Institut Curie is one of the leading medical, biological and biophysical research centres in the world. It is a private non-profit foundation operating a research center on biophysics, cell biology and oncology and a hospital specialized in treatment of cancer. It is located in Paris, France.
Chemotherapy resistance remains a major hurdle for treating patients with triple-negative breast cancer (TNBC). Although cancer-associated fibroblasts (CAF) as an overall population have been shown to modulate treatment response, innovative approaches are required to decipher which and how distinct CAF populations drive chemoresistance. In this study, by combining analysis of data from patients with TNBC with ex vivo modeling using tumor-on-chip technology, we identified a specific CAF population, the extracellular matrix-producing myofibroblasts (ECM-myCAF), that mediated resistance to chemotherapy. The proportion of ECM-myCAFs decreased after chemotherapy in chemosensitive patients but remained unchanged in chemoresistant patients. In tumor-on-chip models, primary ECM-myCAFs promoted TNBC cell survival under chemotherapy treatment. Single-cell RNA sequencing, advanced cell imaging, and functional assays showed that ECM-myCAFs activated SRC kinases in TNBC cells, likely through secreted factors, and upregulated the apoptosis regulator G0-G1 switch 2 (G0S2). SRC inhibition or G0S2 silencing completely abolished TNBC cell chemoresistance driven by ECM-myCAFs. Altogether, this work reveals the unique role of the specific ECM-myCAF population and identifies G0S2 as a key player in chemoresistance in TNBC.Significance: Integration of patient data with ex vivo tumor-on-chip modeling identifies an extracellular matrix-producing myofibroblast population that contributes to chemoresistance and can be targeted to improve outcomes in triple-negative breast cancer.
BACKGROUND:The efficacy of neoadjuvant chemoimmunotherapy in patients with non-metastatic triple-negative inflammatory breast cancer (TN-IBC) remains unclear, as patients with IBC have been poorly represented in pivotal clinical trials. PATIENTS AND METHODS:We conducted an observational, retrospective/prospective, multicenter cohort study from 2023 to 2024 of patients with non-metastatic TN-IBC who received at least one cycle of neoadjuvant pembrolizumab plus multi-agent chemotherapy from September 2018 to April 2023. The median follow-up was 1.4 years [95% confidence interval (CI) 1.2-1.7 years]. The primary endpoint was pathological complete response (pCR). RESULTS:Overall, 63 female patients with TN-IBC were included from four cohorts. The most common regimen was pembrolizumab, taxane/carboplatin, and anthracycline/cyclophosphamide (61.9%). Among all patients, 59 (94%) underwent surgery and 4 (6.4%) experienced local and/or distant disease progression during the neoadjuvant treatment. The pCR rate was 31.7% (20/63; 95% CI 20.6% to 44.7%). CONCLUSIONS:The combination of neoadjuvant chemotherapy and pembrolizumab resulted in a pCR rate of 31.7% in patients with non-metastatic TN-IBC. Compared with triple-negative non-IBC, the lower pCR rate with this combination regimen highlights the need for biomarkers for better patient selection and more active treatment options for this rare and aggressive breast cancer subtype.
BACKGROUND:Retroperitoneal sarcoma (RPS) encompasses a heterogenous group of rare malignancies that develop in the back of the abdomen. For localized primary disease, the mainstay of treatment is surgery. Beyond the primary site, patterns of disease manifestation vary by histologic type and include visceral organ metastasis, as well as intraabdominal multifocal disease. Although cure is extremely rare, some patients may still derive significant benefit from treatment. METHODS:A comprehensive literature search was performed and international, key opinion leaders for RPS met together to discuss principles of practice for multifocal and metastatic disease, summarized in 45 statements, each given a level of evidence and grade of recommendation. RESULTS:Patients should be evaluated in a multidisciplinary sarcoma center with experience in RPS and recognition of histologic type is critical to guide management. After pretreatment assessment that includes imaging and pathology review, the goals of treatment should be clarified upfront and aligned with the anticipated ability for the patient to tolerate treatment. Disease biology (e.g., disease-free interval) should be thoroughly understood. Treatment modalities can include a combination of surgery, non-surgical local therapy (radiation therapy, percutaneous tumor ablation and embolization) and systemic therapy. CONCLUSIONS:This updated consensus document gives comprehensive and practical clinical guidance to providers for the management of multifocal and metastatic RPS. The current document also serves as the foundation for future clinical and translational investigation, as we continue to optimize patient care in these complex and challenging cases.
ABSTRACT:Idecabtagene vicleucel (ide-cel), an adoptive chimeric antigen receptor T-cell therapy directed against B-cell maturation antigen (BCMA), has demonstrated high response rates and improved survival in patients with relapsed/refractory multiple myeloma. However, all patients eventually relapse, and data on salvage therapy outcomes remain limited. We conducted a national, real-world study of 154 patients relapsing after ide-cel, with a median time to progression of 6.0 months (interquartile range, 3.0-9.9). Salvage therapies included anti-BCMA bispecific antibodies (BsAbs) (n = 79), non-BCMA BsAbs targeting GPRC5D or FcRH5 (n = 12), combinations of immunomodulatory agent, proteasome inhibitor, and anti-CD38 monoclonal antibody (n = 40), and others (n = 23). Median overall survival (OS) was 12.12 months (95% confidence interval, 6.6 to not reached), and median progression-free survival (PFS) was 3.48 months (95% CI, 2.6-6.37). The overall response rate (≥ partial response) was higher in patients treated with BsAbs (36%) than others (13%, P = .002). Treatment with non-BCMA BsAbs resulted in significantly higher ORR (67% vs 30%, P = .018), OS (19.48 vs 8.41 months, P = .034) and PFS (9.2 vs 3.81 months, P = .035) compared to anti-BCMA BsAbs. Early relapse after ide-cel (≤6 months) was associated with worse outcomes (OS: 5.95 vs 12.58 months, P = .040), as was extramedullary disease (OS: 13.8 vs 6.28 months, P = .033) and exposure to >3 prior lines of therapy. In summary, anti-BCMA BsAbs offered limited efficacy whereas non-BCMA BsAbs may offer a promising therapeutic approach following ide-cel early relapse. These results underscore the potential benefits of diversifying targets in relapse post-ide-cel treatment strategies. This trial was registered at www.clinicaltrials.gov as #NCT04328298.
Endocrine therapy (ET) is the standard of care for estrogen receptor (ER)-positive breast cancer. Point mutations in the ligand-binding domain of the gene encoding the estrogen receptor (ESR1) are rare in naïve ER+ breast cancer while becoming common in the ET-resistant setting. In this study, we found that ESR1 mutations expose breast cancers to critical vulnerabilities related to lipid metabolism. Particularly, ESR1 mutations that induce constitutive ER activation drove aberrant lipid biogenesis and lipid upload in parallel with increased expression of acyl-CoA synthetase long-chain family member 4 (ACSL4), which plays a crucial role in fatty acid activation and has been shown to correlate with increased ferroptosis susceptibility. Although ER+ breast cancer cells displayed ferroptosis resistance, the presence of ESR1 mutations rendered tumor cells sensitive to ferroptosis induction. Importantly, ferroptosis inducers potentiated the effects of the selective ER degraders fulvestrant and elacestrant, which are the standard of care for breast cancers carrying ESR1 mutations. These findings, validated both in preclinical models and in patient-derived material, identify a combinatory therapeutic approach in the setting of ET resistance and establish ACSL4 as an important biomarker to recognize ER+ breast cancers susceptible to ferroptosis induction. SIGNIFICANCE:ESR1 mutations in breast cancer induce metabolic changes that trigger ferroptosis sensitivity, enabling ferroptosis inducers to enhance selective ER degraders' efficacy and positioning ACSL4 as a biomarker for guiding therapy in endocrine-resistant disease.
