Background

Abemaciclib demonstrated a sustained benefit in invasive disease-free survival and a tolerable safety profile in monarchE at 42 months (mo) median follow-up (mFU). At 19 mo mFU, initial patient (pt)-reported outcome (PRO) findings supported a tolerable profile with most pts remaining on treatment (tx). With all pts now off abemaciclib, we report data including the full 2-year tx period and follow-up to evaluate long-term impact on PROs.

Methods

Pts completed PROs including FACT-B, FACT-ES, and FACIT-Fatigue at baseline, 3, 6, 12, 18, 24 mo, and 1, 6, 12 mo after tx discontinuation (dc). Mixed effects repeated measures model estimated changes from baseline within and between arms for summary scores and individual items. Meaningful change was defined as 0.5 standard deviation of baseline summary scores and 1 point for individual items. Additional analyses included frequencies of responses to items associated with adverse events (AEs; e.g., diarrhea, fatigue) and tx bother.

Results

For the 5591 treated pts, PRO completion rates were >90% on tx and ~80% during follow-up. Within- and between-arms, differences in mean changes from baseline for all PROs were less than prespecified thresholds for meaningful difference, except for diarrhea, with worse scores in abemaciclib plus ET at 3 and 6 mo. During tx, most pts reported being bothered “a little bit” or “not at all” by side effects in both arms and most pts (79-85%) on abemaciclib reported “not at all” to “somewhat” for diarrhea (Table). During post-tx follow-up, PROs in both arms were similar to baseline, with ≥80% of pts on abemaciclib arm reporting “not at all” for diarrhea.

Conclusions

Adjuvant abemaciclib added to ET did not result in meaningful differences in PROs, except for diarrhea,which is considered clinically manageable. Long-term findings suggest reversibility of these effects after tx dc and can help inform pt risk/benefit assessment.

Clinical trial identification

NCT0315599

Editorial acknowledgement

Medical writing support was provided by Trish Huynh (Eli Lilly and Company, IN, USA)

Background

This study determines the prognostic and predictive effect of body mass index (BMI) on the disease-free survival (DFS) of postmenopausal hormone receptor-positive (HR+) breast cancer patients who received (extended) endocrine therapy.

Methods

Patients with a BMI of ≥18.5 kg/m² were identified from the randomised, phase 3 DATA trial (NCT00301457), which evaluated the use of six versus three years of anastrozole in postmenopausal women with HR+ breast cancer who were disease-free after two to three years of adjuvant tamoxifen. Patients were categorised as normal weight (18.5-24.9 kg/m²), overweight (25-29.9 kg/m²), or obese (≥30 kg/m²). The primary endpoint was DFS. Multivariable Cox regression analyses were performed. The prognostic impact of BMI was evaluated from date of randomisation, whereas the predictive impact of BMI on the efficacy of extended anastrozole was evaluated from three years after randomisation, i.e. treatment divergence (adapted DFS).

Results

Overall, 1,781 patients were included: 678 (38%) normal weight, 712 (40%) overweight, and 391 (22%) obese patients. After a median follow-up of 13.1 years, overweight and obese patients had a worse DFS when compared with normal weight patients (hazard ratio (HR)=1.16; 95% confidence interval (CI) 0.97-1.38, p=0.10; and HR=1.26; 95% CI 1.03-1.54, p=0.03, respectively). In women aged <60 years, overweight was associated with a worse DFS (HR=1.29; 95% CI 1.00-1.67, p=0.05) as was obesity (HR=1.83; 95% CI 1.36-2.46, p<0.001), but this was not observed in women aged ≥60 years (HR=1.04; 95% CI 0.82-1.33, p=0.72; and HR=0.94; 95% CI 0.72-1.23, p=0.63, respectively) (p-interaction = 0.009). The effect of extended anastrozole on adapted DFS did not differ between normal weight (HR=1.00; 95% CI 0.74-1.35, p=1.00), overweight (HR=0.74; 95% CI 0.56-0.98, p=0.04), and obese patients (HR=0.97; 95% CI 0.69-1.36, p=0.85) (p-interaction=0.24).

Conclusions

In HR+ breast cancer patients aged <60 years at randomisation, overweight and obesity were adverse prognostic factors for DFS. In patients aged ≥60 years, this adverse prognostic effect was not observed. The effect of extended anastrozole on adapted DFS did not differ between BMI classes.

Clinical trial identification

NCT00301457

Background

The present study investigated the long-term Quality of Life (QoL) and sexual health of premenopausal women, on average 9.5 (range 5 -15) years after being diagnosed with a HR positive breast cancer (BC) registered in the ABCSG 22 registry.

Methods

Between April 2008 and January 2022, ABCSG collected Patient Reported Outcome (PRO) data from a registry of premenopausal women with HR positive BC receiving endocrine therapy with tamoxifen and goserelin for five years (± chemotherapy). After a median follow up of 9 (IQR 8-11) years, a cross-sectional PRO assessment targeting QoL, sexual health and fertility issues was conducted at 11 Austrian centres. PRO was assessed using the EORTC QLQ C30, QLQ-BR45, EORTC QLQ-SHQ22, SABIS, MENQOL and fertility questionnaire. All scores are presented descriptively. Differences between subgroups scores and between register scores and values from reference population were evaluated using MANOVA.

Results

Overall, 469 women were included; the median age was 46 years at BC diagnosis, 55 years at the time of the PRO assessment. 30% of the women had chemotherapy before the start of hormonal therapy. Compared to the general population, women with a history of BC have statistically significant worse score in the emotional and social functional scales of the EORTC C30 as well as more insomnia, constipation, and more financial difficulties. Interestingly, women with a history of BC reported better global health status than the general population (mean 76.9 vs 71.2). Women who had received prior chemotherapy had a statistically significant worse score in the cognitive (mean 80.6 vs 85.8) and social functioning (mean 73.6 vs 80.2) scales of the EORTC C30, more nausea/vomiting, as well as more financial problems compared to the women with endocrine therapy alone. Analyses regarding sexual health, MENQOL and fertility issues is currently ongoing and will also be presented at the meeting.

Conclusions

The long-term side effects of BC therapy and their impact on QoL in premenopausal women are persistent after 10 years of the diagnosis and most pronounced in women who had received additional chemotherapy.

Background

In the phase 3, randomized, open-label KEYNOTE-119 (NCT02555657) study, second- or third-line treatment with pembro monotherapy did not significantly improve OS vs single-agent chemo treatment of physician’s choice (TPC) in patients (pts) with mTNBC, although the pembro treatment effect increased with increasing PD-L1 enrichment. In this exploratory analysis, we evaluated the association of T-cell-inflamed gene expression profile (GEP) with clinical outcomes from KEYNOTE-119.

Methods

Pts with centrally confirmed mTNBC, ECOG PS ≤1, and 1-2 prior systemic treatments for metastatic breast cancer were randomized 1:1 to pembro 200 mg Q3W for up to 35 cycles or TPC (capecitabine, eribulin, gemcitabine, or vinorelbine) per local guidelines. Tumor RNA profiling was conducted on the RNA-seq platform (Illumina, San Diego, CA). Association of GEP with clinical outcomes was evaluated by logistic regression (best objective response [BOR] per RECIST v1.1) and Cox proportional hazards models (PFS and OS) with baseline adjustment for ECOG PS; 95% CIs for BOR were estimated using the Clopper and Pearson method.

Results

As of April 11, 2019, GEP data for 333 pts (pembro, n=177; TPC, n=156) were available for analysis. GEP was significantly associated with improved BOR, PFS, and OS in pts treated with pembro but not TPC (Table). HR for OS was 0.77 (95% CI, 0.58–1.04) in pts with GEP non-low (≥1^st tertile) and 1.72 (1.15–2.55) in pts with GEP low (<1^st tertile). No association was seen between BRCA/HRD status and treatment response.

Conclusions

These findings suggest a positive association between GEP and clinical outcomes in pts with mTNBC who are treated with pembro, with a more favorable treatment effect in the GEP-enriched population. Results may help inform future analyses of outcomes by biomarker status in this population.

Clinical trial identification

NCT02555657

Editorial acknowledgement

Medical writing assistance was provided by Sonia Mohinta, PhD, of ICON plc (Blue Bell, PA, USA). This assistance was funded by Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA.

Background

In the phase 3 KEYNOTE-355 study (NCT02819518), first-line treatment with pembro + chemo resulted in statistically significant and clinically meaningful improvements in PFS and OS versus placebo + chemo in patients (pts) with advanced TNBC with PD-L1 combined positive score (CPS) ≥10. We report efficacy outcomes from the KEYNOTE-355 final analysis for pts who had disease control and discontinued chemo before pembro and for pts who experienced immune-mediated AEs.

Methods

Pts with untreated locally recurrent inoperable or metastatic TNBC were randomized 2:1 to pembro (200 mg Q3W) or placebo for 35 cycles in combination with chemo (nab-paclitaxel, paclitaxel, or gemcitabine/carboplatin). Treatment continued until progression, intolerable toxicity, or (for pembro/placebo) completion of 35 cycles; pts could discontinue chemo independently of pembro/placebo (and vice versa). In this analysis, PFS per RECIST v1.1 by BICR and OS were evaluated in (a) pts who received pembro + chemo, achieved a best objective response of CR, PR, or SD lasting ≥24 wk, and received their last dose of chemo >21 days before their last dose of pembro, and (b) pts who received pembro + chemo and experienced ≥1 immune-mediated AEs (per a list of preferred terms compiled from the CTCAE v4.0).

Results

Pts were randomized to pembro + chemo (n=566) or placebo + chemo (n=281). At data cutoff (June 15, 2021), 317 pts in the pembro + chemo group had CR, PR, or SD ≥24 wk. Among these pts, discontinutation of chemo before pembro was associated with similar efficacy to that in the overall population, irrespective of tumor PD-L1 CPS (Table). Similarly, there was evidence of antitumor activity in pts who had immune-mediated AEs, overall and by tumor PD-L1 CPS (Table).

Conclusions

In this analysis of outcomes among pts who received pembro + chemo in the KEYNOTE-355 study, there was evidence for efficacy of pembro + chemo regardless of discontinuation of chemo before pembro or occurrence of immune-mediated AEs.

Clinical trial identification

NCT02819518

Editorial acknowledgement

Medical writing assistance was provided by Sonia Mohinta, PhD, of ICON plc (Blue Bell, PA, USA). This assistance was funded by Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA.

Background

The recommended cut-off of <1% positive cells to define estrogen receptor (ER) negative status in breast cancer (BC) is highly debated. We compared the tumor immune microenvironment (TME) of HER2-neg BC according to ER status (ER-neg: 0% vs ER-low: 1-9%).

Methods

This multicentric study included patients with stage I-III HER2-neg BC from centers across Italy and France: Istituto Oncologico Veneto IOV; Montpellier Cancer Institute MCI; Istituto Nazionale Tumori Milano; Istituto Europeo di Oncologia. Tumor samples were reviewed for ER: ER-neg and ER-low pts were eligible, pts with ER intermediate expression (ER-int: 10-50%) were included in a control cohort. Tumor-infiltrating lymphocytes (TILs) were evaluated on full-face H&E slides. CD8, FOXP3 and PD-L1 (SP142) status was assessed by IHC and quantified by digital pathology in samples from IOV (full-face slides) and MCI (tissue-microarray).

Results

Of 753 pts included, 613 had ER-neg BC, 80 had ER-low BC, and 60 had ER-int disease. TME characterization in these tumor specimens is summarized in the Table. TILs levels were similar in ER-neg and ER-low tumors, and in both subgroups significantly higher than in ER-int samples. Compared to ER-neg, ER-low BC had significantly higher levels of CD8+ and FOXP3+ cells, with a similar CD8/FOXP3 ratio. The rate of PD-L1 positive tumors was similar between ER-neg and ER-low BC pts.

At the validated ≥30% cut-off, higher TILs were associated with better relapse-free survival in ER-neg (5-yr rates: 89% vs 71%, p<0.001) and ER-low BC pts (93% vs 58%, p=0.047), but not in the ER-int group, where we found an opposite trend (43% vs 69%, p=0.114).

Conclusions

TME composition is similar in ER-neg vs ER-low HER2-neg BC tumors and TILs have a similar prognostic role in these cohorts. Our results support the claim that HER2-neg/ER-low BC pts should be granted access to drugs developed for triple-negative BC, including immune checkpoint inhibitors. Gene expression analysis will be presented at the meeting.

Background

IC markers against which inhibitors are currently used/evaluated clinically, have not yet been studied in detail in metastases (M) from patients with primary HR+/HER2- BC. In this study, we examined expression levels of these IC markers in multiple M and primary tumors (P) from primary HR+/HER2- BC patients who enrolled in our postmortem tissue donation program UPTIDER (NCT04531696).

Methods

326 samples (23 untreated P and 290 postmortem M samples) from 10 UPTIDER patients with primary HR+/HER2- BC underwent bulk RNA sequencing (Lexogen). Quality control (QC) was set for 500000 assigned reads and gene counts were normalized using variance stabilizing transformation. We selected IC markers being clinically investigated in BC (BTLA, CD40, CD47, CD86, CD137, CD137L, CD158A, CD226, CTLA4, ICOS, LAG3, OX40, PD-1, PD-L1, TIM3, TIGIT) from literature and clinicaltrials.gov. Available matched FFPE samples were evaluated for histology (invasive lobular, ILC, and BC of no special type, NST) and ER-status. Associations between sample status (outcome: M vs P/ ER+ vs ER- for M) and individual gene expression were assessed by logistic linear regressions with data clustering by patient using the generalized estimating equation method. We studied the association between sample specific postmortem interval (ssPMI) and gene expression by repeated sampling (at 1.5h intervals) of the same M in 7 patients.

Results

324/326 samples passed QC (289 M and 22 P) and the IC expression was stable with increasing ssPMI. TIM3was highly expressed, and PD-1 was among the least expressed in M. Intra-patient inter-M heterogeneity was observed for all markers. M showed lower expression of PD-1, PD-L1, CTLA4, LAG3, OX40 and TIGIT (Odds ratio (OR) range: 0.27-0.53, p<0.05) and higher expression of TIM3 and BTLA (OR range:1.37-6.19, p<0.05) compared to P. BTLA, CD86, CTLA4, OX40 and TIM3 were more expressed in NST M compared to ILC M (OR range: 1-1.43). PD-L1, CD47, LAG3, CD40 and TIGIT were found more expressed in ER+ vs ER- M in both NST and ILC (OR NST: 1.02-1.37, OR ILC: 1.12-5.52).

Conclusions

This study sheds light on the expression of IC markers in M from patients with HR+/HER2- primary BC as well as on the impact of histology and ER-expression.

Clinical trial identification

clincialtrials.gov - NCT04531696