TEDOVA: vaccine OSE2101 +/- pembrolizumab as maintenance in platinum-sensitive recurrent ovarian cancer.

Ovarian cancer is a leading cause of death from gynecological cancers worldwide. Platinum-based chemotherapy provides the cornerstone of the medical management. In first line and subsequent relapses, maintenance strategies are offered to prolong intervals between lines of chemotherapy. Current maintenance options involve bevacizumab and poly ADP-ribose polymerase inhibitors, but these lines of therapy can only be used once in the disease course. Patients in first or second platinum sensitive relapse after poly ADP-ribose polymerase inhibitors and bevacizumab represent an area of unmet medical need. This academic sponsored, international Phase II randomized trial is evaluating the combination of a therapeutic cancer vaccine (OSE2101) with anti-PD1 (pembrolizumab) as maintenance therapy, in patients with platinum-sensitive recurrence regardless of number of prior lines and no progression after platinum-based chemotherapy.Clinical Trial Registration: NCT04713514 (ClinicalTrials.gov).

Ongoing Phase II study randomizing vaccine OSE2101 +/- Pembrolizumab vs supportive care as maintenance in platinum-sensitive recurrent ovarian cancer.

CDK 4/6 inhibitor successful rechallenge after limiting hepatic toxicity.

A 59-year-old woman presented with a bone-only metastatic luminal breast cancer. She received first-line treatment with aromatase inhibitors associated with a cyclin-dependent kinase (CDK) 4/6 inhibitor, ribociclib. She developed Grade 3 elevated transaminases leading us to interrupt ribociclib permanently. Specific toxicity of the CDK 4/6 inhibitor ribociclib was retained. Once transaminase levels normalized, the patient initiated another CDK4/6 inhibitor, palbociclib, using an escalating dose without reappearance of hepatic injury. This case suggests the possibility of rechallenge after hepatic toxicity with a different CDK 4/6 inhibitor using dose escalation and careful monitoring.

Molecular apocrine tumours in EORTC 10994/BIG 1-00 phase III study: pathological response after neoadjuvant chemotherapy and clinical outcomes.

BACKGROUND: We explored, within the EORTC10994 study, the outcomes for patients with molecular apocrine (MA) breast cancer, and defined immunohistochemistry (IHC) as androgen-receptor (AR) positive, oestrogen (ER) and progesterone (PR) negative. We also assessed the concordance between IHC and gene expression arrays (GEA) in the identification of MA cancers. METHODS: Centrally assessed biopsies for AR, ER, PR, HER2 and Ki67 by IHC were classified into six subtypes: MA, triple-negative (TN) basal-like, luminal A, luminal B HER2 negative, luminal B HER2 positive and "other". The two main objectives were the pCR rates and survival outcomes in the overall MA subtype (and further divided by HER2 status) and the remaining five subtypes. RESULTS: IHC subtyping was obtained in 846 eligible patients. Ninety-three (11%) tumours were classified as the MA subtype. Both IHC and GEA data were available for 64 patients. In this subset, IHC concordance was 88.3% in identifying MA tumours compared with GEA. Within the MA subtype, pCR was observed in 33.3% of the patients (95% CI: 29.4-43.9) and the 5-year recurrence-free interval was 59.2% (95% CI: 48.2-68.6). Patients with MA and TN basal-like tumours have lower survival outcomes. CONCLUSIONS: Irrespective of their HER2 status, the prognosis for MA tumours remains poor and adjuvant trials evaluating anti-androgens should be considered.

Sarcoidosis-like reaction in metastatic triple negative breast cancer treated by anti-PD-L1.

We report the first case of sarcoidosis-like reaction in a patient treated by anti-PD-L1 for a breast cancer. A 69-year-old woman presented with a histologically confirmed lung metastasis of a triple negative breast cancer. She was treated by nab-paclitaxel plus anti-PD-L1 in first line. After 2 months, a dramatic lung response was noticed but an involvement of mediastinal lymph nodes appeared. Endoscopic ultrasound-guided fine-needle aspiration of these lymph nodes revealed multiple epitheloid granulomas without caseating necrosis in favour of a sarcoidosis-like reaction. The patient remained free of symptom and in complete lung response on anti-PD-L1 treatment as a maintenance therapy.

The mammary ducts create a favourable microenvironment for xenografting of luminal and molecular apocrine breast tumours.

There is a paucity of models for hormone receptor-positive (HR+) breast cancer because of the difficulty of establishing xenografts from these tumours. We show that this obstacle can be overcome by injecting human tumour cells directly into the mammary ducts of immunodeficient mice. Tumours from 31 patients were infected overnight with a lentiviral vector expressing tdTomato and injected through the nipple into the mammary ducts of NOD-SCID-IL2RG-/- mice. Tumours formed in the mice in 77% of cases after the first injection (6/8 luminal A, 15/20 luminal B, and 3/3 molecular apocrine). Four luminal A and one molecular apocrine graft were tested in secondary and tertiary grafts: all were successfully passaged in secondary and 4/5 in tertiary grafts. None of the samples engrafted when injected subcutaneously. The morphology, oestrogen receptor (ER), progesterone receptor (PR), androgen receptor (AR), and Ki-67 profiles of the clinical samples were maintained in the tertiary grafts. We also show that the intraductal approach can be used to test the response to targeted therapy with fulvestrant and palbociclib, using a genetically defined ER+ model. We conclude that the mammary ducts create a microenvironment that is uniquely favourable to the survival and growth of tumours derived from mammary hormone-sensing cells. This approach opens the door to testing genomically targeted treatment of HR+ tumours in precision medicine programmes. Copyright © 2016 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

PRognostic factor of Early Death In phase II Trials or the end of 'sufficient life expectancy' as an inclusion criterion? (PREDIT model).

BACKGROUND: Optimizing patient selection is a necessary step to design better clinical trials. 'Life expectancy' is a frequent inclusion criterion in phase II trial protocols, a measure that is subjective and often difficult to estimate. The aim of this study was to identify factors associated with early death in patients included in phase II studies. METHODS: We retrospectively collected medical records of patients with advanced solid tumors included in phase II trials in two French Comprehensive Cancer Centers (Bordeaux, Center 1 set; Lille, Center 2 set). We analyzed patients' baseline characteristics. Predictive factors associated with early death (mortality at 3 months) were identified by logistic regression. We built a model (PREDIT, PRognostic factor of Early Death In phase II Trials) based on prognostic factors isolated from the final multivariate model. RESULTS: Center 1 and 2 sets included 303 and 227 patients, respectively. Patients from Center 1 and 2 sets differed in tumor site, urological (26 % vs 15 %) and gastrointestinal (18 % vs 28 %) and in lung metastasis incidence (10 % vs 49 %). Overall survival (OS) at 3 months was 88 % (95 % CI [83.5; 91.0], Center 1 set) and 91 % (95 % CI [86.7; 94.2], Center 2 set). Presence of a 'life expectancy' inclusion criterion did not improve the 3-month OS (HR 0.6, 95 % CI [0.2; 1.2], p = 0.2325). Independent factors of early death were an ECOG score of 2 (OR 13.3, 95%CI [4.1; 43.4]), hyperleukocytosis (OR 5.5, 95 % CI [1.9; 16.3]) and anemia (OR 2.8, 95 % CI [1.1; 7.1]). Same predictive factors but with different association levels were found in the Center 2 set. Using the Center 1 set, ROC analysis shows a good discrimination to predict early death (AUC: 0.89 at 3 months and 0.86 at 6 months). CONCLUSIONS: Risk modeling in two independent cancer populations based on simple clinical parameters showed that baseline ECOG of 2, hyperleukocytosis and anemia are strong early-death predictive factors. This model allows identifying patients who may not benefit from a phase II trial investigational drug and may, therefore, represent a helpful tool to select patients for phase II trial entry.

PRIMA-1(MET) induces death in soft-tissue sarcomas cell independent of p53.

BACKGROUND: The aim of this study was to explore the efficacy and define mechanisms of action of PRIMA-1(MET) as a TP53 targeted therapy in soft-tissue sarcoma (STS) cells. METHODS: We investigated effects of PRIMA-1(MET) on apoptosis, cell cycle, and induction of oxidative stress and autophagy in a panel of 6 STS cell lines with different TP53 status. RESULTS: Cell viability reduction by PRIMA-1(MET) was significantly observed in 5 out of 6 STS cell lines. We found that PRIMA-1(MET) was capable to induce cell death not only in STS cells harboring mutated TP53 but also in TP53-null STS cells demonstrating that PRIMA-1(MET) can induce cell death independently of TP53 in STS cells. We identified an important role of reactive oxygen species (ROS), involved in PRIMA-1(MET) toxicity in STS cells leading to a caspase-independent cell death. ROS toxicity was associated with autophagy induction or JNK pathway activation which represented potential mechanisms of cell death induced by PRIMA-1(MET) in STS. CONCLUSIONS: PRIMA-1(MET) anti-tumor activity in STS partly results from off-target effects involving ROS toxicity and do not deserve further development as a TP53-targeted therapy in this setting.

Efficacy of antiandrogens in androgen receptor-positive triple-negative metastatic breast cancer: Real-life data.

Antiandrogens (AA) have been tested in clinical trials in androgen receptor (AR) + triple-negative breast cancer (TNBC). We aim to assess the clinical benefit rate (CBR) of AA in real life. The primary end-point was CBR at 6 months. Twenty-four patients were assessable and received: abiraterone acetate (62 %), enzalutamide (8 %) and bicalutamide (30 %). CBR at 6 months was 29 % (7/24) with 2 CR, 3 PR and 2 SD. Four patients had a clinical benefit >12 months. Real-life efficacy of AA use in metastatic AR + TNBC are in line with data from published trials.

Health literacy and the use of digital tools in older patients with cancer and their younger counterparts: A multicenter, nationwide study.

OBJECTIVES: To evaluate health literacy (HL), assess the use of digital tools/sources, and identify factors associated with low or moderate HL in older (aged ≥65) and younger (18-64) patients with cancer. METHODS: A cross-sectional multicenter study including patients with cancer was conducted in 26 centers in France. HL was assessed using the Functional, Communicative and Critical Health Literacy (FCCHL) scale. Factors associated with low/moderate HL (score

Implementation of a remote symptom monitoring pathway in oncology care: analysis of real-world experience across 33 cancer centres in France and Belgium.

Background: Remote patient monitoring (RPM) of symptoms using electronic patient reported outcomes (ePROs) has been shown to reduce symptom burden and hospitalizations, increase dose intensity and improve quality of life of patients during systemic therapy being recommended by international guidelines in routine oncology practice. However, implementation in routine care has been slow and faces several challenges. In this study we report on the real-world multi-center implementation of a RPM pathway encompassing weekly patient symptom ePRO reporting with electronic alert notifications triggered to providers for severe or worsening symptoms. Methods: An RPM pathway was implemented in 33 European cancer centers in France and Belgium between November 2021 and August 2023. The implementation process followed a standardized phasic process of Exploration, Preparation, Implementation and Sustainment. Patient-level and system-level implementation metrics were collected and evaluated according to the Reach, Effectiveness, Adoption, Implementation and Maintenance (RE-AIM) framework. Findings: Across the 33 cancer centers, the RPM pathway was implemented for 3015 patients cared for by 168 providers. The RPM pathway enabled effective and timely symptom management with 94.6% of all alerts (10,132/10,711) evolving to an improvement two weeks later, among which 88.4% (9468/10,711) showed ≥2 grades of improvement on the 5-point scale of the Patient-Reported Outcomes Common Terminology (PRO-CTCAE). The median time to alert management by the care team was 13 h 41 min (25th percentile: 1 h 42 min, 75th percentile: 1 day + 19 h 54 min), with 80% (36,269/45,334) of alerts managed by a nurse navigator telephone call. Patient adherence with weekly ePRO reporting was 82% (2472/3015). In an experience survey, 87% (32/38) of providers were satisfied with integrating the solution into their organization and 90% (276/307) of the patients felt that ePRO reporting positively impacted their care. As of March 2024, the pathway has been maintained in all participating centers, with activation of an additional 18 centers following data lock, and reimbursement for this RPM pathway approved in France in October 2023. Interpretation: These findings demonstrate the feasibility of implementing and maintaining an RPM pathway during routine care across a diverse group of cancer centers in the European setting, with high levels of patient and provider engagement, and positive clinical impact. Funding: Part of this work was funded Breast Cancer Research Foundation (Career Development Award to Maria Alice Franzoi) and Resilience (nurse navigation and technology support).

Angiosarcoma associated with a Kasabach-Merritt syndrome: report of two cases treated with paclitaxel.

Angiosarcomas are rare, aggressive vascular malignancies of endothelial cell differentiation. Kasabach-Merritt syndrome is a rare condition defined by the association of thrombocytopenia and consumption coagulopathy with specific vascular tumors, such as tufted angioma or kaposiform hemangioendothelioma. We report here two cases of angiosarcomas complicated by a Kasabach-Merritt syndrome and their outcome after treatment with paclitaxel.

[Therapeutic strategies for the treatment of endocrine resistant hormone receptor positive advanced breast cancer]. / Stratégies pour la prise en charge des cancers du sein métastatiques récepteurs hormonaux positifs hormonorésistants.

HR+ breast cancers are defined by the prominence of signaling pathways dependent on the estrogen receptor. Endocrine therapy is the standard treatment for these advanced diseases. Resistance to these treatments, called hormone resistance, appears invariably with biological mechanisms that have led to the development of therapeutic opportunities. An exhaustive literature review was carried out concerning the biology of the hormone resistance pathways, the therapeutic options before the era of CDK4/6 inhibitors, the rise of CDK4/6 inhibitors and the therapeutic prospects in a situation of hormone resistance. Various biological abnormalities have been identified in the mechanisms of hormone resistance such as changes in the estrogen receptor, mutations in the ESR1 gene, aberrant activation of the PI3K pathway or cell cycle deregulations. Historical strategies for circumventing this hormone resistance have been based on hormonal manipulation, on the development of new endocrine therapy such as fulvestrant (selective estrogen receptor inhibitor, SERD), on combinations of treatments such as everolimus, a mTOR inhibitor. This strategy combining endocrine therapy and targeted therapy has led to the development of combinations with CDK4/6 inhibitors which have now become a standard treatment in the hormone resistance phase. The future of this therapeutic era remains to be written with new combinations of hormone therapy and targeted therapy such as PI3K inhibitors or even with the positioning of new SERDs in clinical development.

Prognostic Value of Routinely Measured Inflammatory Biomarkers in Older Cancer Patients: Pooled Analysis of Three Cohorts.

BACKGROUND: The prognostic assessment of older cancer patients is complicated by their heterogeneity. We aimed to assess the prognostic value of routine inflammatory biomarkers. METHODS: A pooled analysis of prospective multicenter cohorts of cancer patients aged ≥70 was performed. We measured CRP and albumin, and calculated Glasgow Prognostic Score (GPS) and CRP/albumin ratio. The GPS has three levels (0 = CRP ≤ 10 mg/L, albumin ≥ 35 g/L, i.e., normal values; 1 = one abnormal value; 2 = two abnormal values). One-year mortality was assessed using Cox models. Discriminative power was assessed using Harrell's C index (C) and net reclassification improvement (NRI). RESULTS: Overall, 1800 patients were analyzed (mean age: 79 ± 6; males: 62%; metastases: 38%). The GPS and CRP/albumin ratio were independently associated with mortality in patients not at risk of frailty (hazard ratio [95% confidence interval] = 4.48 [2.03-9.89] for GPS1, 11.64 [4.54-29.81] for GPS2, and 7.15 [3.22-15.90] for CRP/albumin ratio > 0.215) and in patients at risk of frailty (2.45 [1.79-3.34] for GPS1, 3.97 [2.93-5.37] for GPS2, and 2.81 [2.17-3.65] for CRP/albumin ratio > 0.215). The discriminative power of the baseline clinical model (C = 0.82 [0.80-0.83]) was increased by adding GPS (C = 0.84 [0.82-0.85]; NRI events (NRI+) = 10% [2-16]) and CRP/albumin ratio (C = 0.83 [0.82-0.85]; NRI+ = 14% [2-17]). CONCLUSIONS: Routine inflammatory biomarkers add prognostic value to clinical factors in older cancer patients.

[Androgen receptor-positive triple negative breast cancer: From biology to therapy]. / Cancer du sein triple négatif exprimant le récepteur aux androgènes : de la biologie à la thérapeutique.

A subgroup of androgen receptor-expressing tumors represents approximately 30 % of all triple negative tumors. The androgen receptor and its signaling pathways have a central biological role in this tumor entity. These triple negative androgen receptor-positive tumors occur in older patients and do not appear to have a better prognosis compared to other triple negative tumors. In addition to androgen receptor-expression, these tumors are genomically characterized by a high frequency of PIK3CA activating mutation. Three clinical trials reported efficacy data for anti-androgens (bicalutamide, abiraterone acetate and enzalutamide) based on strong preclinical rationale. These trials report clinical benefit rates in about one in five patients. These encouraging but still limited results make a case for the identification of predictive response factors and therapeutic combinations to improve response rates. This review will provide an update on the biological and clinical knowledge of this tumoral subgroup that opens the way to non-cytotoxic anti-androgen therapies.

From palliative to curative intent: PET/CT findings in the light of breast cancer intrinsic subgroup.

PURPOSE: Among breast cancer subgroups, Luminal A is the subgroup with the best prognosis. We report the case of a young woman presenting with a localized luminal A breast cancer with a suspicious liver lesion on initial positron emission tomography (PET)/computed tomography (CT) scan staging. CASE DESCRIPTION: A 31-year-old woman presented with localized breast cancer accessible to curative treatment. However, PET/CT staging revealed an increase of focal activity in the liver, suspicious of a secondary malignant localization, changing the care towards palliative intent. Discrepancy between breast cancer luminal A subtype and the liver lesion led to further investigations (contrast ultrasound, magnetic resonance imaging, and biopsy), excluding a malignant process, and were in favor of toxic hepatitis, probably secondary to herbal tea consumption. CONCLUSIONS: Questioning PET/CT findings in light of the cancer subtype enabled us to rectify the diagnosis and allow this patient to be treated with curative intent.

Enhancing Abiraterone Acetate Efficacy in Androgen Receptor-positive Triple-negative Breast Cancer: Chk1 as a Potential Target.

PURPOSE: Our aim was to identify predictive factors of abiraterone acetate efficacy and putative new druggable targets in androgen receptor (AR)-positive triple-negative breast cancer (TNBC) treated in the UCBG 2012-1 trial.Experimental Design: We defined abiraterone acetate response as either complete or partial response, or stable disease at 6 months. We sequenced 91 general and breast cancer-associated genes from the tumor DNA samples. We analyzed transcriptomes from the extracted RNA samples on a NanoString platform and performed IHC using tissue microarrays. We assessed abiraterone acetate and Chk1 inhibitors (GDC-0575 and AZD7762) efficacies, either alone or in combination, on cell lines grown in vitro and in vivo. RESULTS: Classic IHC apocrine markers including AR, FOXA1, GGT1, and GCDFP15, from patients' tumors allowed identifying abiraterone acetate-responders and nonresponders. All responders had clear apocrine features. Transcriptome analysis revealed that 31 genes were differentially expressed in the two subgroups, 9 of them being linked to proliferation and DNA damage repair. One of the most significant differences was the overexpression, in nonresponders, of CHEK1, a gene encoding Chk1, a protein kinase that can be blocked by specific inhibitors. On the basis of cell line experiments, abiraterone acetate and Chk1 inhibitor combination showed at least additive effect on cell viability, cell cycle, apoptosis, and accumulation of DNA damages. In vivo, orthotopic xenograft experiments confirmed the efficacy of this combination therapy. CONCLUSIONS: This study suggests that apocrine features can be helpful in the identification of abiraterone acetate-responders. We identified Chk1 as a putative drug target in AR-positive TNBCs.

SOX10, GATA3, GCDFP15, Androgen Receptor, and Mammaglobin for the Differential Diagnosis Between Triple-negative Breast Cancer and TTF1-negative Lung Adenocarcinoma.

Triple-negative breast cancer (TNBC) patients have an increased risk of developing visceral metastases and other primary nonbreast cancers, particularly lung cancer. The differential diagnosis of TNBC metastases and primary cancers from other organs can be difficult due to lack of a TNBC standard immunoprofile. We analyzed the diagnostic value of estrogen receptor, progesterone receptor, human epidermal growth factor receptor, thyroid transcription factor-1 (TTF1), Napsin A, mammaglobin, gross cystic disease fluid protein 15 (GCDFP15), Sry-related HMg-Box gene 10 (SOX10), GATA-binding protein 3 (GATA3), and androgen receptor in a series of 207 TNBC and 152 primary lung adenocarcinomas (LA). All tested TNBCs were TTF1 and Napsin A-negative. When comparing TNBC and TTF1-positive or negative LA, SOX10 had the best sensitivity (62.3%) and specificity (100%) as a marker in favor of TNBC compared with LA, irrespective of TTF1 status (P<0.0001). GATA3 had moderate sensitivity (30.4%) and excellent specificity (98.7%) and misclassified only 2/152 LA (1.3%). GCDFP15 had a moderate sensitivity (20.8%) and excellent specificity (98%) and misclassified only 3/152 (2%) LA. Mammaglobin and androgen receptor had moderate sensitivities (38.2% and 30%), good specificities (81.6% and 86%), and misclassified 28/152 and 21/152 LAs, respectively. In multivariate analysis, the best markers, enabling the distinction between SOX10-negative TNBC and TTF1 and Napsin A-negative LA were GATA3 (odds ratio=33.5; 95% confidence interval, 7.3-153.5; P<0.0001) and GCDFP15 (odds ratio=31.7; 95% confidence interval, 6.9-145.6; P<0.0001). Only 13/207 (6.3%) TNBC cases did not express any aforementioned marker. On the basis of our results, the best sequential immunohistochemical analysis to differentiate TNBC from TTF1-negative LA is first SOX10 followed by GATA3, and finally GCDFP15. This order is important in the diagnostic workup of small biopsies from lung nodules in women with a previous history of TNBC.