Clinical implications of the intrinsic molecular subtypes in hormone receptor-positive and HER2-negative metastatic breast cancer

Falato, Claudette; Schettini, Francesco; Pascual, Tomás; Brasó-Maristany, Fara; Prat, Aleix

doi:10.1016/j.ctrv.2022.102496

Cited by 34 publications

(24 citation statements)

References 121 publications

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“…Previous studies and clinical trials demonstrated that CDK4/6 inhibitors are more likely to be treated in a combination therapy rather than monotherapy [ 19 , 32 – 35 ]. Notably, CDK4/6 inhibitors are reported to exhibit good antitumor effects in combination with epigenetic regulatory drugs [ 23 ].…”

Section: Resultsmentioning

confidence: 99%

The BRD4 inhibitor JQ1 augments the antitumor efficacy of abemaciclib in preclinical models of gastric carcinoma

Feng

Zhou

et al. 2023

J Exp Clin Cancer Res

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Background Advanced gastric cancer (GC) is a lethal malignancy, harboring recurrent alterations in cell cycle pathway, especially the CDKN2A-CDK4/CDK6/CCND1 axis. However, monotherapy of CDK4/6 inhibitors has shown limited antitumor effects for GC, and combination treatments were urgently needed for CDK4/6 inhibitors. Methods Here, we performed a comprehensive analysis, including drug screening, pan-cancer genomic dependency analysis, and epigenetic sequencing to identify the candidate combination with CDK4/6 inhibitors. Mechanisms were investigated by bulk RNA-sequencing and experimental validation was conducted on diverse in vitro or in vivo preclinical GC models. Results We found that the BRD4 inhibitor JQ1 augments the antitumor efficacy of the CDK4/6 inhibitor abemaciclib (ABE). Diverse in vitro and in vivo preclinical GC models are examined and synergistic benefits from the combination therapy are obtained consistently. Mechanistically, the combination of ABE and JQ1 enhances the cell cycle arrest of GC cells and induces unique characteristics of cellular senescence through the induction of DNA damage, which is revealed by transcriptomic profiling and further validated by substantial in vitro and in vivo GC models. Conclusion This study thus proposes a candidate combination therapy of ABE and JQ1 to improve the therapeutic efficacy and worth further investigation in clinical trials for GC.

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Section: Resultsmentioning

confidence: 99%

The BRD4 inhibitor JQ1 augments the antitumor efficacy of abemaciclib in preclinical models of gastric carcinoma

Feng

Zhou

et al. 2023

J Exp Clin Cancer Res

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“…From a molecular perspective, HoR+/HER2-negative BC has been segmented into a minimum of 4 distinct molecular subtypes, referred to as intrinsic subtypes (IS): Luminal A, Luminal B, HER2-enriched (HER2-E), and Basal-like [7][8][9]. These entities are detectable through the PAM50 gene expression assay [8,10].…”

Section: Introductionmentioning

confidence: 99%

“…These entities are detectable through the PAM50 gene expression assay [8,10]. Additionally, a fth subgroup termed Normal-like arises due to potential contamination from adjacent normal breast tissue [7,9,10]. Although the most prevalent subtypes are the Luminal A and B [9,11], non-luminal subtypes represent 5-10% of cases in the early-stage setting, and up to 30-44% in the metastatic setting [12,13].…”

Section: Introductionmentioning

confidence: 99%

Gene expression before and after neoadjuvant chemotherapy or endocrine therapy and survival outcomes in hormone receptor-positive, HER2-negative breast cancer: the NEOENDO study

Schettini,

Brasó-Maristany,

Pascual

et al. 2024

Preprint

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Background Neoadjuvant chemotherapy (NACT) and endocrine therapy (NET) are sometimes used to shrink hormone receptor-positive (HoR+)/HER2-negative breast cancer (BC) before surgery. These treatments can change the tumor on a molecular level, but the impact on patient outcomes remains unclear. There is also a lack of detailed comparison between the changes induced by both therapies.Methods We studied 186 patients with early-stage BC treated at our Institution with either NACT or NET. Changes in clinical and gene expression (GE) features before/after treatment were assessed. GE findings were confirmed in HoR+/HER2-negative BC cell lines. Associations with event-free survival (EFS) were conducted with the Kaplan-Meier method, log-rank tests, and Cox regressions. GE comparisons were assessed with SAM analysis. We considered p < 0.05 and a false discovery rate (FDR) < 5% as statistically significant.Results Patients treated with NACT had more aggressive cancer at baseline but also showed higher rates of pathological complete response compared to those treated with NET (18.6% vs. 3.4%, p = 0.001). Both treatments shifted the tumor types towards less aggressive forms (i.e., PAM50 Luminal A/Normal-like) and lowered the risk of recurrence in terms of PAM50 risk-of-relapse score (ROR-P) (all p < 0.001). NACT induced more profound mean reduction in ROR-P than NET. Both treatments induced a significant upregulation of selected immune genes and PAM50 Basal-like-related signature and genes, while a significant downregulation was observed for proliferation-, luminal- and HER2-related genes/signatures (all FDR < 5%). A net reduction in proliferation-related genes and ROR-P was confirmed in cell lines with CT and ET. Higher rates of pathologic responses were achieved with NACT in patients with higher initial levels of ROR-P and proliferation-related genes, while responders to NET showed an upregulation of luminal-related genes vs. NACT responders. Decreasing the risk of recurrence and transitioning the tumor subtype to resemble normal tissue (i.e., PAM50 Normal-like) suggested improved EFS.Conclusions NACT was more effective in molecularly and dimensionally 'downstaging' the cancer compared to NET but baseline genomic features associated to differential responses according to treatment strategy. Examining baseline and post-treatment GE might help tailoring neo/adjuvant systemic treatments, potentially leading to more personalized and effective care.

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“…On the molecular level, mBC is a heterogeneous disease due to alterations acquired during the disease evolution from its early to late stages. The tumour biology of mBC is not always representative of that of eBC 20,21 . The molecular features include activation of human epidermal growth factor receptor 2 (HER2, encoded by ERBB2), activation of hormone receptors (oestrogen receptor and progesterone receptor) and BRCA mutations.…”

Section: Introductionmentioning

confidence: 99%

Planning for return to work during the first year after breast cancer metastasis: A Swedish cohort study

et al. 2023

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Background Planning for return to work (RTW) is relevant among sub‐groups of metastatic breast cancer (mBC) survivors. RTW and protective factors for RTW in patients with mBC were determined. Methods Patients with mBC, ages 18–63 years, were identified in Swedish registers, and data were collected starting 1 year before their mBC diagnosis. The prevalence of working net days (WNDs) (>90 and >180) during the year after mBC diagnosis (y1) was determined. Factors associated with RTW were assessed using regression analysis. The impact of contemporary oncological treatment of mBC on RTW and 5‐year mBC‐specific survival was compared between those diagnosed in 1997–2002 and 2003–2011. Results Of 490 patients, 239 (48.8%) and 189 (36.8%) had >90 and >180 WNDs, respectively, during y1. Adjusted odds ratios (AORs) of WNDs >90 or >180 during y1 were significantly higher for patients with age ≤50 years (AOR180 = 1.54), synchronous metastasis (AOR90 = 1.68, AOR180 = 1.67), metastasis within 24 months (AOR180 = 1.51), soft tissue, visceral, brain as first metastatic site (AOR90 = 1.47) and sickness absence <90 net days in the year before mBC diagnosis, suggesting limited comorbidities (AOR90 = 1.28, AOR180 = 2.00), respectively. Mean (standard deviation) WNDs were 134.9 (140.1) and 161.3 (152.4) for patients diagnosed with mBC in 1997–2002 and 2003–2011, respectively (p = 0.046). Median (standard error) mBC‐specific survivals were 41.0 (2.5) and 62.0 (9.6) months for patients diagnosed with mBC in 1997–2002 and 2003–2011, respectively (p < 0.001). Conclusions RTW of more than 180 WNDs was associated with younger age, early development of metastases and limited comorbidities during the year before the diagnosis of mBC. Patients diagnosed with mBC in 2003 or later had more WNDs and better survival than those diagnosed earlier.

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Clinical implications of the intrinsic molecular subtypes in hormone receptor-positive and HER2-negative metastatic breast cancer

Cited by 34 publications

References 121 publications

The BRD4 inhibitor JQ1 augments the antitumor efficacy of abemaciclib in preclinical models of gastric carcinoma

The BRD4 inhibitor JQ1 augments the antitumor efficacy of abemaciclib in preclinical models of gastric carcinoma

Gene expression before and after neoadjuvant chemotherapy or endocrine therapy and survival outcomes in hormone receptor-positive, HER2-negative breast cancer: the NEOENDO study

Planning for return to work during the first year after breast cancer metastasis: A Swedish cohort study

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