[What is the cross-disciplinary pathway for a patient receiving gene therapy?] / Quel parcours transversal pour un patient recevant une thérapie génique ?

The Department of Hematology-Immunology, headed by Professor Jean-Hugues Dalle, is the leading department in France for the care of patients receiving pediatric hematopoietic stem cell transplants. Since 2018, it has been a "major player" in the development of innovative treatments, such as gene therapy. To date, it is the only care service in France, which offers this treatment to stop the neurodegenerative progression of two genetic diseases, in collaboration with the neuropediatric service of the Kremlin-Bicêtre hospital headed by Prof Kumaran Deiva, in conjunction with the national reference center for rare disaeses didicated to leucodystrophies. It is a complex care that requires all the actors a cooperation (parents-children-caregivers).

Efficacy of second-line chemotherapy or immune checkpoint inhibitors for patients with a prolonged objective response (≥ 6 months) after first-line therapy for recurrent or metastatic head and neck squamous cell carcinoma: a retrospective study.

BACKGROUND: Patients with recurrent or metastatic head and neck squamous cell carcinoma (R/M-HNSCC) have a poor prognosis and limited therapeutic options. Immune checkpoint inhibitors (ICIs) are effective in patients with tumor progression < 6 months following first-line, platinum-based chemotherapy (PBC), but data are missing for patients with progression ≥ 6 months after the last platinum dose. METHODS: Retrospective analysis (six French centers, 2008-2019) of all consecutive R/M-HNSCC patients. treated first-line with PBC and tumor progression ≥ 6 months after the last platinum dose. PRIMARY ENDPOINT: progression-free survival after second-line therapy (PFS2). Additional endpoints: overall survival from Day 1 of first-line (OS1) and second-line (OS2) therapy. RESULTS: R/M-HNSCC patients (n = 144) received cisplatinum (n = 67, 47%) or carboplatinum (n = 77, 53%) first-line. Response after first-line: complete response (CR; n = 16, 11%); partial response (PR; n = 77, 53%); stable disease (n = 22, 15%). Second-line therapy: PBC (n = 95, 66%); platinum-free regimen (PFR) (n = 25, 17%); ICI (n = 24, 17%). Median [95% confidence interval] PFS (months): PBC 5.0 [3.8-6.2]; PFR 4.0 [1-7.0]; ICI 2.0 [0.4-3.6] (p = 0.16). For PBC, PFR, and ICI, respectively: OS1 30, 23, and 29 months (p = 1.02); OS2 14, 10, and 16 months (p = 0.25); PR, 26%, 16%, and 21% patients; CR, 0%, 8%, and 4% patients. For subsequent lines, ICIs were administered for PBC (n = 11, 12%) and PFR (n = 2, 8%). No predictive factor for efficacy (PFS, OS) was identified. CONCLUSIONS: Our retrospective study suggests similar efficacy regarding OS2 for second-line chemotherapy or ICI in R/M-HNSCC patients with progression ≥ 6 months after the last first-line platinum dose.

Prognosis of triple-negative breast cancer associated with pregnancy: A propensity score-matched analysis from the French CALG (Cancer Associé à la Grossesse) network.

INTRODUCTION: Triple-negative (TN) breast cancer represents one third of pregnancy-associated breast cancers (PABC). The aims of the current study were to describe oncological and obstetrical outcomes of patients with TN-PABC and to compare their prognosis with TN-non-PABC patients using a propensity score. MATERIALS AND METHODS: Between January 2005 and December 2020, data of patients with histologically proven TN-PABC were collected and compared with data of TN-non-PABC patients under the age of 46 years diagnosed during the same period using a propensity score (PS). RESULTS: After PS matching (tumor size and lymph node involvement),there were 59 patients in each group. The median follow-up was 14 months (IQR 4.8-40.1) for the TN-PABC group and 60 months (IQR 30.7-101.4) for the TN-non-PABC group. Eight recurrences occurred in the TN-PABC group and 10 in the TN-non-PABC group (adjusted OR (AOR) = 0.60 (0.21-1.60), HR (Cox adjusted model- AHR) = 1.25 (0.53-2.94)). Two patients died in the TN-PABC group, and six in the TN-non-PABC group with an AOR = 0.23 (0.03-1.01) and an AHR = 0.58 (0.12-2.69). All the patients diagnosed during the second (n = 17) and third trimesters (n = 28) continued their pregnancies, with a median term at delivery of 38 WG (IQR 36-39). All patients gave birth to healthy newborns. CONCLUSION: Although the TN subtype is associated with poor prognosis in pregnant patients due to advanced stage at diagnosis and high lymph node involvement, our PS-matched case-control study showed that pregnancy per se does not worsen the prognosis in terms of recurrence-free and overall survival.

Feasibility, Safety and Impact of (18F)-FDG PET/CT in patients with pregnancy-associated cancer: experience of the French CALG (Cancer Associé à La Grossesse) network.

BACKGROUND: The incidence of pregnancy-associated cancers has been increasing for decades. (18F)-FDG Positron Emission Tomography (PET)/Computed Tomography (CT) imaging has become a golden standard in the staging of many malignant diseases. The aims of the current study were to evaluate the feasibility, safety and impact of (18F)-FDG PET/CT performed during pregnancy. MATERIAL AND METHODS: A retrospective analysis from the prospective database of the Cancer Associé à La Grossesse (CALG) network (Tenon Hospital, France) including patients who underwent (18F)-FDG PET/CT during their pregnancy between 2015 and 2020. RESULTS: Of the 536 patients for whom advice from the CALG network was requested during the study period, 359 were diagnosed with cancer during pregnancy. Study population was composed of 63 (17.5%) patients who underwent (18F)-FDG PET/CT. Most cancers were diagnosed during the second trimester. Seventy-five percent were diagnosed with breast cancer, mostly locally advanced invasive ductal carcinomas. Median term of pregnancy at PET/CT was 24.8 weeks of gestation. Twelve (19%), 24 (38.1%) and 22 (34.9%) patients underwent the exam during the 1st, 2nd and 3rd trimester, respectively. (18F)-FDG PET/CT resulted in stage modification for 38 (60.3%) of the patients (28 with more extensive lymph node involvement and 10 with metastatic disease) with subsequently/accordingly modified first-line medical treatment. Fifty patients gave birth to healthy newborns. Two patients had a medical termination of pregnancy, five had a medical abortion, one neonatal death occurred in a patient with severe preeclampsia (unrelated to (18F)-FDG PET/CT). The data of 46 children were available at 6 months, 29 at 12 months, and 15 at 24 months. No cases of mental retardation, childhood cancer, or malformation were reported within 2 years. CONCLUSION: (18F)-FDG PET/CT has a major impact on the management of pregnancy-associated cancers and does not appear to cause fetal side effects suggesting that the exam is feasible during pregnancy as maternal benefits outweigh fetal risks.

Predicting the likelihood of recurrence of pregnancy-associated breast cancer: Nomogram based on analysis of the French cancer network: Cancer Associé à La Grossesse.

OBJECTIVE: Pregnancy associated breast cancer (PABC) are defined as breast cancer diagnosed during pregnancy and during the year following delivery. The prediction of poor prognosis events (PPE) such as recurrence is a major medical challenge of management for women with PABC. The aim of this study was to build a nomogram based on selected clinical and histological variables to predict recurrence. STUDY DESIGN: This retrospective study included 96 patients with PABC from January 2002 to January 2018. A multivariate Cox analysis of selected risk factors was performed and a nomogram to predict recurrence was built. The nomogram was internally validated. RESULTS: The overall recurrence rate was 22% (21/95) and the 3-years recurrence rate was 13% (12/95). Age at diagnosis, histological type, immuno-histological class, tumor stage (TNM), node stage (TNM) were associated with PPE in univariate analysis, and were included in the final Cox model to develop the nomogram. The predictive model had a concordance index of 0.83 (95% Confidence Interval (CI), 0.81-0.85) and 0.78 (95% CI, 0.76-0.80) before and after the 200 repetitions of bootstrap sample corrections, respectively, and showed a good calibration. CONCLUSION: Our results support the use of the present nomogram based on 5 clinical and pathological characteristics to predict PPE in PABC with a high concordance. External validation is required to recommend this nomogram in routine practice.

Prognosis of HER2-positive pregnancy-associated breast cancer: Analysis from the French CALG (Cancer Associé à La Grossesse) network.

INTRODUCTION: The prevalence of pregnancy-associated breast cancer is increasing. HER2-positive breast cancers typically have a poor prognosis. The objective of our study was to compare the prognosis of patients with HER2-positive breast cancer diagnosed during pregnancy (HER2-positive BCP) to young women diagnosed with HER2-positive breast cancer outside of pregnancy (HER2 non-BCP). METHODS: Data of patients managed for invasive breast carcinoma between January 2005 and 2020 were retrospectively collected from the database of Tenon University Hospital (Paris, France), part of the "Cancer lié à la Grossesse" network. RESULTS: Fifty-one patients with HER2-positive BCP were matched on age at diagnosis with 51 HER2-positive non-BCP patients. Locally advanced disease with axillary lymph node involvement were frequent. Tumors were frequently aggressive with high grade (p = 0.57) and high Ki67 (p = 0.15). Among the HER2-positive BCP patients, the mean term at diagnosis was 19.3 week of gestation (WG). Eighty-four percent of the patients continued their pregnancy with a mean term at delivery of 34.2WG. Chemotherapy modalities differed between the two groups: neoadjuvant chemotherapy was more frequent in the HER2-positive BCP group (p = 0.03) and adjuvant chemotherapy more frequent in the HER2 non-BCP group (p = 0.009). The recurrence rate was 10% (n = 5) and 18% (n = 9) in the HER2-positive BCP and HER2 non-BCP groups, respectively, p = 0.25. Breast cancer-free survival was poorer in the HER2-positive BCP group with earlier recurrence, p = 0.008. No difference in type of recurrence was found between the groups (p = 0.58). CONCLUSION: This matched case-control study implies that patients with HER2-positive BCP still have a poorer prognosis than non-pregnant HER-positive patients.

Utility of a mainstreamed genetic testing pathway in breast and ovarian cancer patients during the COVID-19 pandemic.

INTRODUCTION: Mainstreamed genetic testing (MGT) obviates the need for a cancer genetics consultation, since trained oncologists (O) and gynaecologists (G) provide counseling, prescribe testing and deliver results. We report results from our MGT program and emphasize its utility during the COVID-19 lockdown, when cancer genetics clinics had suspended their activity. METHODS: An MGT pathway for breast and ovarian cancer (BC/OC) patients was established in Jan-2018 between the Assistance Publique - Hôpitaux de Paris.Sorbonne Université Cancer Genetics team and the Oncology/Gynecology departments at one teaching and two regional hospitals. Trained O + G evaluated patients with the Manchester Scoring System. A 12-point threshold was recommended for testing. Next-generation sequencing of BRCA1, BRCA2, PALB2, RAD51C and RAD51D was performed. Results were delivered to the patient by O/G. Pathogenic variants (PV) carriers were referred to the genetics clinic. Results are reported for the 2nd-Jan-2018 to 1st-June-2020 period. That includes the eight-week COVID-19 lockdown and three-week de-confinement phase 1. RESULTS: Results were available for 231/234 patients. Twenty-eight (12.1%) carried a PV. Of the 27 patients tested during the COVID-19 period, three carried a PV, two in BRCA1 and one in RAD51C. The clinical impact was immediate for the two BRCA1 BC cases undergoing neo-adjuvant chemotherapy, since double mastectomy and salpingo-oophorectomy will now be performed using two-step strategies. CONCLUSIONS: MGT guaranteed care continuity in BC/OC patients during the critical phases of the COVID-19 pandemic, with immediate implications for PV carriers. More broadly, we report for the first time the successful implementation of MGT in France.

Behavioural inference from signal processing using animal-borne multi-sensor loggers: a novel solution to extend the knowledge of sea turtle ecology.

The identification of sea turtle behaviours is a prerequisite to predicting the activities and time-budget of these animals in their natural habitat over the long term. However, this is hampered by a lack of reliable methods that enable the detection and monitoring of certain key behaviours such as feeding. This study proposes a combined approach that automatically identifies the different behaviours of free-ranging sea turtles through the use of animal-borne multi-sensor recorders (accelerometer, gyroscope and time-depth recorder), validated by animal-borne video-recorder data. We show here that the combination of supervised learning algorithms and multi-signal analysis tools can provide accurate inferences of the behaviours expressed, including feeding and scratching behaviours that are of crucial ecological interest for sea turtles. Our procedure uses multi-sensor miniaturized loggers that can be deployed on free-ranging animals with minimal disturbance. It provides an easily adaptable and replicable approach for the long-term automatic identification of the different activities and determination of time-budgets in sea turtles. This approach should also be applicable to a broad range of other species and could significantly contribute to the conservation of endangered species by providing detailed knowledge of key animal activities such as feeding, travelling and resting.

[Lymph node management in endometrial cancer]. / Stratégies ganglionnaires dans les cancers de l'endomètre.

In 2018, around 382,100 new cases of endometrial cancer (EC) were reported worldwide, accounting for about 4.4% of all new cases of cancer in women. In France, in 2018, the EC is the first gynecological cancer in incidence and the fourth cancer in women. The rationale for the therapeutic management of EC is based on the estimation of a theoretical risk of recurrence and lymph node metastasis using MRI and preoperative biopsy criteria. However, lymph node status remains the determining factor of adjuvant treatment. In order to reduce the morbidity of lymphadenectomy, the concept of sentinel lymph node biopsy (SLN) has been developed. The SLN technique has evolved in recent years, thanks to the advent of robotics and the creation of fluorescence detection cameras. It has been shown that detection of SLN with Indocyanine Green (ICG) allows for more frequent bilateral migration of 88 to 100% and better detection of pelvic GS in 97% of cases with a decrease in morbidity. Recently, in view of the absence of a therapeutic role of lymph node staging, the operational risks and the delay of adjuvant treatments, in case of pelvic lymph node metastasis on definitive histological examination, the question of secondarily performing paraaortic lymphadenectomy arises. The SLN procedure, extended to all early-stage endometrial cancers, should lead to a major reduction in the use of secondary staging and better adaptation of adjuvant therapy.

[Metastatic stomach cancer: Clinical trials in Asia and in Occident]. / Cancer de l'estomac métastatique : les essais cliniques en Asie et en Occident.

Although cytotoxic chemotherapy is the main therapeutic option to treat gastric cancer in the metastatic setting, molecular targeted agents have recently been introduced in an effort to improve survival outcomes which in average do not exceed 1 year. Trastuzumab and ramucirumab, antibodies directed against HER2 and VEGFR2, respectively, may provide clinical benefit for some patients. Results of clinical studies show that Asian patients have increased survival compared to Caucasian patients. Differences between populations, and in particular the presence of polymorphisms capable of influencing the availability of fluorouracil, have been suggested as possible explanations. Other factors including histology, surgical procedures, administration of neoadjuvant chemotherapy in Western countries and screening programs in Asia have also been suggested. However, none of these elements can fully explain this phenomenon. The aim of this article is to present the main protocols used in clinical practice, the perspectives of metastatic gastric cancer treatment and the particularities observed in Asian and Caucasian patients.

Propensity score to evaluate prognosis in pregnancy-associated breast cancer: Analysis from a French cancer network.

PURPOSE: To compare the prognosis of pregnancy associated breast cancer occurring during pregnancy (BCP) to non-pregnancy associated breast cancers (non-BCP) in young women managed at a national expert center. METHODS: Retrospective cohort study of a prospective database using propensity score matching (PSM) analysis with known prognostic factors. RESULTS: We analyzed data of 49 patients with BCP and 104 with non-BCP diagnosed between 2002 and 2017 at Tenon University Hospital (Paris, France). The BCP tumors were often locally advanced (lymph node metastases in 59%), of high grade (55%) and highly proliferative (67% with Ki67 ≥ 20%). After PSM, breast cancer-free survival (p = 0.45) and breast cancer specific survival (p = 0.81) were similar in the two groups. The recurrence rate was 12% vs 18% (p = 0.45) and the death rate was 6% vs 8% (p = 0.74) for the BCP and non-BCP groups, respectively. No difference in recurrence type was observed between the groups (p = 0.60). CONCLUSIONS: After PSM for known prognostic factors, the prognosis of BCP patients did not differ from that of young patients with non-BCP.

Breast cancer metastasis to the spleen: a case report and literature review.

Splenic metastasis from cancers is extremely rare. They usually occur and are detected simultaneously with metastasis to other organs. We present a case of splenic metastasis from carcinoma of the breast occurring 5 years after initial treatment. The metastatic recurrence was an oligometastic form made from the association of a unique bone metastasis to a rib and the metastasis to the spleen. Treatment of the metastatic recurrence was a second line hormonotherapy as the primitive tumor was estrogen receptors positive and gave a 2 year's long control of the disease. A clinical progression occurred then, the patient complained from pain in the left hypochondrium and was objective on [18F]-FDG PET which leaded to splenectomy. This case is being reported because of the rarity of the lesion and its originality is the first reported case with use of an in vivo demonstration of estrogen receptors expression in the spleen metastasis using PET/CT with 16α-[18F]-Fluoroestradiol.

New anti-HER2 agents: from second-generation tyrosine kinases inhibitors to bifunctional antibodies.

PURPOSE OF REVIEW: HER2-positive breast cancers have benefited since the end of the twentieth century, not only from the improvement of biological knowledge, but also from major technological advances. The latter allowed the synthesis of the first generation of enzymatic inhibitors of the HER receptor family such as lapatinib, but above all, monoclonal antibodies such as trastuzumab or pertuzumab having profoundly modified the management of these cancers. However, despite outstanding progresses, there are still patients who are not cured with these first-generation treatments, and they will need new approaches to improve disease control and impact patients' survival. RECENT FINDINGS: Understanding the mechanisms of escape to these treatments, more than real resistance, has profoundly changed our pharmacological approaches. They have enabled the development of molecules blocking the signaling pathway downstream of receptors such as mTOR, PI3K inhibitors or molecules interacting with the cellular traffic of the receptor in combination with the first-generation treatments. In addition, new second-generation tyrosine kinase inhibitors have demonstrated increased in-vitro efficacy, but still need to show clinical relevance because of new toxicity profiles. The antibody engineering had also permitted a paradigm evolution of the role of the antibody treatments, particularly with the synthesis of bispecific and trifunctional antibodies, promoting the link between the tumor and the immune system, with the goal to amplify the immune anticancer response. SUMMARY: Among the new anti-HER2 agents, second-generation tyrosine kinase inhibitors and bifunctional antibodies are promising approaches that will help to improve disease control and curability of HER2-positive breast cancers.

Long-term complete response in a breast cancer patient with skeletal muscle metastases diagnosed using 18F-FDG-PET.

Common sites for metastatic spreading from breast cancer are bones, lungs and liver, the skeletal muscle being an unusual site. Although rare, when skeletal muscle metastases occur they are associated with a poor prognosis. These metastases are clinically difficult to diagnose since they can be found without pain symptoms. Radiologically, magnetic resonance imaging has been considered better than computed tomography for imaging of the muscles and has been the first procedure to use in case of muscle metastasis suspicion. In the last years, positron emission tomography (PET) with 18Fluorine-2-fluoro-2-deoxy-d-glucose (18F-FDG) has emerged as the main imaging tool. We here report a case of a hormone receptor-positive/human epidermal growth factor receptor 2-negative patient who presented with a recurrent infiltrating ductal carcinoma and diffuse skeletal muscle metastases detected by 18F-FDG-PET. The treatment of the patient with exemestane and everolimus led to a durable complete response.

High-Dose Chemotherapy for Adult-Type Ovarian Granulosa Cell Tumors: A Retrospective Study of the European Society for Blood and Marrow Transplantation.

OBJECTIVES: A few small retrospective series reported results with salvage chemotherapy for malignant ovarian adult-type granulosa cell tumors (GCTs), whereas no data are available on high-dose chemotherapy (HDC) with hematopoietic progenitor cell support (HSCS) in these patients. The aim of this study was to analyze the available data of HDC for adult-type GCTs. METHODS: We conducted a retrospective analysis of ovarian cancer treated with salvage HDC registered with the European Society for Blood and Marrow Transplantation. RESULTS: Of 203 adult female patients with a diagnosis of nonepithelial ovarian cancer treated with salvage HDC with HSCS and registered with the European Society for Blood and Marrow Transplantation, 4 (2%) patients were affected by GCTs. All 4 patients had ovarian adult-type GCTs that relapsed/progressed after first-line chemotherapy. The conditioning regimens included a platinum agent in all 4 patients. Bone marrow recovery was promptly achieved; neither treatment-related deaths or life-threatening toxicities occurred. At a median follow-up of 8.5 months, all patients reported a progressive disease. The patient who underwent multicycle HDC enjoyed a long-term remission of 84 months before progression and is the only one alive after 94+ months. CONCLUSIONS: We showed for the first time a case with long-lasting response to salvage multicycle HDC and HSCS in adult-type GCTs.

Pertuzumab and trastuzumab: the rationale way to synergy.

It has now been 15 years since the HER2-targeted monoclonal antibody trastuzumab was introduced in clinical and revolutionized the treatment of HER2-positive breast cancer patients. Despite this achievement, most patients with HER2-positive metastatic breast cancer still show progression of their disease, highlighting the need for new therapies. The continuous interest in novel targeted agents led to the development of pertuzumab, the first in a new class of agents, the HER dimerization inhibitors. Pertuzumab is a novel recombinant humanized antibody directed against extracellular domain II of HER2 protein that is required for the heterodimerization of HER2 with other HER receptors, leading to the activation of downstream signalling pathways. Pertuzumab combined with trastuzumab plus docetaxel was approved for the first-line treatment of patients with HER2-positive metastatic breast cancer and is currently used as a standard of care in this indication. In the neoadjuvant setting, the drug was granted FDA-accelerated approval in 2013. Pertuzumab is also being evaluated in the adjuvant setting. The potential of pertuzumab relies in the dual complete blockade of the HER2/3 axis when administered with trastuzumab. This paper synthetises preclinical and clinical data on pertuzumab and highlights the mechanisms underlying the synergistic activity of the combination pertuzumab-trastuzumab which are essentially due to their complementary mode of action.

A Phase I Trial of High-Dose Chemotherapy Combining Topotecan plus Cyclophosphamide with Hematopoietic Stem Cell Transplantation for Ovarian Cancer: The ITOV 01bis Study.

BACKGROUND: Dose-intensive chemotherapy with hematopoietic stem cell transplantation has been evaluated as a salvage treatment for recurrent ovarian cancer, but its benefit has not yet been demonstrated. In a previous phase I trial, we reported the feasibility of administering topotecan as a salvage regimen. METHODS: Twenty-one patients were treated with escalating doses of topotecan associated with a fixed dose of cyclophosphamide. RESULTS: The maximum tolerated dose was established at 9.0 mg/m2 on a 5-day regimen, analogously to what was reported for topotecan monotherapy. One toxic death from septic shock and multiorgan failure occurred. Although hematopoietic toxicities were overcome by peripheral blood stem cell transplantation, superior nonhematological toxicities were observed as compared to the initial trial. CONCLUSION: Response rates were generally short and survival rates were poor. Results of the ITOV 01bis study demonstrate that, in the setting of recurrent ovarian cancer, intensive chemotherapy based on topotecan-cyclophosphamide association is not currently clinically indicated.