Sandrine Richard

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.

Breast cancer: Weekly paclitaxel—still preferred first-line taxane for mBC

Taxane-based regimens are among the preferred first-line chemotherapy options for metastatic breast cancer, with weekly paclitaxel considered equivalent to 3-weekly docetaxel. The CALGB 40502/NCCTG N063H (Alliance) trial has now compared bevacizumab plus weekly paclitaxel, nab-paclitaxel, or ixabepilone in this setting; ixabepilone was inferior and nab-paclitaxel was not superior, with a trend towards inferiority. Paclitaxel thus remains the standard-of-care taxane chemotherapy.

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

Abstract 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.

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

Abstract 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.

Salvage high-dose chemotherapy in female patients with relapsed/refractory germ-cell tumors: a retrospective analysis of the European Group for Blood and Marrow Transplantation (EBMT)

Background High-dose chemotherapy (HDC) with hematopoietic progenitor cell transplantation is a standard option for relapsed/refractory testicular germ-cell tumor (GCT), but only few data have been reported in female patients with GCT. We conducted a retrospective analysis of female patients with GCT treated with HDC and registered with the European Society for Blood and Marrow Transplantation. Patients and methods Between 1985 and 2013, 60 registered female patients with GCT, median age 27 years (range 15-48), were treated with salvage HDC. Forty patients (67%) had primary ovarian GCT, 8 (13%) mediastinal, 7 (12%) retroperitoneal and 5 (8%) other primary sites/unknown. Twenty-two patients (37%) received HDC as second-line therapy, 29 (48%) as third-line, and 9 (15%) as fourth- to sixth-line. Nine of 60 patients (15%) received HDC as late-intensification with no evidence of metastasis before HDC. The conditioning HDC regimens comprised carboplatin in 51 of 60 cases (85%), and consisted of a single HDC cycle in 31 cases (52%), a multi-cycle HDC regimen in 29 (48%). Results Nine cases who underwent late intensification HDC were not evaluable for response. Of the other 51 assessable patients, 17 (33%) achieved a complete response (CR), 8 (16%) a marker-negative partial remission (PRm-), 5 (10%) a marker-positive partial remission, 5 (10%) stable disease, and 13 (25%) progressive disease. There were 3 toxic deaths (6%). With an overall median follow-up of 14 months (range 1-219), 7 of 9 (78%) patients with late intensification and 18 of the 25 patients (72%) achieving a CR/PRm- following HDC were free of relapse/progression. In total, 25 of 60 patients (42%) were progression-free following HDC at a median follow-up of 87 months (range 3-219 months). Conclusions Salvage HDC based on carboplatin represents a therapeutic option for female patients with relapsed/refractory GCT.

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.

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.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.

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.

Résistance aux traitements antihormonaux : théorie et pratique

Le cancer du sein est un cancer dit hormonodependant dans la majorite des cas. Historiquement, la demonstration de l’interet therapeutique d’une manipulation hormonale ayant un impact therapeutique antitumoral et l’emergence, de ce fait, d’une strategie de traitement cible, expliquent les progres realises depuis pres d’un siecle sur la comprehension des voies de signalisation impliquees dans la sensibilite et la resistance a ces traitements. Les progres scientifiques ont permis non seulement le developpement de nouvelles classes therapeutiques ciblant soit le recepteur des œstrogenes, soit la synthese de ces œstrogenes, mais egalement une serie de medicaments visant des proteines impliquees dans les mecanismes de resistance a ces traitements. Toutefois, l’impact de ces traitements et leur mise en perspective strategique demeurent compliques et necessitent une meilleure comprehension non seulement des mecanismes de resistance, mais egalement des populations etudiees dans les essais explorant ces strategies, afin de definir au mieux leur interet et leur positionnement en clinique.

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.