Neuromuscular and cardiac adverse events associated with immune checkpoint inhibitors: pooled analysis of individual cases from multiple institutions and literature.

BACKGROUND: Immune checkpoint inhibitors (ICIs) have revolutionized the management of multiple tumors, due to improved efficacy, quality of life, and safety. While most immune-related adverse events (irAEs) are mild and easily managed, in rare cases such events may be life-threatening, especially those affecting the neuromuscular and cardiac system. The management of neuromuscular/cardiac irAEs is not clear due to the lack of consistent data. Therefore, we carried out a pooled analysis of collected cases from selected Italian centers and individual data from published case reports and case series, in order to improve our understanding of these irAEs. PATIENTS AND METHODS: We collected retrospective data from patients treated in six Italian centers with ICIs (programmed cell death protein 1 or programmed death-ligand 1 and/or cytotoxic T-lymphocyte antigen 4 inhibitor) for any solid tumor who experienced neuromuscular and/or cardiovascular toxicity. Then, we carried out a search of case reports and series of neuromuscular/cardiac irAEs from ICIs with any solid tumor. RESULTS: This analysis includes cases from Italian institutions (n = 18) and the case reports identified in our systematic literature search (n = 120), for a total of 138 patients. Among these patients, 50 (36.2%) had complete resolution of their neuromuscular/cardiac irAEs, in 21 (15.2%) cases there was a clinical improvement with mild sequelae, and 53 (38.4%) patients died as a result of the irAEs. Factors significantly associated with worse outcomes were early irAE onset, within the first two cycles of ICI (Fisher P < 0.0001), clinical manifestation of both myositis and myocarditis when compared with patients who developed only myositis or myocarditis (chi-square P = 0.0045), and the development of arrhythmia (Fisher P = 0.0070). CONCLUSIONS: To the best of our knowledge, this is the largest collection of individual cases of immune-related myocarditis/myositis. Early irAE onset, concurrent development of myositis and myocarditis, as well as occurrence of arrhythmias are associated with worse outcomes and should encourage an aggressive immunomodulatory treatment.

The predictive and prognostic role of single nucleotide gene variants of PD-1 and PD-L1 in patients with advanced melanoma treated with PD-1 inhibitors.

Background: Despite having revolutionized the treatment paradigm for advanced melanoma, not all patients benefit from immune checkpoint inhibitor therapy. To date, there are no predictive biomarkers for response or the occurrence of immune-related adverse events (irAEs) to programmed cell death protein 1 (PD-1) inhibitors. Our aim was to investigate the predictive and prognostic role of single nucleotide variants (SNVs) of genes involved in the PD-1 axis. Methods: We analysed, in metastatic melanoma patients treated with nivolumab or pembrolizumab, five PD-1 SNVs, namely PD1.3 G>A (rs11568821), PD1.5 C>T (rs2227981), PD1.6 G>A (rs10204525), PD1.7 T>C(rs7421861), PD1.10 C>G (rs5582977) and three programmed death-ligand 1 (PD-L1) SNVs: +8293 C>A (rs2890658), PD-L1 C>T (rs2297136) and PD-L1 G>C (rs4143815). Association of SNV genotypic frequencies with best overall response to PD-1 inhibitors and development of irAEs were estimated through a modified Poisson regression. A Cox regression modelling approach was applied to evaluate the SNV association with OS. Results: A total of 125 patients with advanced melanoma were included in the analysis. A reduction in irAEs risk was observed in patients carrying the PD-L1 +8293 C/A genotype compared with those carrying the C/C genotype (risk ratio = 0.45; 95% CL 0.22-0.93; P = 0.031). A trend for a reduction in irAEs was also observed with the PD1.5 T allele (risk ratio = 0.70, 95% confidence limits 0.48-1.01 versus C allele). None of the SNVs was associated with response to therapy. Finally, a survival benefit was observed in patients harbouring the PD1.7 C/C genotype (hazard ratio = 0.37; 95% confidence limits 0.14-0.96; P = 0.028) in the homozygous model. Conclusions: Our study showed that PD-1.5 and PD-L1 +8293 SNVs may play a role as a predictive biomarker of development of irAEs to PD-1 inhibitors. PD1.7 SNV may also be associated with a reduction of the risk of death, although further translational research is needed to confirm these results.

Nine weeks versus 1 year adjuvant trastuzumab in combination with chemotherapy: final results of the phase III randomized Short-HER study‡.

Background: Chemotherapy plus 1-year trastuzumab is the standard adjuvant treatment of HER2-positive breast cancer. The efficacy of less extended trastuzumab exposure is under investigation. The short-HER study was aimed to assess the non-inferiority of 9 weeks versus 1 year of adjuvant trastuzumab combined with chemotherapy. Patients and methods: HER2-positive breast cancer patients with node-positive or, if node negative, with at least one risk factor (pT>2 cm, G3, lympho-vascular invasion, Ki-67 > 20%, age ≤35 years, or hormone receptor negativity) were randomly assigned to receive sequential anthracycline-taxane combinations plus 1-year trastuzumab (arm A, long) or plus 9 weeks trastuzumab (arm B, short). This study was designed as a non-inferiority trial with disease-free survival (DFS) as primary end point. A DFS hazard ratio (HR) <1.29 was chosen as the non-inferiority margin. Analyses according to the frequentist and Bayesian approach were planned. Secondary end points included 2-year failure rate and cardiac safety. Results: A total of 1254 patients from 82 centers were randomized (arm A, long: n = 627; arm B, short: n = 626). Five-year DFS is 88% in the long and 85% in the short arm. The HR is 1.13 (90% CI 0.89-1.42), with the upper limit of the CI crossing the non-inferiority margin. According to the Bayesian analysis, the probability that the short arm is non-inferior to the long one is 80%. The 5-year overall survival (OS) is 95.2% in the long and 95.0% in the short arm (HR 1.07, 90% CI 0.74-1.56). Cardiac events are significantly lower in the short arm (risk-ratio 0.33, 95% CI 0.22-0.50, P < 0.0001). Conclusions: This study failed to show the non-inferiority of a shorter trastuzumab administration. One-year trastuzumab remains the standard. However, a 9-week administration decreases the risk of severe cardiac toxicity and can be an option for patients with cardiac events during treatment and for those with a low risk of relapse. Trial Registration: EUDRACT number: 2007-004326-25; NCI ClinicalTrials.gov number: NCT00629278.

Concurrent versus sequential adjuvant chemo-endocrine therapy in hormone-receptor positive early stage breast cancer patients: a systematic review and meta-analysis.

BACKGROUND: Although in clinical practice adjuvant chemotherapy (CT) and endocrine therapy (ET) are administered sequentially in patients with hormone-receptor positive breast cancer, the optimal timing, i.e. concurrent or sequential administration, of these treatments has been scarcely investigated. To better clarify this issue we conducted a systematic review and meta-analysis of randomized studies comparing these two modalities of administrations in terms of disease-free survival (DFS) and overall survival (OS). METHODS: Relevant studies were identified by searching PubMed, Web of Knowledge and the proceedings of the major conferences with no date restriction up to March 2016. The summary risk estimates (pooled hazard ratio [HR] and 95% confidence intervals [CI]) for DFS and OS were calculated using random effect models (DerSimonian and Laird method). RESULTS: A total of three randomized studies were eligible including 2021 breast cancer patients. Overall, 755 DFS events were observed, 365 in the sequential arm and 390 in the concomitant arm, with a pooled HR of 0.95 (95% CI = 0.76 to 1.18, P = 0.643). No association between timing of treatment and OS was observed (HR = 0.95; 95% CI = 0.80 to 1.12, P = 0.529). CONCLUSION: Our pooled analysis showed no association between the timing of administration of adjuvant CT and ET and DFS and OS in breast cancer patients candidates for both adjuvant treatments. Because of the small number of published trials, the lack of data on the timing with modern adjuvant treatments, i.e. taxane-containing CT and aromatase inhibitors, this topic remain still controversial and requires further studies to be clarified.

Ovarian suppression using luteinizing hormone-releasing hormone agonists during chemotherapy to preserve ovarian function and fertility of breast cancer patients: a meta-analysis of randomized studies.

BACKGROUND: The role of temporary ovarian suppression with luteinizing hormone-releasing hormone agonists (LHRHa) in the prevention of chemotherapy-induced premature ovarian failure (POF) is still controversial. Our meta-analysis of randomized, controlled trials (RCTs) investigates whether the use of LHRHa during chemotherapy in premenopausal breast cancer patients reduces treatment-related POF rate, increases pregnancy rate, and impacts disease-free survival (DFS). METHODS: A literature search using PubMed, Embase, and the Cochrane Library, and the proceedings of major conferences, was conducted up to 30 April 2015. Odds ratios (ORs) and 95% confidence intervals (CIs) for POF (i.e. POF by study definition, and POF defined as amenorrhea 1 year after chemotherapy completion) and for patients with pregnancy, as well hazard ratios (HRs) and 95% CI for DFS, were calculated for each trial. Pooled analysis was carried out using the fixed- and random-effects models. RESULTS: A total of 12 RCTs were eligible including 1231 breast cancer patients. The use of LHRHa was associated with a significant reduced risk of POF (OR 0.36, 95% CI 0.23-0.57; P < 0.001), yet with significant heterogeneity (I(2) = 47.1%, Pheterogeneity = 0.026). In eight studies reporting amenorrhea rates 1 year after chemotherapy completion, the addition of LHRHa reduced the risk of POF (OR 0.55, 95% CI 0.41-0.73, P < 0.001) without heterogeneity (I(2) = 0.0%, Pheterogeneity = 0.936). In five studies reporting pregnancies, more patients treated with LHRHa achieved pregnancy (33 versus 19 women; OR 1.83, 95% CI 1.02-3.28, P = 0.041; I(2) = 0.0%, Pheterogeneity = 0.629). In three studies reporting DFS, no difference was observed (HR 1.00, 95% CI 0.49-2.04, P = 0.939; I(2) = 68.0%, Pheterogeneity = 0.044). CONCLUSION: Temporary ovarian suppression with LHRHa in young breast cancer patients is associated with a reduced risk of chemotherapy-induced POF and seems to increase the pregnancy rate, without an apparent negative consequence on prognosis.

HER2-positive metastatic breast cancer: a changing scenario.

Adjuvant trastuzumab (AT) dramatically improved HER2-positive breast cancer prognosis. Relapsed disease after AT has different patterns and information is available from observational studies. In this Review Chemotherapy regimens combined to anti-HER2 blockade are discussed, focusing in particular the role of anthracyclines, taxanes and capecitabine. The use of trastuzumab beyond progression and the role of other anti-HER2 agents like lapatinib, pertuzumab and T-DM1 are explored, as also dual blockade and in trastuzumab resistant Patients. Metastatic "de novo" HER2 Luminal (co-expression of HER2 and hormone receptors) Patients are eligible for anastrozole and trastuzumab but if pretreated with trastuzumab they are also eligible for lapatinib and letrozole. In any case endocrine treatment plays a complementary role to chemotherapy which remains pivotal. The last topic explored is treatment options for patients with brain metastases where both trastuzumab given concurrent with radiotherapy or lapatinib and capecitabine appear as potentially active.

Safety and efficacy outcomes with erythropoiesis-stimulating agents in patients with breast cancer: a meta-analysis.

BACKGROUND: New data on erythropoiesis-stimulating agents (ESAs) regarding overall survival and disease progression-related outcomes in patients with breast cancer receiving chemotherapy are presented in a meta-analysis of controlled trials of ESA use (epoetin α, epoetin ß, darbepoetin α, biosimilars). PATIENTS AND METHODS: A literature search identified reports from January 1997 through March 2014. We used company databases for Amgen, Inc., or Janssen studies and published data for other studies. Random-effects odds ratios (ORs) were calculated to compare results for patients randomized to ESA with those randomized to control. RESULTS: Deaths were reported for 571 of 2346 patients (24%) in the ESA groups and 523 of 2367 patients (22%) in the control groups [OR, 1.20; 95% confidence interval (CI) 1.03-1.40]. Sensitivity analyses were conducted to explore the effects of individual studies and exclusion of one study (BEST) resulted in an OR for death of 1.12 (95% CI 0.94-1.34). In seven studies reporting progression-related end points (N = 4197; ESA n = 2088; control n = 2109), the OR was 1.01 (95% CI 0.87-1.16) for ESA compared with control. CONCLUSIONS: After incorporating recent results of ESA use in patients with breast cancer, risks of survival and progression-free survival remain consistent with previously published data.

A prospective observational study to evaluate G-CSF usage in patients with solid tumors receiving myelosuppressive chemotherapy in Italian clinical oncology practice.

Febrile neutropenia (FN) is a severe dose-limiting side effect of myelosuppressive chemotherapy in patients with solid tumors. Clinical practice guidelines recommend primary prophylaxis with G-CSF in patients with an overall ≥ 20 % risk of FN. AIOM Italian guidelines recommend starting G-CSF within 24-72 h after chemotherapy; for daily G-CSF, administration should continue until the absolute neutrophil count (ANC) is 1 × 10(9)/L post-nadir and should not be terminated after ANC increase in the early days of administration. The aim of this study was to assess guideline adherence in oncology practice in Italy. In this multicenter, prospective, observational study, patients were enrolled at the first G-CSF use in any cycle and were followed for two subsequent cycles (or until the end of chemotherapy if less than two additional cycles). Primary objective was to explore G-CSF use in Italian clinical practice; therefore, data were collected on the G-CSF type, timing of administration, and number of doses. 512 eligible patients were enrolled (median age, 62). The most common tumor types were breast (36 %), lung (18 %), and colorectal (13 %). A total of 1,164 G-CSF cycles (daily G-CSF, 718; pegfilgrastim, 446) were observed. Daily G-CSF was administered later than 72 h after chemotherapy in 42 % of cycles, and the median [range] number of doses was four [1, 10]. Pegfilgrastim was administered later than 72 h in 8 % of cycles. G-CSF prophylaxis in Italy is frequently administered in a manner which is not supported by evidence-based guidelines. As this practice may lead to poor outcomes, educational initiatives are recommended.

Biological characteristics and medical treatment of breast cancer in young women-a featured population: results from the NORA study.

BACKGROUND: The present paper described the biological characteristics and clinical behavior of young women in the cohort NORA study PATIENTS AND METHODS: From 2000-2002, patients (N > 3500) were enrolled at 77 Italian hospitals. Women aged ≤50 years (N = 1013) were stratified into age groups (≤35, 36-40, 41-45, and 46-50 years). The relationship between age and patient characteristics, cancer presentation, and treatment was analyzed. RESULTS: Younger women more frequently had tumors with ER/PgR-negative(χ(2) = 7.07; P = .008), HER2 amplification (χ(2) = 5.76; P = .01), and high (≥10%) Ki67 labelling index (χ(2) = 9.53; P = .002). Positive nodal status, large tumors, and elevated Ki67 all associated with the choice for chemotherapy followed by endocrine therapy in hormone receptor-positive patients (P < .0001). At univariate analysis, ER-ve status, chemotherapy and age resulted as the only statistically significant variables (HR = 2.02, P = .004, and >40 versus ≤40, P < .0001, resp.). At multivariate analysis, after adjustment for significant clinical and pathological factors, age remains a significant prognostic variable (HR = 0.93, P = .0021). CONCLUSION. This cohort study suggests that age per sè is an important prognostic factor. The restricted role of early diagnosis and the aggressive behavior of cancer in this population make necessary the application of targeted medical strategies crucial.

Pathological and molecular characteristics distinguishing contralateral metastatic from new primary breast cancer.

BACKGROUND: Breast cancer patients have a cumulative lifetime risk of 2%-15% of developing a contralateral metastatic or ex novo primary cancer. From prognostic and therapeutic viewpoints, it is important to differentiate metastatic from second primary. To distinguish these entities, we investigated whether the pattern of X chromosome inactivation could determine whether the two tumors derived from different progenitor cells. MATERIALS AND METHODS: The clonality of bilateral breast cancer was evaluated through the X-inactivation analysis using the human androgen receptor gene (HUMARA) polymorphism and the histopathologic and molecular results were compared. A different or an identical pattern of X inactivation was considered as indicator of a second primary cancer or not informative, respectively. We considered morphological indicators of a new primary cancer the absence of concordance in the histological type or a better histological differentiation. RESULTS: Ten patients with bilateral breast cancer were evaluated. Morphological criteria indicated that eight were second primary, a conclusion confirmed by the X-inactivation analysis. Two cases classified as recurrence according to morphological criteria were classified as second tumor by molecular analysis. CONCLUSION: Our results show that the HUMARA clonality assay can improve the histological parameters in differentiating metastatic cancer from second primary cancer.

Timing of adjuvant chemotherapy and tamoxifen in women with breast cancer: findings from two consecutive trials of Gruppo Oncologico Nord-Ovest-Mammella Intergruppo (GONO-MIG) Group.

BACKGROUND: The timing of adjuvant chemotherapy and tamoxifen (TAM) has been investigated only in postmenopausal women with breast cancer. We analyzed the outcome of both pre- and postmenopausal women who entered two randomized trials (Gruppo Oncologico Nord-Ovest-Mammella Intergruppo studies) on adjuvant chemotherapy and received either concomitant or sequential TAM. PATIENTS AND METHODS: Patients who received anthracycline-based regimens and either concomitant or sequential TAM were eligible. The primary end point was overall survival (OS). Hazard ratios (HRs) of death or recurrence for treatment comparisons were estimated by Cox proportional hazards regression models. RESULTS: Among the 1096 eligible patients, 507 (46.3%) and 589 (53.7%) received concomitant and sequential TAM, respectively. The median follow-up time was 6.6 years. Ten-year OS was 83% [95% confidence interval (CI) 78-88%] and 80% (95% CI 74-86%) in the concomitant and sequential groups, respectively. Multivariate analyses confirmed no significant difference in the hazard of death (HR = 1.13; 95% CI 0.78-1.64; P = 0.534) and recurrence (HR = 1.03; 95% CI 0.80-1.33; P = 0.88) between the two groups. A decreasing trend (P = 0.015) in HR of death with increasing age was observed indicating, that concomitant therapy might be more effective than sequential therapy in young patients. CONCLUSIONS: We observed no outcome difference between sequential and concomitant chemo-endocrine therapy. The potential advantage of concomitant TAM in young patients needs to be further addressed in prospective trials.

Adjuvant treatment of early breast cancer: do the St Gallen recommendations influence clinical practice? Results from the NORA study.

BACKGROUND: The NORA study is a prospective longitudinal cohort study aiming at investigating treatment in patients with early breast cancer. Here, we present the impact of the St Gallen recommendations on clinical practice. PATIENTS AND METHODS: We compared adjuvant strategies in patients enrolled in 2000-2002 to those in 2003-2004 to verify the impact of the 2003 St Gallen recommendations. RESULTS: The use of aromatase inhibitors (AIs) doubled: 65/629 patients (10.3%) vs 100/458 patients (21.8) (P < 0.0001). Following chemotherapy, AIs were administered in 8.5% of the retrospective cohort and in 15.1% of the prospective one (P < 0.0001). The use of taxanes plus hormones dropped (P = 0.0026), but not when used as single agents. A marked increase was observed in the use of anthracycline-based chemotherapy (46.3% vs 65.2%), mainly three-drug regimens (33.3% vs 46.6%). CONCLUSION: Our results suggest that the St Gallen recommendations have had a major impact on clinical practice.

Breast cancer in elderly women: a different reality? Results from the NORA study.

BACKGROUND: The incidence of breast cancer increases with age, and the disease affects many older women; however, attitudes about prevention and treatment of breast cancer vary based on the patient's age. Older women have less access to clinical trials and fewer opportunities for treatment with innovative therapies. The National Oncological Research observatory on Adjuvant therapy in breast cancer (NORA) study was a cohort study designed to obtain information about adjuvant strategies for treatment of breast cancer after surgery, patterns of recurrence, and possible correlations between cancer-related events and biological factors. PATIENTS AND METHODS: This report describes patient characteristics, disease status, and local and systemic adjuvant treatments in a population of breast cancer patients aged >or=65 years. The NORA study consecutively enrolled >3500 patients from 2000 through 2002 at 77 Italian hospitals; of these, 1085 were aged >or=65 years. Data on patient characteristics, cancer presentation, and treatments were analyzed to identify possible relationships between these factors and age. RESULTS: The findings indicate that age is significantly related to later diagnosis and different patterns of treatment. Choice of adjuvant systemic treatment was primarily related to hormone receptor status and tumor stage but was strongly influenced by the patient's age; there was a proportional relationship between endocrine treatment and increasing age. Cyclophosphamide, methotrexate, and 5-fluorouracil as well as anthracyclines were widely used, but the use of taxanes was limited to a very small percentage of patients. CONCLUSIONS: The findings of the NORA study may help to change attitudes that currently exclude a significant proportion of breast cancer patients from secondary prevention policies, more active treatment strategies, and clinical research trials based on age.

First line chemotherapy of metastatic breast cancer.

In the last 20-30 years the approach to metastatic breast cancer by chemotherapy has been largely studied. Anthracyclines, taxanes and, more recently, capecitabine and gemcitabine represent the breakthrough of treatment. In the next future the combination of chemotherapy and target therapy will be considered more frequently.