Purpose
Trastuzumab improves survival in patients with HER2+ early breast cancer. However, cardiotoxicity remains a concern, particularly in the curative setting, and there are limited data on its ...incidence outside of clinical trials. We retrospectively evaluated the cardiotoxicity rates left ventricular ejection fraction (LVEF) decline, congestive heart failure (CHF), cardiac death or trastuzumab discontinuation and assessed the performance of a proposed model to predict cardiotoxicity in routine clinical practice.
Methods
Patients receiving curative trastuzumab between 2011 and 2018 were identified. Demographics, treatments, assessments and toxicities were recorded. Fisher’s exact test, Chi-squared and logistic regression were used.
Results
931 patients were included in the analysis. Median age was 54 years (range 24–83) and Charlson comorbidity index 0 (0–6), with 195 patients (20.9%) aged 65 or older. 228 (24.5%) were smokers. Anthracyclines were given in 608 (65.3%). Median number of trastuzumab doses was 18 (1–18). The HFA-ICOS cardiovascular risk was low in 401 patients (43.1%), medium in 454 (48.8%), high in 70 (7.5%) and very high in 6 (0.6%). Overall, 155 (16.6%) patients experienced cardiotoxicity: LVEF decline ≥ 10% in 141 (15.1%), falling below 50% in 55 (5.9%), CHF NYHA class II in 42 (4.5%) and class III–IV in 5 (0.5%) and discontinuation due to cardiac reasons in 35 (3.8%). No deaths were observed. Cardiotoxicity rates increased with HFA-ICOS score (14.0% low, 16.7% medium, 30.3% high/very high;
p
= 0.002).
Conclusions
Cardiotoxicity was relatively common (16.6%), but symptomatic heart failure on trastuzumab was rare in our cohort. The HFA-ICOS score identifies patients at high risk of cardiotoxicity.
Despite recent advances, HER2-positive advanced breast cancer (ABC) remains a largely incurable disease, with resistance to conventional anti-HER2 drugs ultimately unavoidable for all but a small ...minority of patients who achieve an enduring remission and possibly cure. Over the past two decades, significant advances in our understanding of the underlying molecular mechanisms of HER2-driven oncogenesis have translated into pharmaceutical advances, with the developing of increasingly sophisticated therapies directed against HER2. These include novel, more potent selective HER2 tyrosine kinase inhibitors (TKIs); new anti-HER2 antibody-drug conjugates; and dual epitope targeting antibodies, with more advanced pharmacological properties and higher affinity. With the introduction of adjuvant T-DM1 for incomplete responders to neoadjuvant therapy, fewer patients are relapsing, but for those who do relapse, disease that may be resistant to standard first- and second-line therapies requires new approaches. Furthermore, the risk of CNS relapse has not been abrogated by current (neo)adjuvant strategies; therefore, current research efforts are being directed towards this challenging site of metastatic disease. In this article, we review the currently available clinical data informing the effective management of HER2-positive breast cancer beyond standard first-line therapy with pertuzumab, trastuzumab, and taxanes, and the management of relapse in patients who have already been exposed to both these agents and T-DM1 for early breast cancer (EBC). We additionally discuss novel anti-HER2 targeted agents and combinations in clinical trials, which may be integrated into standard treatment paradigms in the future.
A critical decline of functional insulin-producing pancreatic β-cells is the central pathologic element of both type 1 and type 2 diabetes. Mammalian Sterile 20-like kinase 1 (MST1) is a key mediator ...of β-cell failure and the identification of neratinib as MST1 inhibitor with potent effects on β-cell survival represents a promising approach for causative diabetes therapy. Here we report a case of robust glycemia and HbA1c normalization in a patient with breast cancer-T2D comorbidity under neratinib, a potent triple kinase inhibitor of HER2/EGFR and MST1. The patient, aged 62 years, was enrolled in the plasmaMATCH clinical trial and received 240 mg neratinib once daily. Neratinib therapy correlated with great improvement in glucose and HbA1c both to physiological levels during the whole treatment period (average reduction of random glucose from 13.6 ± 0.4 to 6.3 ± 0.5 mmol/l and of HbA1c from 82.2 ± 3.9 to 45.6 ± 4.2 mmol/mol before and during neratinib). 18 months later, when neratinib was withdrawn, random glucose rapidly raised together with high blood glucose fluctuations, which reflected in elevated HbA1c levels. This clinical case reports the combination of HER2/EGFR/MST1-inhibition by neratinib for the pharmacological intervention to effectively restore normoglycemia in a patient with poorly controlled T2D and suggests neratinib as potent therapeutic regimen for the cancer-diabetes comorbidity.
DNA mismatch repair (MMR) deficiency and the associated microsatellite instability (MSI) phenotype has become a subject of enormous interest in recent years due to the demonstrated efficacy of immune ...checkpoint inhibitors (ICI) in advanced tumours. Assessing MSI in patients with gastrointestinal tract (GI) cancers is useful to exclude Lynch syndrome, but also to predict benefit for ICI. Following review of the relevant literature, this review article aims to outline the clinicopathologic spectrum of MSI and mismatch repair deficiency (dMMR) in the GI tract, hepatobiliary system and pancreas and discuss the therapeutic consideration in this disease.
•Defects in DNA mismatch repair can be seen in several GI tumours.•Tissue based immunohistochemistry and next generation sequencing are used to detect microsatellite instability.•Evidence to support the use of immune checkpoint inhibitors in GI cancers including in both early and late stage disease is evolving.
Patients with cancer are purported to have poor COVID-19 outcomes. However, cancer is a heterogeneous group of diseases, encompassing a spectrum of tumour subtypes. The aim of this study was to ...investigate COVID-19 risk according to tumour subtype and patient demographics in patients with cancer in the UK.
We compared adult patients with cancer enrolled in the UK Coronavirus Cancer Monitoring Project (UKCCMP) cohort between March 18 and May 8, 2020, with a parallel non-COVID-19 UK cancer control population from the UK Office for National Statistics (2017 data). The primary outcome of the study was the effect of primary tumour subtype, age, and sex and on severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) prevalence and the case–fatality rate during hospital admission. We analysed the effect of tumour subtype and patient demographics (age and sex) on prevalence and mortality from COVID-19 using univariable and multivariable models.
319 (30·6%) of 1044 patients in the UKCCMP cohort died, 295 (92·5%) of whom had a cause of death recorded as due to COVID-19. The all-cause case–fatality rate in patients with cancer after SARS-CoV-2 infection was significantly associated with increasing age, rising from 0·10 in patients aged 40–49 years to 0·48 in those aged 80 years and older. Patients with haematological malignancies (leukaemia, lymphoma, and myeloma) had a more severe COVID-19 trajectory compared with patients with solid organ tumours (odds ratio OR 1·57, 95% CI 1·15–2·15; p<0·0043). Compared with the rest of the UKCCMP cohort, patients with leukaemia showed a significantly increased case–fatality rate (2·25, 1·13–4·57; p=0·023). After correction for age and sex, patients with haematological malignancies who had recent chemotherapy had an increased risk of death during COVID-19-associated hospital admission (OR 2·09, 95% CI 1·09–4·08; p=0·028).
Patients with cancer with different tumour types have differing susceptibility to SARS-CoV-2 infection and COVID-19 phenotypes. We generated individualised risk tables for patients with cancer, considering age, sex, and tumour subtype. Our results could be useful to assist physicians in informed risk–benefit discussions to explain COVID-19 risk and enable an evidenced-based approach to national social isolation policies.
University of Birmingham and University of Oxford.
In light of the coronavirus disease 2019 (COVID-19) pandemic, cancer centres in the United Kingdom and Europe re-organised their services at an unprecedented pace, and many patients with cancer have ...had their treatments severely disrupted. Patients with cancer were considered at high risk on sparse evidence, and despite a small number of emerging observational studies, the true incidence and impact of COVID-19 in the ‘at-risk’ population of patients with cancer is yet to be defined.
Epidemiological and clinical data were collected prospectively for patients attending the Royal Marsden Hospital and three network hospitals between March 1st and April 30th 2020 that were confirmed to have Severe acute respiratory syndrome coronavirus 2 (SARS-CoV2) infection. Significance of clinical and pathological characteristics was assessed using the Fisher's exact test and Wilcoxon rank sum test, whilst univariate and multivariate logistic regression models were used to further assess risk. The number of patients attending in March/April 2020 for face-to-face attendances was also extracted.
During the 2-month study period, 867 of 13,489 (6.4%) patients met the criteria leading to swab testing. Of the total at-risk population, only 113 of 13,489 (0.84%) were swab positive, 101 of 13,489 (0.75%) required hospital admission and 29 of 13,489 (0.21%) died of COVID-19. Of the patients that attended the hospital to receive cytotoxic chemotherapy alone or in combination with other therapy, 59 of 2001 (2.9%) were admitted to the hospital for COVID-19–related issues and 20 of 2001 (1%) died. Of the patients that collected targeted treatments, 16 of 1126 (1.4%) were admitted and 1 of 1126 (0.1%) died. Of the 11 patients that had received radiotherapy, 6 of 1042 (0.6%) required inpatient admission and 2 of 1042 (0.2%) died.
Administration of systemic anticancer therapy appears to be associated with a modest risk of severe COVID-19 infection. Based on this snapshot taken as the first wave of COVID-19 hit our practice, we conclude that continuation of active cancer treatment, even in the palliative setting, is appropriate.
•Of 13,489 cancer patients, 867 were tested and 113 were coronavirus disease 2019 (COVID-19) swab-positive.•Of these only 101 patients required hospital admission and 29 died of COVID-19.•Systemic anticancer therapy (SACT) and radiotherapy confer only a modest risk of significant COVID-19 infection.•Incidence of clinically significant COVID-19 was as in the general population.•We encourage oncology centres to continue to deliver SACT and radiotherapy.
The orally administered combination trifluridine/tipiracil has been approved as third line treatment in mCRC, demonstrating survival benefit and acceptable toxicity profile in the phase III RECOURSE ...study.
We performed a multicenter retrospective real-world analysis of patients with mCRC receiving trifluridine/tipiracil between 2016 and 2019 in eight cancer centers across the United Kingdom.
A total of 236 patients were included with median age of 69 years. All patients had received at least 2 lines of fluoropyrimidine-based chemotherapy doublet with oxaliplatin or irinotecan. About 10% of patients had ECOG ≥ 2. Median duration of trifluridine/tipiracil treatment was 3 months with an ORR of 2.1% and disease control rate of 21.6%. Median OS was 7.6 and median PFS 3.3 months. A dose reduction was required in 27% of patients, while 7.6% discontinued treatment due to toxicity. The most common grade 3 toxicities were neutropenia (34%), fatigue (10%), anemia (9%) and febrile neutropenia (5%). Baseline NLR <5 and CEA <200 had favorable prognostic (HR: 0.52 and 0.39, P≤ .001) and predictive value (OR: 4.1 and 6.7, P< .05). Development of grade 3 neutropenia predicted treatment response (OR: 0.32, P< .001). Following treatment with trifluridine/tipiracil 41% were referred for phase I trial or rechallenged with chemotherapy.
Trifluridine/tipiracil is well tolerated in refractory mCRC patients with comparable efficacy and toxicity profile to that of the phase III RECOURSE. Pretreatment NLR and CEA could serve as potential markers for patient selection, while treatment-induced grade 3 neutropenia predicted response. Prospective validation is needed.
This multicenter retrospective study assessed the safety and efficacy of trifluridine/tipiracil in the real-world setting in patients with chemotherapy refractory metastatic colorectal cancer (mCRC), while identifying predictive and prognostic clinicopathological factors. Our findings suggest that real-world safety and efficacy of trifluridine/tipiracil are in keeping with the pivotal clinical trial outcomes. Pretreatment neutrophil to lymphocyte ratio (NLR) and carcinoembryonic antigen (CEA) were prognostic, while treatment-induced grade 3 neutropenia was predictive for response.
BackgroundAs management and prevention strategies against COVID-19 evolve, it is still uncertain whether prior exposure to immune checkpoint inhibitors (ICIs) affects COVID-19 severity in patients ...with cancer.MethodsIn a joint analysis of ICI recipients from OnCovid (NCT04393974) and European Society for Medical Oncology (ESMO) CoCARE registries, we assessed severity and mortality from SARS-CoV-2 in vaccinated and unvaccinated patients with cancer and explored whether prior immune-related adverse events (irAEs) influenced outcome from COVID-19.FindingsThe study population consisted of 240 patients diagnosed with COVID-19 between January 2020 and February 2022 exposed to ICI within 3 months prior to COVID-19 diagnosis, with a 30-day case fatality rate (CFR30) of 23.6% (95% CI 17.8 to 30.7%). Overall, 42 (17.5%) were fully vaccinated prior to COVID-19 and experienced decreased CFR30 (4.8% vs 28.1%, p=0.0009), hospitalization rate (27.5% vs 63.2%, p<0.0001), requirement of oxygen therapy (15.8% vs 41.5%, p=0.0030), COVID-19 complication rate (11.9% vs 34.6%, p=0.0040), with a reduced need for COVID-19-specific therapy (26.3% vs 57.9%, p=0.0004) compared with unvaccinated patients. Inverse probability of treatment weighting (IPTW)-fitted multivariable analysis, following a clustered-robust correction for the data source (OnCovid vs ESMO CoCARE), confirmed that vaccinated patients experienced a decreased risk of death at 30 days (adjusted OR, aOR 0.08, 95% CI 0.01 to 0.69).Overall, 38 patients (15.8%) experienced at least one irAE of any grade at any time prior to COVID-19, at a median time of 3.2 months (range 0.13–48.7) from COVID-19 diagnosis. IrAEs occurred independently of baseline characteristics except for primary tumor (p=0.0373) and were associated with a significantly decreased CFR30 (10.8% vs 26.0%, p=0.0462) additionally confirmed by the IPTW-fitted multivariable analysis (aOR 0.47, 95% CI 0.33 to 0.67). Patients who experienced irAEs also presented a higher median absolute lymphocyte count at COVID-19 (1.4 vs 0.8 109 cells/L, p=0.0098).ConclusionAnti-SARS-CoV-2 vaccination reduces morbidity and mortality from COVID-19 in ICI recipients. History of irAEs might identify patients with pre-existing protection from COVID-19, warranting further investigation of adaptive immune determinants of protection from SARS-CoV-2.
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