Abstract
Background
Soft tissue sarcomas (STS) are heterogeneous and pro-metastatic tumors. Identification of accurate prognostic factors and novel therapeutic targets are crucial. CSPG4 is a cell ...surface proteoglycan with oncogenic functions. It recently emerged as a potential target for immunotherapy, including cell therapy based on CSPG4-specific chimeric antigen receptor (CAR)-redirected cytokine-induced killer lymphocytes (CSPG4-CAR.CIKs) in STS. However, expression of CSPG4 is poorly known in STS so far.
Methods
We analyzed CSPG4 gene expression in 1378 localized STS clinical samples, and searched for correlations with clinicopathological data, including disease-free survival (DFS), and with tumor immune features.
Results
CSPG4 expression was heterogeneous across samples. High expression was associated with younger patients’ age, more frequent undifferentiated pleomorphic sarcoma and myxofibrosarcoma pathological subtypes, more frequent internal trunk tumor site, and more CINSARC high-risk samples. No correlation existed with pathological tumor size and grade, and tumor depth. Patients with high CSPG4 expression displayed 49% (95% CI 42–57) 5-year DFS
versus
61% (95% CI 56–68) in patients with low expression (p = 3.17E−03), representing a 49% increased risk of event in the “
CSPG4
-high” group (HR = 1.49, 95% CI 1.14–1.94). This unfavorable prognostic value persisted in multivariate analysis, independently from other variables. There were significant differences in immune variables between “
CSPG4
-high” and “
CSPG4
-low” tumors. The "
CSPG4
-low" tumors displayed profiles suggesting higher anti-tumor cytotoxic immune response and higher potential vulnerability to immune checkpoint inhibitors (ICI). By contrast, the "
CSPG4
-high" tumors displayed profiles implying an immune-excluded tumor microenvironment, potentially induced by hypoxia, resulting from an immature chaotic microvasculature, and/or the presence of contractile myofibroblasts.
Conclusions
Patients with “CSPG4-high” STS, theoretically candidate for CAR.CIKs, display shorter DFS and an immune environment unfavorable to vulnerability to CAR.CIKs, which could be improved by combining anti-angiogenic drugs able to normalize the tumor vasculature. By contrast, “CSPG4-low” STS are better candidates for immune therapy involving ICI.
Soft-tissue sarcomas (STSs) are a group of rare, heterogeneous, and aggressive tumors, with high metastatic risk and relatively few efficient systemic therapies. We hypothesized that the Genomic ...Grade Index (GGI), a 108-gene signature previously developed in early-stage breast cancer, might improve the prognostic assessment of patients with early-stage STS.
We collected gene expression and clinicopathological data of 678 operated STS, and searched for correlations between the GGI-based classification and clinicopathological variables, including the metastasis-free survival (MFS).
Based on GGI, 275 samples (41%) were classified as ‘GGI-low’ and 403 (59%) as ‘GGI-high’. The ‘GGI-high’ class was more associated with poor-prognosis features than the ‘GGI-low’ class: pathological grade 3 (P = 9.50E–11), undifferentiated sarcomas and leiomyosarcomas (P < 1.00E–06), location in extremities (P < 1.00E–06), and complex genetic profile (P = 2.1E–20). The 5-year MFS was 53% (95%CI 47–59) in the ‘GGI-high’ class versus 78% (95%CI 72–85) in the ‘GGI-low’ class (P = 3.02E–11), with a corresponding hazard ratio for metastatic relapse equal to 2.92 (95%CI 2.10–4.07; P = 2.23E–10). In multivariate analysis, the GGI-based classification remained significant, whereas the pathological grade did not. In fact, the GGI-based classification stratified the patients with pathological grades 1 and 2 and those with pathological grade 3 in two classes with different 5-year MFS. Comparison of the GGI and CINSARC multigene signatures revealed similar correlations with clinicopathological variables, which were, however, stronger with GGI than with CINSARC, a strong concordance (71%) in terms of low-risk or high-risk classifications, and independent prognostic value for MFS in multivariate analysis, suggesting complementary prognostic information.
GGI refines the prediction of MFS in operated STS and might improve the tailoring of adjuvant chemotherapy. Further clinical validation is warranted in larger retrospective, then prospective series, as well as the functional validation of relevant genes that could provide new therapeutic targets.
Triple-negative breast cancers (TNBCs) are considered as associated with poor outcome, but prognosis of subcentimetric, node-negative disease remains controversial and evidence that adjuvant ...chemotherapy (CT) is effective in these small tumours remains limited.
Our objective was to investigate the impact of CT on survival in pT1abN0M0 TNBC. Patients were retrospectively identified from a cohort of 22,475 patients who underwent primary surgery in 15 French centres between 1987 and 2013. As rare pathological types may display very particular prognoses in these tumours, we retained only the invasive ductal carcinomas of no special type according to the last World Health Organisation (WHO) classification which is the most common TNBC histological type. End-points were disease-free survival (DFS) and metastasis-free survival (MFS). A propensity score for receiving CT was estimated using a logistic regression including age, tumour size, Scarff Bloom and Richardson (SBR) grade and lymphovascular invasion.
Of a total of 284 patients with pT1abN0M0 ductal TNBC, 144 (51%) received CT and 140 (49%) did not. Patients receiving CT had more adverse prognostic features, such as tumour size, high grade, young age, and lymphovascular invasion. CT was not associated with a significant benefit for DFS (Hazard ratio, HR = 0.77 0.40–1.46; p = 0.419, log-rank test) or MFS (HR = 1.00 0.46–2.19; p = 0.997), with 5-year DFS and MFS in the group with CT versus without of 90% 81–94% versus 84% 74–90%, and 90% 81–95% versus 90% 83%–95%, respectively. Results were consistent in all supportive analyses including multivariate Cox model and the use of the propensity score for adjustment and as a matching factor for case–control analyses.
This study did not identify a significant DFS or MFS advantage for CT in subcentimetric, node-negative ductal TNBC. Although current consensus guidelines recommend consideration of CT in all TNBC larger than 5 mm, clinicians should carefully discuss benefit/risk ratio with patients, given the unproven benefits.
•Consensus guidelines recommend consideration of treatment in patients with triple-negative breast cancer larger than 5 mm.•We did not identify significant advantage for adjuvant chemotherapy in pT1abN0M0 TNBC patients.•Clinicians should carefully discuss benefit/risk ratio with patients.
We determined the prognostic impact of lymphovascular invasion (LVI) in a large, national, multicenter, retrospective cohort of patients with early breast cancer (BC) according to numerous factors.
...We collected data on 17 322 early BC patients treated in 13 French cancer centers from 1991 to 2013. Survival functions were calculated using the Kaplan–Meier method and multivariate survival analyses were carried out using the Cox proportional hazards regression model adjusted for significant variables associated with LVI or not. Two propensity score-based matching approaches were used to balance differences in known prognostic variables associated with LVI status and to assess the impact of adjuvant chemotherapy (AC) in LVI-positive luminal A-like patients.
LVI was present in 24.3% (4205) of patients. LVI was significantly and independently associated with all clinical and pathological characteristics analyzed in the entire population and according to endocrine receptor (ER) status except for the time period in binary logistic regression. According to multivariate analyses including ER status, AC, grade, and tumor subtypes, the presence of LVI was significantly associated with a negative prognostic impact on overall (OS), disease-free (DFS), and metastasis-free survival (MFS) in all patients hazard ratio (HR) = 1.345, HR = 1.312, and HR = 1.415, respectively; P < 0.0001, which was also observed in the propensity score-based analysis in addition to the association of AC with a significant increase in both OS and DFS in LVI-positive luminal A-like patients. LVI did not have a significant impact in either patients with ER-positive grade 3 tumors or those with AC-treated luminal A-like tumors.
The presence of LVI has an independent negative prognostic impact on OS, DFS, and MFS in early BC patients, except in ER-positive grade 3 tumors and in those with luminal A-like tumors treated with AC. Therefore, LVI may indicate the existence of a subset of luminal A-like patients who may still benefit from adjuvant therapy.
•In a study of 17 322 early BC patients, LVI had a significant independent negative prognostic impact on survival.•LVI negatively impacted survival in almost every patient category and cancer subtype, with and without AC.•LVI did not have a negative survival impact in patients with ER+ grade 3 or with luminal A-like tumors with chemotherapy.•Results suggest a possible benefit of AC in LVI-positive luminal A-like patients.
Le cancer du sein triple-négatif (CSTN), défini par l’absence d’expression des récepteurs hormonaux et d’HER2 (
human epidermal growth factor receptor-2
), représente 15 à 20 % des cancers du sein. ...Cependant, cette définition, essentiellement négative, masque la très grande hétérogénéité des entités biologiques qui constituent ce soustype. Si la chimiothérapie est le principal traitement systémique établi de la maladie à la fois dans la prise en charge des stades précoces et avancés, la compréhension progressive des composantes moléculaires impliquées dans la pathogenèse des CSTN permet des perspectives thérapeutiques novatrices. L’objectif de cette synthèse est de décrire ces cibles potentielles et d’explorer les traitements d’aujourd’hui et de demain qui permettront de lutter contre ce cancer au comportement particulièrement agressif.
Triple-negative breast cancer (TNBC), defined by the lack of expression of hormone receptors and HER2 (Human Epidermal growth factor Receptor-2), accounts for 15–20% of breast cancers. However, this definition, which is essentially negative, masks the large biological heterogeneity of this subtype. While chemotherapy is the main established systemic treatment in both early and advanced stages of the disease, the progressive understanding of the molecular components involved in the pathogenesis of TNBC allows innovative therapeutic perspectives. The objective of this review is to describe these potential targets and to explore current and future treatments that will help fighting this cancer with particular aggressive behaviors.
Prognostic impact of lymph node micro-metastases (pN1mi) has been discordantly reported in the literature. The need to clarify this point for decision-making regarding adjuvant therapy, particularly ...for patients with endocrine receptor (ER)-positive status and HER2-negative tumors, is further reinforced by the generalization of gene expression signatures using pN status in their recommendation algorithm.
We retrospectively analyzed 13 773 patients treated for ER-positive breast cancer in 13 French cancer centers from 1999 to 2014. Five categories of axillary lymph node (LN) status were defined: negative LN (pN0i−), isolated tumor cells pN0(i+), pN1mi, and pN1 divided into single (pN1 = 1) and multiple (pN1 > 1) macro-metastases (>2 mm). The effect of LN micro-metastases on outcomes was investigated both in the entire cohort of patients and in clinically relevant subgroups according to tumor subtypes. Propensity-score-based matching was used to balance differences in known prognostic variables associated with pN status.
As determined by sentinel LN biopsy, 9427 patients were pN0 (68.4%), 546 pN0(i+) (4.0%), 1446 pN1mi (10.5%) and 2354 pN1 with macro-metastases (17.1%). With a median follow-up of 61.25 months, pN1 status, but not pN1mi, significantly impacted overall survival (OS), disease-free survival (DFS), metastasis-free survival (MFS), and breast-cancer-specific survival. In the subgroup of patients with known tumor subtype, pN1 = 1, as pN1 > 1, but not pN1mi, had a significant prognostic impact on OS. DFS and MFS were only impacted by pN1 > 1. Similar results were observed in the subgroup of patients with luminal A-like tumors (n = 7101). In the matched population analysis, pN1macro, but not pN1mi, had a statistically significant negative impact on MFS and OS.
LN micro-metastases have no detectable prognostic impact and should not be considered as a determining factor in indicating adjuvant chemotherapy. The evaluation of the risk of recurrence using second-generation signatures should be calculated considering micro-metastases as pN0.
•LN micro-metastases have no detectable prognostic impact.•pN1 status, but not pN1mi, significantly impacted overall survival, disease-free survival, metastasis-free survival.•In the subgroup of patients with known tumor subtype, pN1=1, as pN1>1, but not pN1mi, had a significant prognostic impact on OS.•LN micro-metastases should not be considered as a determining factor in indicating adjuvant chemotherapy.
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