How to Treat HR+/HER2- Metastatic Breast Cancer Patients after CDK4/6 Inhibitors: An Unfinished Story.

CDK4/6 inhibitors in association with endocrine therapy represent the best therapeutic choice for either endocrine-sensitive or resistant hormone-receptor-positive advanced breast cancer patients. On the contrary, the optimal therapeutic strategy after the failure of CDK4/6 inhibitors-based treatment still remains an open question worldwide. In this review, we analyze the most studied mechanisms of resistance to CDK4/6 inhibitors treatment, as well as the most significant results of retrospective and prospective trials in the setting of progression after CDK4/6 inhibitors, to provide the reader a comprehensive overview from both a preclinical and especially a clinical perspective. In our opinion, an approach based on a deeper knowledge of resistance mechanisms to CDK4/6 inhibitors, but also on a careful analysis of what is done in clinical practice, can lead to a better definition of prospective randomized trials, to implement a personalized sequence approach, based on molecular analyses.

Comparison of tumor microenvironment in primary and paired metastatic ER+/HER2- breast cancers: results of a pilot study.

BACKGROUND: Tumor microenvironment (TME) is a dynamic setting and changes in TILs and their subpopulations are potential candidates to influence the metastatic process. Aim of this pilot study is to describe the changes occurring between primary breast cancers and their paired metastases in terms of TILs composition. To assess if these changes influence the process of metastasis development, we used a control group of patients. METHODS: We retrospectively identified 18 Luminal patients, for whom primary and metastatic tissue were available (cases) and 18 paired-matched patients (controls), not relapsed after at least 9 years of follow-up, and we quantified TILs and their composition (i.e. T CD8+ and CD4+/FOXP3+). The presence of TILs was defined as ≥10%. RESULTS: Our results showed that the microenvironment composition of relapsed patients was poor of TILs (median = 5%, I-III quartiles = 0.6-5%), CD8+ (2.5%, 0-5%) and CD4+/FOXP3 + (0%, 0-0.6%) in the primary tumor. Comparable results were observed in their related metastases (TILs 3.8%, 0.6-5%; CD8+ 0%, 0-1.3%; CD4+/FOXP3+ 0%,0-1.9%). On the contrary, the microenvironment in the control group was richer of TILs (5%, 5-17.5%) in comparison to cases, both in primary tumor (p = 0.035) and related metastases (p = 0.018). Although CD8+ in controls were similar to cases at primary tumor (p = 0.6498), but not at metastasis (p = 0.0223), they expressed only one part on the TILs subpopulations (p = 0.0060), while TILs in the cases at primary tumor were almost completely CD8+ (p = 0.5034). CONCLUSIONS: These findings suggest that the lack of activation of immune system in the primary tumor might influence the multifactor process of cancer progression.

Validation of the Italian version of the full and abbreviated Trust in Oncologist Scale.

INTRODUCTION: The Trust in Oncologist Scale (TiOS) is an 18-item questionnaire aimed to assess the cancer patients' trust in their oncologist and has been validated in Dutch and English language. This study aims to validate the Italian version of the TiOS (IT-TiOS) and the TiOS-Short Form (IT-TiOS-SF). METHODS: The IT-TiOS was administered to 194 patients recruited in an Italian oncology department from April to December 2018. Data collected included socio-demographic data, health and clinical information, satisfaction with the most recent oncology visit and trust in the regional healthcare system. Internal consistency, test-retest reliability, convergent and the structural validity of both the full and short form were tested. RESULTS: Factor analyses indicated that neither four-factor nor one-factor models of the full scale were acceptable. However, confirmatory factor analysis supported the one-dimensionality of the IT-TiOS-SF, and internal consistency assessed with Cronbach's alpha was 0.88. Mean scores on the IT-TiOS-SF correlated with satisfaction with the oncologist (rs = 0.64) and willingness to recommend the oncologist to others (rs = 0.67), confirming good construct validity. CONCLUSION: The IT-TiOS-SF demonstrates good psychometric properties and can be used to assess trust for both clinical and research purposes.

Efficacy and safety of vinorelbine-capecitabine oral metronomic combination in elderly metastatic breast cancer patients: VICTOR-1 study.

PURPOSE: Elderly patients with metastatic breast cancer are expected to derive similar benefits from chemotherapy as younger patients, but are more likely to experience therapy-related toxicity. Data from the VICTOR-1 study showed that metronomic therapy with vinorelbine and capecitabine was effective and well tolerated in patients with metastatic breast cancer. This analysis determined the efficacy and safety of the metronomic combination of oral vinorelbine and capecitabine in a subgroup of VICTOR-1 study patients aged ≥70 years. METHODS: Eighteen of the 32 patients enrolled in VICTOR-1 were aged ≥70 years. Objective response and clinical benefit rates were calculated and toxicity was determined using the NCI-CTCAE criteria. RESULTS: All patients had at least 1 comorbidity (4 had 2 comorbidities), and 77.7% were taking concomitant medication. Eight patients (44%) had received ≥1 chemotherapy regimens for metastatic disease and most (78%) had ≥2 metastatic sites. Grade 1-2 adverse events occurred in 45.8% of cycles, whereas the incidence of grade 3 and grade 4 events was very low (1.5% and 0.7%, respectively). Median time to progression was 10.5 months (range 1-40). The objective response rate was 33% and the clinical benefit rate was 67%. CONCLUSIONS: The all-oral metronomic combination of vinorelbine and capecitabine had an acceptable efficacy profile and appears to be better tolerated than standard treatment schedules in elderly metastatic breast cancer patients (age ≥70 years).

Gemcitabine-induced thrombocytosis as a potential predictive factor in non-small cell lung cancer: analysis of 318 patients.

INTRODUCTION: In spite of the progress in the treatment of non-small-cell lung cancer (NSCLC), the majority of patients with advanced disease still receive chemotherapy. Gemcitabine alone or combined with a platinum compound is a valid option. Thrombocytosis is a recognized prognostic factor in lung cancer and an adverse event that may occur during gemcitabine infusion. METHODS: We retrospectively evaluated all patients with NSCLC treated with first-line gemcitabine-based chemotherapy in two Italian hospitals. We assessed the onset of thrombocytosis within the third cycle of therapy and the relation between thrombocytosis and survival. RESULTS: We included 318 patients. Thrombocytosis occurred in 156 patients (49.1%). Median progression-free survival (PFS) was 5.6 months (95% CI, 4.7-6.9 months) in patients who developed thrombocytosis versus 6 months (95% CI, 5.1-7.2 months) in patients without thrombocytosis (p = 0.21). Median overall survival (OS) was 11.2 months (95% CI, 9.8-13.4 months) in patients with thrombocytosis versus 12 months (95% CI, 10.1-14.4 months) in patients without thrombocytosis (p = 0.25). We observed no difference in terms of PFS or OS according to age, sex, stage, chemotherapy (single-agent versus combination chemotherapy) and thrombocytosis. CONCLUSIONS: Thrombocytosis is neither a prognostic nor a predictive factor for PFS or OS in patients with advanced NSCLC treated with first-line gemcitabine-based chemotherapy.

Isolated cardiac metastasis from squamous cell esophageal cancer.

Although heart metastases are uncommon and generally a sign of disseminated disease, they are up to 40 times more frequent than primary cancers of the heart, and typically arise from melanoma or primary mediastinal cancer, but also from lymphoma, breast cancer, esophageal cancer, and leukemia. They are usually asymptomatic and found only at autopsy. Symptomatic patients generally die within a few weeks of diagnosis and usual treatments are chemotherapy, radiotherapy, or both. Surgical resection is recommended only for a single lesion, which is rare. We describe a 49-year-old man treated for squamous cell cancer of the esophagus in whom a single asymptomatic left heart metastasis was discovered incidentally during follow-up. The lesion was debulked surgically and multimodal treatment followed. The patient survived 1 year after diagnosis with good performance status during which time no other lesion was discovered. Cardiac metastasis is challenging and necessitates skilled multidisciplinary management to maximize the clinical outcome.

Isotretinoin plus clindamycin seem highly effective against severe erlotinib-induced skin rash in advanced non-small cell lung cancer.

INTRODUCTION: Erlotinib is useful in advanced non-small cell lung cancer although compliance and efficacy are diminished by skin rash in a high proportion of patients, often necessitating dose reduction or drug withdrawal. No effective treatment for the rash is available. METHODS: We carried out a preliminary investigation on isotretinoin and clindamycin. Among 56 advanced lung cancer patients treated with erlotinib, 31 (53%) developed rash. Seven (35%) of the 20 G2/G3 cases agreed to treatment with clindamycin (450 mg/d, days 1-10; 300 mg/d, days 11-20) plus isotretinoin (20 mg/d, days 11-20) after being informed of the experimental nature of the combination. RESULTS: In 6 of 7 (86%) patients, the rash resolved (G1/G0) without dose reduction; in the other patient (G3), the erlotinib dose also had to be reduced. Median time to resolution was 14 days (range 7-20 days). No rash-treatment adverse events occurred during 20 days of administration. CONCLUSIONS: Isotretinoin plus clindamycin promises to be the first effective treatment for erlotinib rash and is being tested further.