[Male breast cancer: a lesser-known battle]. / Cancer du sein chez l'homme : un combat méconnu.

Breast cancer in men is a rare and understudied disease. Until recently, prospective studies and clinical trials on breast cancer treatments often excluded men. Treatment recommendations were generally extrapolated from the results of clinical trials that included only women. Significant efforts have been made to better understand the biological characteristics, the most effective treatments, and the outcomes of breast cancer in men, as well as to identify clinically relevant differences of this disease. This article reviews the current data on the epidemiology, pathological and clinical characteristics, as well as the treatment of breast cancer in men.

Le cancer du sein chez l'homme est une maladie rare et peu étudiée. Jusqu'à récemment, les études prospectives et les essais cliniques sur les traitements du cancer du sein excluaient souvent les hommes. Les recommandations de traitement étaient généralement extrapolées à partir des résultats d'essais cliniques incluant uniquement des femmes. Des efforts significatifs ont été déployés pour mieux comprendre les caractéristiques biologiques, les traitements les plus efficaces et les résultats du cancer du sein chez les hommes, ainsi que pour identifier les différences cliniquement pertinentes de cette maladie. Cet article passe en revue les données actuelles sur l'épidémiologie, les caractéristiques pathologiques et cliniques, ainsi que le traitement du cancer du sein chez l'homme.

[Oncology: what's new in 2023]. / Oncologie: ce qui a changé en 2023.

The oncology field continues its remarkable evolution over the years, with promising advances leading to innovative and individualized treatments. The development of new molecules, the identification of new therapeutic targets and the search for new sequences or combinations promise to revolutionize cancer treatments and contribute to improving survival rates, patients' quality of life and to open new perspective in oncology research. In this article, the newest data released in 2023 are reviewed.

Le domaine de l'oncologie poursuit son évolution remarquable au fil des années, avec des avancées prometteuses ouvrant la voie à des traitements novateurs et individualisés. L'élaboration de nouvelles molécules, l'identification de nouvelles cibles thérapeutiques et la recherche de nouvelles séquences ou combinaisons de traitements promettent de révolutionner la prise en charge du cancer et de contribuer à améliorer les taux de survie, la qualité de vie des patients et à ouvrir de nouvelles perspectives dans la recherche en oncologie. Dans cet article, les nouveautés parues en 2023 sont passées en revue.

[Oncology: what's new in 2022]. / Oncologie : ce qui a changé en 2022.

The past year has brought several innovations in medical oncology, opening up promising new options for many solid tumors, both localized and metastatic. Immunotherapy, a real spearhead of emerging therapies in metastatic diseases, is seeing its use extend to adjuvant and neoadjuvant modalities, particularly in colon and lung cancers. 2022 also sees a great deal of focus on targeted therapies, as well as on antibody-drug conjugates, which creates new standards in both breast and lung cancers. Here we present the major advances in solid tumors.

L'année écoulée a apporté son lot d'innovations en oncologie médicale, ouvrant de nouvelles options prometteuses pour bon nombre de tumeurs solides, qu'elles soient localisées ou métastatiques. L'immunothérapie, véritable fer de lance des thérapies émergentes dans les maladies métastatiques, voit son usage s'étendre à des modalités adjuvantes et néoadjuvantes, notamment dans les cancers du côlon et du poumon. 2022 donne également la part belle aux thérapies ciblées mais aussi aux conjuguées anticorps-médicaments qui apportent de nouveaux standards tant pour les cancers du sein que du poumon. Nous vous présentons ici les avancées majeures concernant les tumeurs solides.

[Adverse effects of new breast cancer therapies : when to react ?] / Effets indésirables des nouvelles thérapies du cancer du sein : quand faut-il réagir ?

In last years, the therapeutic arsenal against breast cancer increased considerably with the arrival of signaling pathway inhibitors, immunotherapy, PARP inhibitors, tyrosine kinase inhibitors and antibody-drug conjugates. Consequently, the range of potential adverse events has also widened and differs from the usual chemotherapies and endocrine therapies. Depending on the administered therapy, the same symptoms can be harmless and treated symptomatically or the warning sign of a potential serious complication requiring a rapid action. We therefore discuss in this article the therapeutic role and some typical adverse events of these new therapies.

Ces dernières années, l'arsenal thérapeutique contre le cancer du sein s'est passablement enrichi avec les inhibiteurs des voies de signalisation, l'immunothérapie, les inhibiteurs de PARP (polyADP-ribose polymérase), les inhibiteurs de tyrosine kinase et les chimiothérapies immunoconjuguées. De ce fait, la gamme d'effets indésirables potentiels s'est également élargie et diffère des habituelles chimiothérapies et hormonothérapies. En fonction de la substance administrée, les mêmes symptômes peuvent être anodins et traités symptomatiquement, ou alors être le signe d'alerte d'une potentielle complication sévère et nécessiter une réaction rapide. Nous discutons dans cet article du rôle thérapeutique et des quelques effets indésirables typiques de ces nouvelles thérapies.

[2021 Oncology update]. / Oncologie.

Despite COVID-19 pandemic, which is still deeply affecting world economy and global health, medical oncology specialists keep pursuing their effort for the identification of new therapeutic options to improve patients' life expectancy and quality of life. 2021 confirms the immunotherapy efficacy, alone or in combination with other modalities, across several indications. This year, we are summarizing the new approaches in the following sectors: lung, breast, melanoma, gynecological, digestive, urological and ENT areas.

En dépit de la pandémie de Covid-19 qui continue à grandement impacter l'économie mondiale et la santé, l'oncologie médicale poursuit sa quête d'identification de nouvelles options thérapeutiques ayant pour buts la prolongation de l'espérance de vie et l'amélioration de la qualité de vie de ses patients, en nombre croissant. L'année 2021 confirme également l'efficacité de l'immunothérapie, seule ou en combinaison à d'autres modalités, dans de nombreuses indications. Cette année, nous vous résumons les nouvelles approches dans les domaines suivants: poumon, sein, mélanome, sphères gynécologique, digestive, urologique et ORL.

[Breast cancer during pregnancy]. / Cancer du sein chez la femme en.

The management of patients with breast cancer during their pregnancy is challenging. A good coordination is required between the oncology and obstetrics teams in order to ensure appropriate care, while providing a reassuring environment during this stressful period. Most often, the pregnancy can continue without delaying the initiation of oncological treatments, offering a prognosis similar to non-pregnant women. Surgery and chemotherapy can be done during pregnancy, unlike endocrine therapy, radiotherapy and antibody treatments which can only be given postpartum. While some imaging techniques are compatible, others require special measures or are contraindicated. We discuss these points in the context of a clinical situation.

La prise en charge des patientes présentant un cancer du sein durant leur grossesse est un challenge. Elle exige une bonne coordination entre les équipes oncologique et obstétricale afin d'assurer des soins appropriés tout en offrant un cadre rassurant en cette période de grand stress. Le plus souvent, la grossesse peut être poursuivie sans retarder l'initiation des traitements oncologiques, avec un pronostic similaire aux femmes non enceintes. La chirurgie et la chimiothérapie peuvent être entreprises en cours de grossesse, contrairement à l'hormonothérapie, la radiothérapie et les traitements par anticorps qui ne peuvent être administrés qu'en post-partum. Si certaines techniques d'imagerie sont compatibles, d'autres requièrent des mesures particulières ou sont contre-indiquées. Nous discutons de ces points dans le cadre d'une situation clinique.

[2020 oncology update]. / Oncologie.

The COVID-19 pandemic that has swept around the world in early 2020 has changed our daily practice and habits. Fortunately, however, 2020 also brings its share of new approaches and therapeutic combinations as well as new therapies. These advances are improving the outcomes and quality of life of our patients across the spectrum of oncological diseases. This article summarises the latest oncological advances and novelties for 2020 in the following tumor entities : lung, breast, digestive, gynecological, urological and ENT.

La pandémie de Covid-19 survenue début 2020 dans le monde entier aura bouleversé notre pratique quotidienne et nos habitudes. Heureusement, sur le plan thérapeutique, l'année 2020 apporte également son lot de nouvelles approches et combinaisons thérapeutiques ainsi que l'introduction de nouvelles molécules, permettant d'améliorer le pronostic vital et la qualité de vie de nos patients, dans de nombreux domaines. Cet article résume les dernières avancées et nouveautés oncologiques de l'année 2020 dans les domaines suivants : poumon, sein, sphère digestive, gynécologique, urologique et ORL.

Intraductal patient-derived xenografts of estrogen receptor α-positive breast cancer recapitulate the histopathological spectrum and metastatic potential of human lesions.

Estrogen receptor α-positive (ER-positive) or 'luminal' breast cancers were notoriously difficult to establish as patient-derived xenografts (PDXs). We and others recently demonstrated that the microenvironment is critical for ER-positive tumor cells; when grafted as single cells into milk ducts of NOD Scid gamma females, >90% of ER-positive tumors can be established as xenografts and recapitulate many features of the human disease in vivo. This intraductal approach holds promise for personalized medicine, yet human and murine stroma are organized differently and this and other species specificities may limit the value of this model. Here, we analyzed 21 ER-positive intraductal PDXs histopathologically. We found that intraductal PDXs vary in extent and define four histopathological patterns: flat, lobular, in situ and invasive, which occur in pure and combined forms. The intraductal PDXs replicate earlier stages of tumor development than their clinical counterparts. Micrometastases are already detected when lesions appear in situ. Tumor extent, histopathological patterns and micrometastatic load correlate with biological properties of their tumors of origin. Our findings add evidence to the validity of the intraductal model for in vivo studies of ER-positive breast cancer and raise the intriguing possibility that tumor cell dissemination may occur earlier than currently thought. © 2018 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.

[Breast cancer: perspectives from integrative medicine]. / Cancer du sein: perspectives de médecine intégrative.

Integrative medicine combines the virtues of conventional medicine and complementary medicine in order to improve the quality of life of patients suffering from cancer. Thanks to a multidisciplinary and multi-professional team, the Center for integrative and complementary medicine (CEMIC) allows since 2017 cancer patients at CHUV to have access to certain therapies, for which there are sufficient data suggesting a benefit in terms of quality of life. The concepts of tolerance, safety, risk of interactions and potential adverse biological effects remain central. In this article, we discuss acupuncture, art therapy, mindfulness and some natural therapies that are encountered regularly.

La médecine intégrative propose aux patients touchés par le cancer une combinaison des soins offerts par la médecine conventionnelle et la médecine complémentaire avec comme objectif l'amélioration de la qualité de vie des patients. Grâce à des équipes multidisciplinaires et multiprofessionnelles, le Centre de médecine intégrative et complémentaire (CEMIC) permet depuis 2017 aux patients oncologiques du CHUV d'avoir accès à certaines thérapies pour lesquelles il existe des données suggérant un bénéfice en termes de qualité de vie. Les notions de tolérance aux traitements, de sécurité, de risque d'interactions et d'éventuels effets biologiques non souhaités restent centrales. Dans cet article, nous discutons de l'acupuncture, de l'art-thérapie, de la méditation et de certaines substances et thérapies naturelles rencontrées régulièrement.

[Advances in Oncology 2019]. / Oncologie.

Driven by highly specialized medicine, research and the quest for personalization of treatments, oncology witnessed substantial advances in 2019. This year numerous treatments have consolidated their importance and broadened their indications. Multiple innovative treatments, currently under study, brought hope for future advances, while biomarkers, such as PD-L1, microsatellite instability (MSI), tumor mutational burden (TMB), BRCA1/2 gene mutations, and homologous recombination deficiency (HRD) allowed better selection and customization of available treatments. This article provides an overview of this year's advances in oncology.

Sous l'égide de la médecine hautement spécialisée, de la personnalisation des traitements et secondée par une recherche énergique, l'oncologie a connu en 2019 des avancées considérables. Cette année, de nombreux traitements ont consolidé leur importance et élargi leurs indications. L'annonce d'une pléthore de traitements novateurs, en étude, est source d'espoir pour l'avenir. Des biomarqueurs simples ou composites, tels que l'expression PD-L1, l'instabilité de microsatellite (MSI), la charge mutationnelle tumorale (TMB), les mutations des gènes BRCA1/2 ou un déficit du mécanisme de la recombinaison homologue des bases (HRD) permettent une meilleure sélection et personnalisation des traitements disponibles. Le but du présent article est de rassembler les avancées oncologiques de l'année.

[New therapeutic strategies in advanced stage breast and tubo-ovarian cancers]. / Nouvelles stratégies thérapeutiques dans les cancers mammaire et tubo-ovarien de stade avancé.

New targeted therapies modify therapeutic strategies for advanced stage breast and tubo-ovarian cancers. Chemotherapy and endocrine therapy remain the cornerstones of breast cancer treatment. Inhibitors of CDK4/6, mTOR and PI3K are associated with endocrine therapy to increase its effectiveness. PARP inhibitors outperform chemotherapy in BRCA1/2 mutation carriers. Immunotherapy integrates into the treatment of triple-negative cancers with very promising results. For tubo-ovarian cancers, the concept of « platinum-sensitive ¼ has been tempered since the arrival of antiangiogenic treatment and PARP inhibitors that prolong the disease control not only in patients with BRCA1/2 mutation, but also in others.

Les nouvelles thérapies ciblées modifient les stratégies thérapeutiques des cancers du sein et tubo-ovarien de stade avancé. La chimiothérapie et l'hormonothérapie restent les pierres angulaires du traitement du cancer du sein. Les inhibiteurs de CDK4/6, de mTOR et de PI3K sont associés à l'hormonothérapie pour augmenter son efficacité. Les inhibiteurs de la PARP (poly(ADP-ribose) polymérase) surpassent la chimiothérapie chez les porteuses de mutation BRCA1/2. L'immunothérapie arrive dans le traitement des cancers triple négatifs avec des résultats très prometteurs. Pour le cancer tubo-ovarien, le concept « platine-sensible ¼ est relativisé depuis l'arrivée du traitement anti-angiogénique et des inhibiteurs de la PARP qui prolongent la durée de contrôle de la maladie non seulement chez les patientes avec mutation de BRCA1/2, mais également chez les autres.

[Oncology, what's new in 2018]. / Oncologie.

The year 2018 has been incredibly prolific regarding novelties. Several studies have given impressive results and offer new anticancer perspectives. Immunotherapy is gaining more and more place defining a new standard of care for different types of cancer. In parallel with a new approach combining immunotherapy and chemotherapy that is emerging, new forms of adoptive immunotherapy are on the path of approval by regulatory authorities. At the decision-making level, a large somatic genetic analysis is becoming dominant, whereas the addition of more specific biomarkers is still needed regarding immunotherapy. This article aims to summarize the significant new developments in oncology for 2018 concerning the five most common cancers and adoptive cellular immunotherapy.

L'année 2018 a été extrêmement prolifique en termes de nouveautés. Plusieurs études ont amené des résultats intéressants et offrent de nouvelles perspectives anticancéreuses. L'immunothérapie prend de plus en plus de place définissant un nouveau standard pour le traitement des différents types de cancer. En parallèle d'une nouvelle approche combinant l'immunothérapie et la chimiothérapie qui voit le jour, des nouvelles formes d'immunothérapie adoptive se situent sur la voie d'approbation par les autorités réglementaires. Sur le plan décisionnel, l'analyse génétique somatique large des tumeurs devient prépondérante, alors que l'addition de biomarqueurs plus spécifiques est encore nécessaire concernant l'immunothérapie. Cet article a pour but de résumer les nouveautés majeures survenues en oncologie pour 2018 concernant les cinq cancers les plus fréquents et l'immunothérapie cellulaire adoptive.

[Hormone therapy in invasive breast cancer : update 2016]. / Hormonothérapie dans le cancer du sein invasif, update 2016.

Invasive breast cancer is the most common malignancy in women in industrialized countries. Three-quarters of breast cancers express estrogen and/or progesterone receptors and are considered endocrine-sensitive. Endocrine therapy reduces the risk of loco-regional, contralateral and distant recurrence. The management has become more complex with estrogen receptor inhibitors, aromatase inhibitors and ovarian function suppression. The choice of the regimen and its duration depend on the age, the menopausal status of the patient, her co-morbidities, the risk of cancer relapse and the tolerance. We summarize here the recent modifications of the endocrine therapy in early and advanced stage breast cancer.

Le cancer du sein est le cancer invasif le plus fréquent chez la femme dans les pays industrialisés. Trois quarts des cancers du sein expriment des récepteurs aux oestrogènes et/ou à la progestérone et sont susceptibles de répondre à un traitement antihormonal. En postopératoire, ce dernier permet de réduire le risque de rechute locorégionale, controlatérale et à distance. Entre inhibiteurs du récepteur, inhibiteurs de l'aromatase et suppression de la fonction ovarienne, la prise en charge s'est complexifiée et doit être dorénavant individualisée. Le choix du schéma thérapeutique ainsi que la durée du traitement dépendent de l'âge, du status hormonal de la patiente, de ses comorbidités, du risque de rechute et de la tolérance. Cet article résume les changements intervenus ces dernières années dans le traitement antihormonal en adjuvant et en situation métastatique.

[BRCA mutations: from Angelina Jolie to specific therapies]. / Mutations de BRCA1/2: d'Angelina Jolie à la thérapie.

While mutations in BRCA1 and BRCA2 are found in only a minority of breast cancer patients, their impact for those patients is important. It is a powerful risk factor for this disease with respectively 65% and 45% of the women developing breast cancer. It requires a specific screening program starting at age of 25 that includes magnetic resonance imaging and risk reduction measures such as bilateral mastectomy and oophorectomy can be proposed. The psychological impacts of the mutation and its implications are not negligible. The testimony of Angelina Jolie in 2013 certainly contributed to public awareness and helped the affected women to cope better with the situation. Cancer treatments are also influenced by detection of a mutation with an increased role for platinum derivatives and the recently developed specific therapies, such as PARP inhibitors.

MART-1 peptide vaccination plus IMP321 (LAG-3Ig fusion protein) in patients receiving autologous PBMCs after lymphodepletion: results of a Phase I trial.

BACKGROUND: Immunotherapy offers a promising novel approach for the treatment of cancer and both adoptive T-cell transfer and immune modulation lead to regression of advanced melanoma. However, the potential synergy between these two strategies remains unclear. METHODS: We investigated in 12 patients with advanced stage IV melanoma the effect of multiple MART-1 analog peptide vaccinations with (n = 6) or without (n = 6) IMP321 (LAG-3Ig fusion protein) as an adjuvant in combination with lymphodepleting chemotherapy and adoptive transfer of autologous PBMCs at day (D) 0 (Trial registration No: NCT00324623). All patients were selected on the basis of ex vivo detectable MART-1-specific CD8 T-cell responses and immunized at D0, 8, 15, 22, 28, 52, and 74 post-reinfusion. RESULTS: After immunization, a significant expansion of MART-1-specific CD8 T cells was measured in 83% (n = 5/6) and 17% (n = 1/6) of patients from the IMP321 and control groups, respectively (P < 0.02). Compared to the control group, the mean fold increase of MART-1-specific CD8 T cells in the IMP321 group was respectively >2-, >4- and >6-fold higher at D15, D30 and D60 (P < 0.02). Long-lasting MART-1-specific CD8 T-cell responses were significantly associated with IMP321 (P < 0.02). At the peak of the response, MART-1-specific CD8 T cells contained higher proportions of effector (CCR7⁻ CD45RA⁺/⁻) cells in the IMP321 group (P < 0.02) and showed no sign of exhaustion (i.e. were mostly PD1⁻CD160⁻TIM3⁻LAG3⁻2B4⁺/⁻). Moreover, IMP321 was associated with a significantly reduced expansion of regulatory T cells (P < 0.04); consistently, we observed a negative correlation between the relative expansion of MART-1-specific CD8 T cells and of regulatory T cells. Finally, although there were no confirmed responses as per RECIST criteria, a transient, 30-day partial response was observed in a patient from the IMP321 group. CONCLUSIONS: Vaccination with IMP321 as an adjuvant in combination with lymphodepleting chemotherapy and adoptive transfer of autologous PBMCs induced more robust and durable cellular antitumor immune responses, supporting further development of IMP321 as an adjuvant for future immunotherapeutic strategies.

Neo-adjuvant therapies for ER positive/HER2 negative breast cancers: from chemotherapy to hormonal therapy, CDK inhibitors, and beyond.

INTRODUCTION: Chemotherapy has been traditionally used as neo-adjuvant therapy in breast cancer for down-staging of locally advanced disease in all sub-types. In the adjuvant setting, genomic assays have shown that a significant proportion of ER positive/HER2 negative patients do not derive benefit from the addition of chemotherapy to adjuvant endocrine therapy. An interest in hormonal treatments as neo-adjuvant therapies in ER positive/HER2 negative cancers has been borne by their documented success in the adjuvant setting. Moreover, cytotoxic chemotherapy is less effective in ER positive/HER2 negative disease compared with other breast cancer subtypes in obtaining pathologic complete responses. AREAS COVERED: Neo-adjuvant therapies for ER positive/HER2 negative breast cancers and associated biomarkers are reviewed, using a Medline survey. A focus of discussion is the prediction of patients that are unlikely to derive extra benefit from chemotherapy and have the highest probabilities of benefiting from hormonal and other targeted therapies. EXPERT OPINION: Predictive biomarkers of response to neo-adjuvant chemotherapy and hormonal therapies are instrumental for selecting ER positive/HER2 negative breast cancer patients for each treatment. Chemotherapy remains the standard of care for many of those patients requiring neo-adjuvant treatment, but other neo-adjuvant therapies are increasingly used.

A pharmacist-led interprofessional medication adherence program improved adherence to oral anticancer therapies: The OpTAT randomized controlled trial.

BACKGROUND: Oral anticancer therapies such as protein kinase inhibitors (PKIs) are increasingly prescribed in cancer care. We aimed to evaluate the impact of a pharmacist-led interprofessional medication adherence program (IMAP) on patient implementation (dosing history), persistence (time until premature cessation of the treatment) and adherence to 27 PKIs prescribed for various solid cancers, as well as the impact on patients' beliefs about medicines (BAM) and quality of life (QoL). METHODS: Patients (n = 118) were randomized 1:1 into two arms. In the intervention arm, pharmacists supported patient adherence through monthly electronic and motivational feedback, including educational, behavioral and affective components, for 12 months. The control arm received standard care plus EM without intervention. All PKIs were delivered in electronic monitors (EMs). Medication implementation and adherence were compared between groups using generalized estimating equation models, in which relevant covariables were included; persistence was compared with Kaplan‒Meier curves. Information on all treatment interruptions was compiled for the analysis. Questionnaires to evaluate BAM and QoL were completed among patients who refused and those who accepted to participate at inclusion, 6 and 12 months post-inclusion or at study exit. RESULTS: Day-by-day PKI implementation was consistently higher and statistically significant in the intervention arm (n = 58) than in the control arm (n = 60), with 98.1% and 95.0% (Δ3.1%, 95% confidence interval (CI) of the difference 2.5%; 3.7%) implementation at 6 months, respectively. The probabilities of persistence and adherence were not different between groups, and no difference was found between groups for BAM and QoL scores. No difference in BAM or QoL was found among patients who refused versus those who participated. The intervention benefited mostly men (at 6 months, Δ4.7%, 95% CI 3.4%; 6.0%), those younger than 60 years (Δ4.0%, 95% CI 3.1%; 4.9%), those who had initiated PKI more than 60 days ago before inclusion (Δ4.5%, 95% CI 3.6%; 5.4%), patients without metastasis (Δ4.5%, 95% CI 3.4%; 5.7%), those who were diagnosed with metastasis more than 2 years ago (Δ5.3%, 95% CI 4.3%; 6.4%) and those who had never used any adherence tool before inclusion (Δ3.8%, 95% CI 3.1%; 4.5%). CONCLUSIONS: The IMAP, led by pharmacists in the context of an interprofessional collaborative practice, supported adherence, specifically implementation, to PKIs among patients with solid cancers. To manage adverse drug events, PKI transient interruptions are often mandated as part of a strategy for treatment and adherence optimization according to guidelines. Implementation of longer-term medication adherence interventions in the daily clinic may contribute to the improvement of progression-free survival. TRIAL REGISTRATION: ClinicalTrials.gov NCT04484064.

Homologous Recombination Defects and Mutations in DNA Damage Response (DDR) Genes Besides BRCA1 and BRCA2 as Breast Cancer Biomarkers for PARP Inhibitors and Other DDR Targeting Therapies.

Homologous recombination repair (HRR) is the cellular mechanism for error-free repair of double strand DNA (dsDNA) breaks. Cancer cells with mutations in both alleles of genes encoding for proteins involved in HRR, such as BRCA1 and BRCA2, have defects in the repair process. As a result, these cells repair dsDNA breaks with alternative mechanisms, such as non-homologous end joining. In breast cancers with germline mutations in BRCA1 and BRCA2 genes, HRR defects result in sensitivity to PARP inhibitors, drugs that interfere with the function of PARP enzyme and promote trapping of the enzyme on DNA and stalling of the process of repairing single strand breaks. HRR defects also lead to sensitivity to DNA damaging chemotherapy due to the inability of cells to repair chemotherapy induced DNA lesions. Besides germline mutations in BRCA1 and BRCA2, somatic mutations in these genes or germline and somatic mutations or other genetic and epigenetic alterations of other genes involved in homologous recombination (HR) may produce HRR defects leading to sensitivity to PARP inhibitors. However, studies are less conclusive, a fact that may relate to the common lack of bi-allelic loss of function in these cases, as opposed to cancers with germline BRCA1 or BRCA2 defects that usually acquire bi-allelic loss of function. In addition, there is heterogeneity between the different HRR genes and the severity of the resulting HRR defects, as measured by HR defect assays. This review article examines the landscape of HRR gene mutations in breast cancer and the possible therapeutic implications of HRR defects other than germline BRCA1 and BRCA2 mutations for targeted therapies. Identification of a wider range of breast cancers with HRR defects may expand the subset of patients that derive benefit from PARP inhibitors and other DDR-targeting drugs in the clinic.

Cytokine storm complicated by cardiogenic shock induced by anti-HER2 therapies.

Cytokine storm induced by anti-human epidermal growth factor receptor-2 (HER2) therapies has not been reported. We report a patient with breast cancer treated with trastuzumab/pertuzumab who developed severe biventricular dysfunction and cardiogenic shock (CS) 6 months after starting double anti-HER2 therapy. The CS was accompanied by severe systemic inflammation, and cardiac MRI (cMRI) showed structural changes typical of myocardial inflammation. The immuno-inflammatory profile showed significantly increased levels of activation of the complement system, proinflammatory cytokines (IL-1ß, IL-6, IL-18, IL-17A, TNF-alpha) with increased activity of classical monocytic, T helper 17 cells (Th17), CD4 T and effector memory CD8 T subsets, whereas NK cell activation was not observed. The data suggest an important role for monocytes as initiators of this FcγR-dependent antibody-dependent cytotoxicity, leading to the overactivation of an adaptive T cell response, in which Th17 cells may act in synergy with T helper 1 cells (Th1) to drive the severe cytokine release syndrome. After discontinuation of trastuzumab/pertuzumab, hypercytokinemia and complement activity normalized along with clinical recovery. Cardiac function returned to baseline within 2 months of initial presentation, together with a resolution of the myocardial inflammation on MRI.

Adherence to the CDK 4/6 Inhibitor Palbociclib and Omission of Dose Management Supported by Pharmacometric Modelling as Part of the OpTAT Study.

The cyclin-dependent kinase 4/6 inhibitor (CDK4/6i) palbociclib is administered orally and cyclically, causing medication adherence challenges. We evaluated components of adherence to palbociclib, its relationship with pharmacokinetics (PK), and drug-induced neutropenia. Patients with metastatic breast cancer (MBC) receiving palbociclib, delivered in electronic monitors (EM), were randomized 1:1 to an intervention and a control group. The intervention was a 12-month interprofessional medication adherence program (IMAP) along with monthly motivational interviews by a pharmacist. Implementation adherence was compared between groups using generalized estimating equation models, in which covariates were included. Model-based palbociclib PK and neutrophil profiles were simulated under real-life implementation scenarios: (1) optimal, (2) 2 doses omitted and caught up at cycle end. At 6 months, implementation was slightly higher and more stable in the intervention (n = 19) than in the control (n = 19) group, 99.2% and 97.3% (Δ1.95%, 95% CI 1.1−2.9%), respectively. The impact of the intervention was larger in patients diagnosed with MBC for >2 years (Δ3.6%, 95% CI 2.1−5.4%), patients who received >4 cycles before inclusion (Δ3.1%, 95% CI 1.7−4.8%) and patients >65 (Δ2.3%, 95% CI 0.8−3.6%). Simulations showed that 25% of patients had neutropenia grade ≥3 during the next cycle in scenario 1 versus 30% in scenario 2. Education and monitoring of patient CDK4/6i cycle management and adherence along with therapeutic drug monitoring can help clinicians improve prescription and decrease toxicity.