, 75% had invasive ductal carcinoma and 66% had histological grade 2 tumors. RNA-seq derived PAM50 subtypes were Luminal A, Luminal B, and non-Luminal in 56%, 36% and 8% of patients, respectively. Among the 73 patients, 31 (42%) had absence of US response (28 and 3 patients had stable and progressive disease by US, respectively) and 23 (31%) had RCB 3 tumors. Fifty-three of 73 patients had Ki67 by IHC available at surgery out of whom, 14 (26%) had absence of CCCA. Neither baseline clinicopathological characteristics nor PAM50 subtypes nor expression of ESR1, Ki67, CCNE1 and RB1 were associated with absence of US response or absence of CCCA. Interestingly, we observed higher baseline mRNA expression of CDK6 in patients with absence of US response (p = 0.039) or those with no CCCA (p = 0.004). We observed an enrichment in inflammatory / IFN-γ response and proliferation-related, G2M checkpoint gene sets in patients with US response (NES: 2.06, 2.30, 1.47; FDR: 7.04e-9, 5.48e-17, 0.0193 respectively) and an enrichment in early estrogen response gene set in patients with absence of US response (NES: -1.78, FDR: 0.0006). No signaling pathway was enriched in patients without CCCA. Conclusions: High pre-treatment mRNA expression of the CDK6 gene was associated with no US response or absence of CCCA in patients treated with neoadjuvant palbociclib and ET. Independent validation is needed. Clinical trial information: NCT03065621 .

Clinico-molecular characteristics associated with outcomes in breast cancer patients treated with CDK4/6 inhibitors: Results from the AURORA Molecular Screening Initiative.

1019 Background: CDK4/6 inhibitor (CDK4/6i) plus endocrine therapy (ET) is the recommended first line standard of care for patients with estrogen receptor positive (ER+), HER2-negative (HER2-) advanced breast cancer (ABC). However, not all patients derive the same benefit from this treatment. We aimed to identify factors associated with outcome in patients treated with CDK4/6i in a real-world setting. Methods: AURORA (NCT02102165) is an international program aimed at studying ABC by performing multi-omics profiling on paired primary tumors and metastases. Here we present exploratory results from AURORA patients treated with first line CDK4/6i + ET. DNA from primary and/or metastatic lesions and germline DNA was sequenced for 411 cancer-related genes. Endocrine resistance was defined according to the 5th ABC international consensus guidelines at the start of the first line. Local histology assessment of the primary tumor was used. Progression-free survival (PFS) was calculated from the start of CDK4/6i treatment until disease progression or death (whichever occurred first). Results: We analyzed 339 patients treated with CDK4/6i + ET in the first line. PFS differed significantly among the endocrine resistance subgroups (p&lt;0.001). Both TP53 and acquired ESR1 mutations were associated with shorter PFS (hazard ratio [HR] 1.59 [95% CI 1.43-6.73], p=0.004 and 3.10 [95% CI 1.16-2.18], p=0.004 respectively). In a multivariable analysis, acquired ESR1 mutations were significantly associated with worse PFS independently of endocrine resistance status (HR 2.42 [95% CI 1.01-5.79], p=0.048). Mutations in PIK3CA were not associated with outcome (HR 0.84 [95% CI 0.63-1.13], p=0.25). No PFS difference was observed between lobular and ductal tumors (HR 1.07 [95% CI 0.66-1.75], p=0.61). Conclusions: Endocrine resistance status and TP53 and acquired ESR1 mutations were associated with shorter PFS. Factors associated with poor outcome may be used to select patients to test alternative treatment strategies in clinical trials. Clinical trial information: NCT02102165 . [Table: see text]

Oral elacestrant vs standard-of-care in estrogen receptor-positive, HER2-negative (ER+/HER2-) advanced or metastatic breast cancer (mBC) without detectable ESR1 mutation (EMERALD): Subgroup analysis by prior duration of CDK4/6i plus endocrine therapy (ET).

1070 Background: The phase 3 EMERALD trial reported significantly prolonged progression-free survival (PFS) and a manageable safety profile with oral elacestrant (Ela) vs standard of care ET (SoC) in patients (pts) with ER+/HER2− mBC following progression on prior endocrine and CDK4/6i therapy. Duration of prior CDK4/6i was shown to be a potential predictor of efficacy in pts with ESR1 mutations ( ESR1m) receiving elacestrant. Median PFS (mPFS) for pts with ESR1m receiving &lt;6 mos of prior CDK4/6i was 1.87 mos (Ela) vs 1.87 mos (SoC), compared with 4.14 mos (Ela) vs 1.87 mos (SoC) for pts receiving CDK4/6i ≥6 mos and 8.61 mos (Ela) vs 1.91 mos (SoC) for pts receiving ≥12 mos of prior CDK4/6i. Understanding the clinical activity of Elacestrant in ESR1 non-detected ( ESR1nd) ER+/HER2- mBC is still needed. Preclinical ER+ PDX models suggest that elacestrant is equally active in ESR1 wild-type ( ESR1wt) and ESR1m. In the PDX model ST3932 ( ESR1wt), derived from a pt treated with palbociclib plus aromatase inhibitor (AI) that was resistant to palbociclib in vivo, elacestrant demonstrated statistically significant single-agent antitumor activity (Patel, 2019). Methods: Pts with ER+/HER2- advanced or mBC who previously had 1-2 lines of ET, mandatory CDK4/6i, and ≤1 chemotherapy were randomized, 1:1 to receive oral elacestrant or SoC (investigator’s choice of AI or fulvestrant). An ad hoc subgroup analysis was performed on pts with ESR1nd by prior duration of CDK4/6i plus ET (&lt;6 mos, ≥6 mos, ≥12 mos) in the advanced or metastatic setting. Results: Among the 478 pts enrolled, 250 (n=124, Ela; n=126, SoC) did not have a detectable ESR1m. Interestingly, in 41 pts with ESR1nd (n=20, Ela; n=21, SoC) that rapidly progressed on prior CDK4/6i plus ET (&lt;6 mos), treatment with elacestrant was associated with prolonged mPFS vs SoC (5.32 mos vs 1.87 mos, respectively) (HR=0.518 [95% CI 0.216-1.165]), compared with a mPFS of 1.91 mos (Ela) vs 1.97 mos (SoC) for pts who were on CDK4/6i for ≥6 mos (HR=0.911 [95% CI 0.640-1.298]) and 2.33 mos (Ela) vs 2.04 mos (SoC) for pts who were on CDK4/6i for ≥12 mos (HR=0.886 [95% CI 0.586 - 1.337]). In these 41 pts, mean time to chemotherapy was 137.7 days for elacestrant vs 75.5 days for SoC. Safety results were consistent with previously reported data. Specific pt characteristic information will be provided in the presentation. Conclusions: In this post-hoc analysis, oral elacestrant delayed disease progression and time to subsequent chemotherapy in pts who did not have a detectable ESR1m and rapidly progressed within 6 months of CDK4/6i plus ET before study entry. Preclinical data support these findings. While caution needs to be exerted given small numbers, the results highlight the potential role of elacestrant in ESR1wt tumors, and more research is warranted. Clinical trial information: NCT03778931 .