Residual ANTXR1+ myofibroblasts after chemotherapy inhibit anti-tumor immunity via YAP1 signaling pathway.

Although cancer-associated fibroblast (CAF) heterogeneity is well-established, the impact of chemotherapy on CAF populations remains poorly understood. Here we address this question in high-grade serous ovarian cancer (HGSOC), in which we previously identified 4 CAF populations. While the global content in stroma increases in HGSOC after chemotherapy, the proportion of FAP+ CAF (also called CAF-S1) decreases. Still, maintenance of high residual CAF-S1 content after chemotherapy is associated with reduced CD8+ T lymphocyte density and poor patient prognosis, emphasizing the importance of CAF-S1 reduction upon treatment. Single cell analysis, spatial transcriptomics and immunohistochemistry reveal that the content in the ECM-producing ANTXR1+ CAF-S1 cluster (ECM-myCAF) is the most affected by chemotherapy. Moreover, functional assays demonstrate that ECM-myCAF isolated from HGSOC reduce CD8+ T-cell cytotoxicity through a Yes Associated Protein 1 (YAP1)-dependent mechanism. Thus, efficient inhibition after treatment of YAP1-signaling pathway in the ECM-myCAF cluster could enhance CD8+ T-cell cytotoxicity. Altogether, these data pave the way for therapy targeting YAP1 in ECM-myCAF in HGSOC.

Clinical Utility of Pre-Therapeutic [18F]FDG PET/CT Imaging for Predicting Outcomes in Breast Cancer.

BACKGROUND: [18F]FDG PET/CT is used for staging and could also provide information associated with clinical outcomes. The objective of this study was to determine the clinical utility of biomarkers measured using [18F]FDG PET/CT to predict the absence of pathological complete response (no-pCR) and recurrence. METHODS: In this retrospective study, we included patients with non-special-type breast carcinoma who underwent [18F]FDG PET/CT before neoadjuvant chemotherapy between 2011 and 2019. Clinicopathological data were collected. Tumor SUVmax and total metabolic tumor volume (TMTV) were measured from PET images. The association between biomarkers and no-pCR was studied using logistic regression. The cut-off value was determined using the area under the ROC Curve. To predict 3-year recurrence-free survival (RFS), we used a multivariable Cox model, and the cut-off value was determined using time-dependent ROC and predictiveness curves. RESULTS: Two hundred and eighty-six patients were included in the analysis. One hundred and twelve patients had a pCR (39.2%). The pCR rate was significantly higher in patients with a high nuclear grade (p < 0.01), HER2+ and TNBC subtypes (p < 0.01), high Ki67 (p < 0.01), and low TMTV (p < 0.01). A high TMTV value (>9.0 cm3) was significantly associated with no-pCR in the whole cohort (OR = 2.4, 95% CI: 1.3-4.2, p < 0.01). After a median follow-up of 4.5 years, 65 patients experienced recurrence and 39 patients died. High TMTV (>13.5 cm3) was associated with shorter RFS (HR = 4.0, 95% CI: 1.9-8.4, p < 0.01). CONCLUSION: High TMTV in pre-therapeutic imaging is associated with no-pCR and recurrence. It can help in identifying high-risk patients and be considered as an intensified or alternative adjuvant therapy for closely monitoring patients.

[18F]FDG PET/CT for predicting triple-negative breast cancer outcomes after neoadjuvant chemotherapy with or without pembrolizumab.

PURPOSE: To determine if pretreatment [18F]FDG PET/CT could contribute to predicting complete pathological complete response (pCR) in patients with early-stage triple-negative breast cancer (TNBC) undergoing neoadjuvant chemotherapy with or without pembrolizumab. METHODS: In this retrospective bicentric study, we included TNBC patients who underwent [18F]FDG PET/CT before neoadjuvant chemotherapy (NAC) or chemo-immunotherapy (NACI) between March 2017 and August 2022. Clinical, biological, and pathological data were collected. Tumor SUVmax and total metabolic tumor volume (TMTV) were measured from the PET images. Cut-off values were determined using ROC curves and a multivariable model was developed using logistic regression to predict pCR. RESULTS: N = 191 patients were included. pCR rates were 53 and 70% in patients treated with NAC (N = 91) and NACI (N = 100), respectively (p < 0.01). In univariable analysis, high Ki67, high tumor SUVmax (> 12.3), and low TMTV (≤ 3.0 cm3) were predictors of pCR in the NAC cohort while tumor staging classification (< T3), BRCA1/2 germline mutation, high tumor SUVmax (> 17.2), and low TMTV (≤ 7.3 cm3) correlated with pCR in the NACI cohort. In multivariable analysis, only high tumor SUVmax (NAC: OR 8.8, p < 0.01; NACI: OR 3.7, p = 0.02) and low TMTV (NAC: OR 6.6, p < 0.01; NACI: OR 3.5, p = 0.03) were independent factors for pCR in both cohorts, albeit at different thresholds. CONCLUSION: High tumor metabolism (SUVmax) and low tumor burden (TMTV) could predict pCR after NAC regardless of the addition of pembrolizumab. Further studies are warranted to validate such findings and determine how these biomarkers could be used to guide neoadjuvant therapy in TNBC patients.

Prevalence of sexual dysfunction after breast cancer compared to controls, a study from CONSTANCES cohort.

PURPOSE: Sexuality, a substantial factor in quality of life, may be altered after breast cancer (BC) treatments as they intimately afflict femininity. This study aimed to assess the prevalence of sexual dysfunction in women with a history of BC and to compare it with women without a BC history. METHODS: The French general epidemiological cohort CONSTANCES includes more than 200,000 adults. All inclusion questionnaires from CONSTANCES non-virgin adult female participants were analyzed. Women reporting a history of BC were compared to controls in univariate analysis. Multivariate analysis was performed to highlight any demographic risk factor for sexual dysfunction. RESULTS: Among the 2,680 participants who had a history of BC, 34% did not engage in sexual intercourse (SI) in the month preceding the completion of the questionnaire (n = 911), 34% had pain during SI (n = 901) and 30% were not satisfied with their sex life (n = 803). Sexual dysfunction was significantly more frequent in women who had a history of BC: they had less sexual interest (OR 1.79 [1.65;1.94], p < 0.001), experienced more pain during SI (OR 1.10 [1.02;1.19], p < 0.001) and were more dissatisfied with their sex life (OR 1.58 [1.47;1.71], p < 0.001). This stayed true after adjustment on multiple demographic factors such as age, menopausal status, body mass index and depression. CONCLUSIONS: Overall, in this real-life study in a large national cohort, history of BC appeared to be a risk factor for sexual disorders. IMPLICATIONS FOR CANCER SURVIVORS: Efforts to detect sexual disorders in BC survivors and offer quality support must be pursued.

[Bisphenol A and breast cancer: State of knowledge and meta-analysis]. / Bisphénol A et cancer du sein : état des lieux des connaissances et méta-analyse.

INTRODUCTION: Bisphenol A is an endocrine disruptor used in the composition of food containers. It was partially banned in France in 2015 and classified as a "very high-risk substance" in 2017. Bisphenol A's carcinogenic effects have been demonstrated in animal testing. Bisphenol A acts through estrogen-dependent and estrogen-independent pathways. It induces epigenetic changes and impacts the microenvironment of the mammary gland. However, the role of bisphenol A exposure in the development of breast cancer in humans remains controversial. This study documents the current thinking on bisphenol A with an analysis of the mechanisms and a meta-analysis. MATERIALS AND METHODS: A literature review and a statistical analysis of linear regression type, with the creation of a Forest plot, were used to perform the meta-analysis of 9 studies including 10,695 patients. RESULTS: Nine case-control studies, published between 1990 and 2021, investigating the association between breast cancer and mean urinary, blood or tissue bisphenol A levels were selected. The meta-analysis did not find a significant association between bisphenol A exposure and the development of breast cancer with an OR=(1 IC95% [0.92-1.08]). DISCUSSION: This meta-analysis does not show a link between breast cancer and bisphenol A exposure. Nevertheless, the analysis of a pathogenic link between bisphenol A and breast cancer requires additional cohort studies to conclude because of methods of available studies.

Sexuality after breast cancer, how to provide a global and contemporary approach.

Patients' sexuality is one of the major and most neglected impact of breast cancer (BC) and its treatment. Even though research is ongoing on the subject, sexuality issues are rarely taken into account and efficiently dealt with in clinical practice. The objective is to review the impact of BC and its treatment on modern women sexuality. In the literature, a heterogeneous level of advancement is notable in the different publishing countries depending on the cultural background; some countries simply do not publish on the matter, others mainly discuss the male partners and practicians experience, and lastly, the most progressive countries have moved up to studying niches of patients such as sexual and gender minorities. A multidisciplinary approach, including pharmacologic and nonpharmacologic management, appears most efficient. There is a need for greater inclusion of partners and for providing a specific training to first-line health care providers. This review provides a general contemporary worldwide overview of the state of the art in sexuality issues in BC patients and survivors.

Phase II study of intrathecal administration of trastuzumab in patients with HER2-positive breast cancer with leptomeningeal metastasis.

BACKGROUND: Patients with HER2-positive breast cancer (HER2 + BC) develop central nervous system metastases twice as often as patients with luminal HER2-negative breast cancer. Leptomeningeal progression results in a drastically altered prognosis with limited therapeutic options. This phase II study was conducted to assess the efficacy of intrathecal (IT) trastuzumab in HER2 + BC patients with leptomeningeal metastasis (LM), based on a phase I dose-escalation study that had determined the recommended weekly dose of 150 mg for phase II. METHODS: Eligible patients received weekly administrations of 150 mg of IT trastuzumab. The primary endpoint was clinical neurologic progression-free survival (LM-related-PFS) after 8 weeks. Overall survival (OS), toxicities, and quality of life (QoL) were secondary endpoints. RESULTS: Among the 19 enrolled patients, 16 (84%) had concomitant brain metastases, 15 of them had received prior radiotherapy to the brain. All patients had received at least one line of systemic anti-HER2 therapy. After 8 weeks, 14 patients (74%) were free of neurological progression. The median LM-related-PFS was 5.9 months and the median OS was 7.9 months. According to the QLQ-C30 and BN20 scales, the global health-related QoL status seemed preserved and no toxicity above grade 3 was observed. CONCLUSIONS: Conducting studies on patients with LM poses significant challenges and ethical dilemmas inherent to this population. Despite some limits, this phase II study's findings in terms of clinical neurologic response and QoL's control confirms weekly administration of 150 mg of IT trastuzumab as a valuable option for HER + BC patients with LM and support the interest for further investigations.

Impact of catch-up human papillomavirus vaccination on cervical conization rate in a real-life population in France.

OBJECTIVE: To evaluate the impact of catch-up human papillomavirus (HPV) vaccination on conization rates in France in a large population-based study. METHODS: We conducted a retrospective real-life cohort study on data collected prospectively by French National Health Insurance. Echantillon généralistes des bénéficiaires (EGB) is a database composed of demographic and health care utilization data for a 1/97th sample of the French population. We extracted data about all women born between 1983 and 1991, corresponding to the catch-up population (vaccination after 14 years old) at the time of implementation of HPV vaccination. The primary outcome was the occurrence of conization (all types of procedures) compared between vaccinated and non-vaccinated women. RESULTS: The cohort consisted of 42,452 women. Vaccination coverage (at least one dose) was low (9.8%, n = 4,129), but increased with time from vaccine implementation, from 0% in the 1983 cohort to 31% in the 1991 cohort. The conization rate was 1% for the overall population. The risk of conization for women between the ages of 19 and 30 years was reduced in the vaccinated group with a Hazard Ratio (HR) of 0.59 (95% CI[0.39-0.90]; p = 0.043). CONCLUSIONS: With a 10-year follow-up, catch-up HPV vaccination is associated with risk reduction of conization between the ages of 19 and 30.

Quality of Life in an e-Cohort of Women Treated by Endocrine Therapy for Early Breast Cancer.

OBJECTIVE: The objective of our study was to analyze quality of life (QOL) in an e-cohort of patients treated for breast cancer (BC) by endocrine therapy (ET), by means of validated quality of life questionnaires. STUDY DESIGN AND SETTING: A retrospective, observational, e-cohort study was conducted (Seintinelles platform). Female patients treated for nonmetastatic and nonrecurrent BC, treated in France after 2005, filled in online questionnaires concerning: QOL (QLQ-C30 and QLQ-BR23), tolerability of treatment and demographic characteristics. A multivariate analysis including variables significant on univariate analysis (P < .05) to select QOL predictors was performed. RESULTS: We included 1,198 patients, 1140 of whom declared that they were taking ET (37.7% tamoxifen, 17.1% aromatase inhibitor (AI), 5.6% LHRH-agonist and 39.6% sequential tamoxifen and AI). Different tolerability profiles were observed when comparing the tamoxifen and AI groups. Treatment adherence was similar in the 2 groups. QOL varied slightly according to the type of ET. On multivariate analysis, ET had no impact on QOL. However, individual patient characteristics (socioeconomic, education and age) were significantly associated with QOL CONCLUSION: Using a real-life study questionnaire on a large e-cohort, individual patient characteristics were strongly associated with deterioration of QOL. The use of e-cohorts must be encouraged to modulate the conclusions of randomized trials.

Impact of Vulvar Cancer Surgery on Quality of Sex Life: A Review of Literature.

OBJECTIVES: Vulvar cancer is a gynecological cancer for which posttreatment morbidity must be known to propose the appropriate medical strategy. The objectives of this article were to review and to summarize the available studies evaluating the impact of vulvar surgery on the quality of sex life. MATERIALS AND METHODS: We searched MEDLINE abstracts (source PubMed) and included all studies published between 1990 and 2020 that evaluated the impact of vulvar surgery on the patients' sex life. Articles were selected in accordance with Preferred Reporting Items for Systematic Reviews and Meta-Analyses criteria. We evaluated the quality of the studies using the "study quality assessment tools" established by the National Heart Lung and Blood Institute and the health-related quality-of-life score. Summary statistics were used to report the results of the studies selected. RESULTS: A total of 41 articles were screened, and 15 studies were included in this review. Two questionnaires, that is, European Organization for Research and Treatment of Cancer QLC C30 and Female Sexual Function Index, were used in 60% of the studies. The quality of the studies was heterogeneous. None of them had a high level of evidence. Eleven of the 16 studies reported an impairment of quality of sex life, mainly related to the size of the initial lesion and the type of surgery performed. Preoperative sexual status, that is, active sex life, age, and morbidity seemed to be important factors. CONCLUSIONS: None of the studies had a high level of evidence, and their methodological quality was heterogeneous. More powerful studies using validated questionnaires are necessary. Because this is essential surgery, patients should be informed that if it impacts their sexual life, management strategies will be part of their postoperative care.

Circulating HPV DNA as a Marker for Early Detection of Relapse in Patients with Cervical Cancer.

PURPOSE: Almost all cervical cancers are caused by human papillomavirus (HPV) and patients with advanced stage are at high risk for relapse. Circulating HPV DNA (HPV ctDNA) may serve as a residual tumor marker at the end of chemoradiation or to predict relapse during the follow-up period. EXPERIMENTAL DESIGN: We analyzed serum samples from 94 HPV16- or HPV18-related CCs from the BioRAIDs prospective cohort. Samples were collected before and after treatment and during an 18-month follow-up period. Using digital droplet PCR (ddPCR), we assessed the relevance of circulating HPV E7 gene as a marker for residual disease compared to HPV integration site and PIK3CA mutations. Finally, the prognostic impact of circulating HPV E7 gene was assessed with its prediction value of relapse. RESULTS: HPV E7 gene was the most sensitive tumor marker, superior to both HPV integration sites and PIK3CA mutations in serum. Circulating HPV DNA (HPV ctDNA) was detected in 63% (59/94) of patients, before treatment. HPV ctDNA detection in serum sample was associated with high FIGO stage (P = 0.02) and para-aortic lymph node involvement (P = 0.01). The level of HPV ctDNA was positively correlated with HPV copy number in the tumor (R = 0.39, P < 0.001). Complete clearance of HPV ctDNA by the end of treatment was significantly associated with a longer PFS (P < 0.0001). Patients with persistent HPV ctDNA in serum relapsed with a median time of 10 months (range, 2-15) from HPV ctDNA detection. CONCLUSIONS: HPV ctDNA detection is a useful marker to predict relapse in cervical cancer.See related commentary by Wentzensen and Clarke, p. 5733.

Has tumor doubling time in breast cancer changed over the past 80 years? A systematic review.

Over the past century, epidemiologic changes and implementation of screening may have had an impact on tumor doubling time in breast cancer. Our study was designed to evaluate changes in tumor doubling time in breast cancer over the past 80 years. A systematic review of published literature and meta-regression analysis was performed. An online electronic database search was undertaken using the PubMed platform from inception until June 2020. All studies that measured tumor doubling time in breast cancer were included. A total of 151 publications were retrieved. Among them, 16 full-text articles were included in the qualitative analysis. An exponential growth model was used for quantitative characterization of tumor growth rate. Tumor doubling time has remained stable over the past 80 years. Recent studies have not only identified "fast growing tumor" (grade 3, human epidermal growth factor receptor 2-positive, triple-negative, or tumor with an elevated Ki-67) but also "inactive breast cancer" feeding the ongoing debate of overdiagnosis due to screening programs. The stability of tumor doubling time over the past 80 years, despite increasing and changing risk factors, supports the validity for our screening guidelines. Prospective studies based on more precise measurement of tumor size and adjustment for tumor characteristics are necessary to more clearly characterize the prognostic and predictive impact of tumor doubling time in breast cancer.

Antigen Mass May Influence Trastuzumab Concentrations in Cerebrospinal Fluid After Intrathecal Administration.

Intravenous administration of monoclonal antibodies leads to low concentrations in the central nervous system, which is a serious concern in neuro-oncology, especially in leptomeningeal carcinomatosis of HER2-overexpressing breast cancer. Case reports of i.t. administrations of trastuzumab have shown promising results in these patients but dosing regimens are empirical in absence of pharmacokinetic (PK) study. With a population PK approach, we described the fate of trastuzumab after i.t. administration in 21 women included in a phase I-II clinical trial. Trastuzumab was administered by i.t. route every week for 8 weeks and both cerebrospinal fluid (CSF) and serum were sampled to measure trough concentrations. Some patients showed noticeable CSF concentration fluctuations predicted using a target-mediated drug disposition. This target was latent and produced with a delayed feedback. Apparent volumes of distribution were close to physiological volumes (V1  = 3.25 L, V2  = 0.644 L, for serum and CSF, respectively). Estimated (constant) transfer from serum to CSF was very slow (k12  = 0.264 mg/day) whereas estimated half-life of transfer from CSF to serum was rapid (2.2 days). From the individual parameters of patients, a single i.t. administration of 150 mg of trastuzumab corresponded to median mean residence times of 3.8 days and 15.6 days in CSF and serum, respectively. Survival without neurological relapse was not related to trastuzumab exposure. This study confirms that transfer of trastuzumab from serum to CSF is very limited and that this monoclonal antibody, when administered by i.t. route, is rapidly transferred to the serum.

[Physical activity after breast cancer diagnosis and survival: A systematic review]. / Activité physique après diagnostic de cancer du sein et survie : revue de la littérature.

INTRODUCTION: The benefits of physical activity (PA) in breast cancer are currently recognized in primary prevention. The World Cancer Research Fund (WCRF) and then the National Cancer Institute (INCa) have reported conflicting results regarding the impact of post-diagnosis PA on breast cancer outcomes. The aim of this systematic review is to assess the association between PA after breast cancer diagnosis and overall mortality, specific mortality and risk of breast cancer recurrence in the literature. METHODS: Randomized trials, prospective cohorts and meta-analyses studying post-diagnosis PA and overall mortality, breast cancer mortality or risk of recurrence after breast cancer published between January 1, 2014 and October 1, 2019 were included. The articles selected by the INCa report prior to 2014 were included in the literature review. RESULTS: Eighteen articles have been selected. Studies unanimously concluded that overall mortality was reduced by post-diagnosis PA practice. For specific mortality, 5 meta-analyses showed a significant decrease in breast cancer mortality and 2 found a decrease in the risk of recurrence. CONCLUSION: Post-diagnosis PA reduces overall mortality and appears to impact specific breast cancer mortality and risk of recurrence. However, these results need to be confirmed by larger randomized trials.

A subset of activated fibroblasts is associated with distant relapse in early luminal breast cancer.

BACKGROUND: Early luminal breast cancer (BC) represents 70% of newly diagnosed BC cases. Among them, small (under 2 cm) BC without lymph node metastasis (classified as T1N0) have been rarely studied, as their prognosis is generally favorable. Nevertheless, up to 5% of luminal T1N0 BC patients relapse with distant metastases that ultimately prove fatal. The aim of our work was to identify the mechanisms involved in metastatic recurrence in these patients. METHODS: Our study addresses the role that autonomous and non-autonomous tumor cell features play with regard to distant recurrence in early luminal BC patients. We created a cohort of T1N0 luminal BC patients (tumors between 0.5-2 cm without lymph node metastasis) with metastatic recurrence ("cases") and corresponding "controls" (without relapse) matched 1:1 on main prognostic factors: age, grade, and proliferation. We deciphered different characteristics of cancer cells and their tumor micro-environment (TME) by deep analyses using immunohistochemistry. We performed in vitro functional assays and highlighted a new mechanism of cooperation between cancer cells and one particular subset of cancer-associated fibroblasts (CAF). RESULTS: We found that specific TME features are indicative of relapse in early luminal BC. Indeed, quantitative histological analyses reveal that "cases" are characterized by significant accumulation of a particular CAF subset (CAF-S1) and decrease in CD4+ T lymphocytes, without any other association with immune cells. In multivariate analysis, TME features, in particular CAF-S1 enrichment, remain significantly associated with recurrence, thereby demonstrating their clinical relevance. Finally, by performing functional analyses, we demonstrated that CAF-S1 pro-metastatic activity is mediated by the CDH11/osteoblast cadherin, consistent with bones being a major site of metastases in luminal BC patients. CONCLUSIONS: This study shows that distant recurrence in T1N0 BC is strongly associated with the presence of CAF-S1 fibroblasts. Moreover, we identify CDH11 as a key player in CAF-S1-mediated pro-metastatic activity. This is independent of tumor cells and represents a new prognostic factor. These results could assist clinicians in identifying luminal BC patients with high risk of relapse. Targeted therapies against CAF-S1 using anti-FAP antibody or CDH11-targeting compounds might help in preventing relapse for such patients with activated stroma.

Single-Cell Analysis Reveals Fibroblast Clusters Linked to Immunotherapy Resistance in Cancer.

A subset of cancer-associated fibroblasts (FAP+/CAF-S1) mediates immunosuppression in breast cancers, but its heterogeneity and its impact on immunotherapy response remain unknown. Here, we identify 8 CAF-S1 clusters by analyzing more than 19,000 single CAF-S1 fibroblasts from breast cancer. We validate the five most abundant clusters by flow cytometry and in silico analyses in other cancer types, highlighting their relevance. Myofibroblasts from clusters 0 and 3, characterized by extracellular matrix proteins and TGFß signaling, respectively, are indicative of primary resistance to immunotherapies. Cluster 0/ecm-myCAF upregulates PD-1 and CTLA4 protein levels in regulatory T lymphocytes (Tregs), which, in turn, increases CAF-S1 cluster 3/TGFß-myCAF cellular content. Thus, our study highlights a positive feedback loop between specific CAF-S1 clusters and Tregs and uncovers their role in immunotherapy resistance. SIGNIFICANCE: Our work provides a significant advance in characterizing and understanding FAP+ CAF in cancer. We reached a high resolution at single-cell level, which enabled us to identify specific clusters associated with immunosuppression and immunotherapy resistance. Identification of cluster-specific signatures paves the way for therapeutic options in combination with immunotherapies.This article is highlighted in the In This Issue feature, p. 1241.

Clinical Interest of Combining Transcriptomic and Genomic Signatures in High-Grade Serous Ovarian Cancer.

High-grade serous ovarian cancer is one of the deadliest gynecological malignancies and remains a clinical challenge. There is a critical need to effectively define patient stratification in a clinical setting. In this study, we address this question and determine the optimal number of molecular subgroups for ovarian cancer patients. By studying several independent patient cohorts, we observed that classifying high-grade serous ovarian tumors into four molecular subgroups using a transcriptomic-based approach did not reproducibly predict patient survival. In contrast, classifying these tumors into only two molecular subgroups, fibrosis and non-fibrosis, could reliably inform on patient survival. In addition, we found complementarity between transcriptomic data and the genomic signature for homologous recombination deficiency (HRD) that helped in defining prognosis of ovarian cancer patients. We also established that the transcriptomic and genomic signatures underlined independent biological processes and defined four different risk populations. Thus, combining genomic and transcriptomic information appears as the most appropriate stratification method to reliably subgroup high-grade serous ovarian cancer patients. This method can easily be transferred into the clinical setting.