key: cord-1021072-mpg8tstm
authors: Barba, Maddalena; Krasniqi, Eriseld; Pizzuti, Laura; Mazzotta, Marco; Marinelli, Daniele; Giuliano, Greta; Di Liso, Francesca Sofia; Cappuzzo, Federico; Landi, Lorenza; Tomao, Silverio; Ciliberto, Gennaro; Vici, Patrizia
title: COVID‐19 risk in breast cancer patients receiving CDK4/6 inhibitors: literature data and a monocentric experience
date: 2021-03-06
journal: Breast J
DOI: 10.1111/tbj.14204
sha: d573a38cfd0364b6f088d3baf51bc8c87eb590d1
doc_id: 1021072
cord_uid: mpg8tstm

Substantial changes in the management of cancer patients have been required worldwide in response to the COVID‐19 pandemic. Beyond the due details on the primitive cancer site and setting at diagnosis, these latter adaptions are most commonly exemplified by a significant reduction in the screening of asymptomatic subjects, delays in elective surgery and radiotherapy for primary tumors, and dose reductions and/or delays in systemic therapy administration. Advanced breast cancer patients with hormonal receptor positive, HER2 negative tumors are usually treated with endocrine therapy combined with CDK 4/6 inhibitors as first‐ and second‐line treatment. During the pandemic, experts’ recommendations have suggested the omission or delay of CDK 4/6 inhibitors delivery, or a careful evaluation of their real need due to the hypothesized increased risk of SARS‐Cov‐2 infection and disease possibly related to neutropenia. The inherent literature is sparse and inconsistent. We herein present data on the use of CDK 4/6 inhibitors during the pandemic. The evidence reported punctually reflects the experience matured at our Institution, a comprehensive cancer centre, on the topic of interest.

of cancer-specific treatments, possibly including surgery, radiotherapy, chemotherapy, and targeted therapies, either singularly or combined. Peculiar pathogenetic aspects have been advocated in support of a separated discussion concerning the risks eventually conferred by immunotherapy. 6 However, to the best of our knowledge, no questions have been openly and specifically posed, nor evidence-based opinions expressed, concerning the risk associated with the administration of cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitors combined with aromatase inhibitors or fulvestrant in hormone receptor positive (HR+), human epidermal growth factor receptor 2 negative (HER2-) metastatic breast cancer. These latter agents represent the newest frontier of endocrine therapy in HR+/HER2-advanced breast cancer. Their widespread use, consistently supported by significantly improved progression-free survival and overall survival, along with the extremely common hematologic toxicity, justifies our research question. 7 In brief, palbociclib, ribociclib, and abemaciclib are regulators of cell-cycle progression, through cyclin D. The interaction of cyclin D with CDK4/6 induces hyperphosphorylation of the retinoblastoma (Rb) gene product, leading to the transition from G1 to S cell-cycle phase; CDK4/6 inhibitors cause arrest of cell cycle progression. The most common side effects of palbociclib and ribociclib are neutropenia and leucopenia, less frequent observed with abemaciclib. Importantly, neutropenia induced by CDK4/6 inhibitors differs from chemotherapy-associated neutropenia in several aspects, including grade of toxicity, underlying mechanisms, and time to recovery. In a recent systematic review and meta-analysis including six eligible randomized trials, the relative risk (RR) for grade ¾ neutropenia was 44.0 (p < 0.0001), whereas there was no significant increase in the relative risk of febrile neutropenia compared with endocrine therapy alone (RR: 3.29, p 0.06). Indeed, the rate of febrile neutropenia related to CDK4/6 inhibitors is particularly low, about 2-3%, based on data from the registrative trials. Conversely, in first-line trials of metastatic breast cancer patients treated with citotoxic agents, febrile neutropenia rates raised up to 36%. 8, 9 Importantly, neutropenia induced by CDK4/6 inhibitors differs from chemotherapy-associated neutropenia in several aspects, including underlying mechanisms, degree of toxicity, and time to recovery. The issues related to the explicative mechanisms and time to recovery are tightly related. Bone marrow suppression from CDK4/6 inhibitors is due to cell-cycle arrest by decreased hematopoietic stem cells proliferation. This process is rapidly reverted by CDK4/6 inhibitors dose-reduction or interruption. This makes toxic effects rapidly reversible. Conversely, chemotherapy-induced neutropenia is caused by apoptotic death of bone marrow progenitor cells, a process which imposes longer time to restoration of the quo ante conditions and implies longer time to recovery. In addition, on the long term, due to the lack of DNA damage response following CDK4/6 inhibitors treatment in normal bone marrow-proliferating cells, the risk of secondary hematologic cancers, a known risk of DNA-damaging chemotherapy, may be lower. [10] [11] [12] One of the most debated decisions during the COVID-19 pandemic relates to the addition of CDK 4/6 inhibitors to endocrine therapy, because of the necessarily more frequent in-visits of the patients, and because of the immunosuppressive effect. Experts recommendation suggest that, during the pandemic, the decision to add a CDK 4/6 inhibitor to endocrine therapy should take into account the burden of metastatic disease, the sites of disease progression, and to consider the possibility of postpone their use later in the course of the disease. 13 Though not specifically referred to the patients population and combination with endocrine therapy were retrospectively recruited and analyzed. At physicians' discretion regimens were withdrawn or dose adjusted considering age, comorbidities, and previous neutropenia. The analysis was retrospectively performed to evaluate the impact of CDK 4/6 withdrawal/dose adjustment (non-exposed) on developing COVID-19 infection. An overall incidence of COVID-19 of 7.7% was found among all the casistic, 12.8% in exposed patients and 2.7% in non-exposed patients with a 5.8 odds ratio for exposed patients (p 0.077). The incidence of COVID-19 in patients receiving ribociclib, abemaciclib, and palbociclib was 14.29%, 7.69%, and 4.55%, respectively. Additionally, patients who had a CDK 4/6 inhibitor withdrawal or dose reduction did not show disease progression. The authors conclusions are that, although without statistically significant difference, withdrawn/dose-reduction of CDK 4/6 inhibitors may reduce the incidence of Covid-19. 18 Lastly, it was recently published the first case-report of an ad- by interval of enrollment, that is, prior to and following the lockdown establishment in Italy.

We finally turn back to the original question, that is, "In the Covid-19 era, is there an increased risk for breast cancer patients treated with palbociclib, ribociclib, or abemaciclib?". Based on the available literature data and the aforementioned results from our institutional experience, caution is invited in drawing any firm conclusions, mainly due to the still restricted sample size of the patient subsets and considered and the paucity of data from the literature.

Further evidence is, thus, warranted to reinforce or disconfirm the findings discussed. 

Cancer patients in SARS-CoV-2 infection: a nationwide analysis in China

Risk of COVID-19 for cancer patients

Clinical relevance of host immunity in breast cancer: from TILs to the clinic

Elements of cancer immunity and the cancerimmune set point

Aging and the immune system: An overview

Controversies about COVID-19 and anticancer treatment with immune checkpoint inhibitors

CDK4/6 inhibition in breast cancer: current practice and future directions

hematological adverse effects in breast cancer patients treated with cyclin-dependent kinase 4 and 6 inhibitors: a systematic review and meta-analysis

Phase III randomized study comparing docetaxel plus trastuzumab with vinorelbine plus trastuzumab as first-line therapy of metastatic or locally advanced human epidermal growth factor receptor 2-positive breast cancer: The HERNATA study

Management of adverse events due to cyclin-dependent Kinase 4/6 Inhibitors

Mechanistic investigation of bone marrow suppression associated with palbociclib and its differentiation from cytotoxic chemotherapies

Chemotherapy-induced secondary malignancies

editorial board of The Breast. Recommendations for triage, prioritization and treatment of breast cancer patients during the COVID-19 pandemic

Hematologic parameters in patients with COVID-19 infection

Clinical features of patients infected with 2019 novel coronavirus in Wuhan

Clinical findings in a group of patients infected with the 2019 novel coronavirus (SARS-Cov-2) outside of Wuhan, China: retrospective case series

COVID-19 in breast cancer patients: a cohort at the Institut Curie hospitals in the Paris area

Impact of CDK 4/6i withdrawal or dose adjustment on Covid-19 incidence in HR+/ HER2-mBC patients during the pandemic

A protracted course of COVID19 infection in a metastatic breast cancer patient during CDK4/6 inhibitor therapy