Assessment of Resistance Mechanisms and Clinical Implications in Patients with KRAS Mutated-Metastatic Breast Cancer and Resistance to CDK4/6 Inhibitors.

Despite therapeutic improvements, resistance to palbociclib is a growing clinical challenge which is poorly understood. This study was conducted in order to understand the molecular mechanisms of resistance to palbociclib, and to identify biomarkers to predict who will take advantage from cyclin-dependent kinase 4/6 inhibitors (CDK4/6i). A total of about a thousand blood samples were collected from 106 patients with hormone receptor positive (HR+) human epidermal growth factor receptor 2 (HER2) negative metastatic breast cancer who received palbociclib in combination with fulvestrant as the first-line metastatic therapy enrolled in this study. The genotyping of their plasma cell-free DNA was studied, including serial plasma samples. Collectively, our findings identify the appearance of KRAS mutations leading to palbociclib resistance acquisition within 6 months, and provide critical information for the prediction of therapeutic responses in metastatic breast cancer. By monitoring KRAS status through liquid biopsy, we could predict who will take advantage from the combination of palbociclib and fulvestrant, offering highly-individualized treatment plans, thus ensuring the best patient quality of life.

The Proper Ki-67 Cut-Off in Hormone Responsive Breast Cancer: A Monoinstitutional Analysis with Long-Term Follow-Up.

INTRODUCTION: Breast cancer is a heterogeneous disease. Our study focuses on a monoinstitutional series of patients affected by Hormone Responsive carcinomas (luminal A and luminal B) and aims to define an optimal Ki-67 cut-off, to correctly stratify these patients into risk classes, using the ImmunoHistoChemical (IHC) surrogates of the Molecular Subtypes, according to the St. Gallen guidelines. METHODS: We analyzed 1685 patients. These patients underwent both radical and conservative surgeries with Sentinel Lymph Node Biopsy eventually followed by Axillary Dissection (AD). Furthermore, all the patients underwent adjuvant therapies according to the guidelines. A retrospective univariate analysis was performed and survival curves (Disease-Related Survival, DRS, and Disease-Free Survival, DFS) were carried out according to the following ki-67 risk classes: Low Risk (Ki-67 ≤ 14%); Intermediate Risk (Ki-67 15% ÷ 20%); High Risk (Ki-67 > 20%). RESULTS: 14 yy DRS was 98% in LA and 85% in LB with a ki-67 cut-off of 14% (p=0.037) vs 95% (LA) and 83% (LB) with a ki-67 cut-off of 20% (p=0.003). 14yy DFS was 85% in LA and 72% in LB with a ki-67 cut-off of 14% (p=0.017) vs 83% (LA) and 66% (LB) with a ki-67 cut-off of 20% (p<0.000). DISCUSSION: Our results confirmed that the 20% Ki-67 cut-off is more reliable in differentiating patients at low or high risk of recurrence and death, and stratifying patients eligible for adjuvant chemotherapy. Thus, despite its poor reproducibility, the identification of the most accurate ki-67 index assumes a pivotal relevance in guiding a tailored strategy among patients with this specific profile of breast cancer, as well as the molecular surrogates, in order to avoid harmful overtreatments.

Gemcitabine-induced dilated-cardiomyopathy in patient with platinum-refractory ovarian-cancer: A case report and literature review.

INTRODUCTION: Gemcitabine is a nucleoside analog and pyrimidine antimetabolite that inhibits RNA synthesis, currently approved for use to treat a variety of cancers, among which ovarian cancers. Gemcitabine is considered relatively safe and it is generally well tolerated, with rarely reported cardiac side effects. CASE REPORT: We report a case of gemcitabine induced dilated cardiomyopathy in a 41-year-old woman receiving gemcitabine as second line treatment for platinum-resistant ovarian cancer without pre-existing hypertension or significant cardiac history.Management and Outcome: The patient presented with clinical symptoms and laboratory and imaging results suggestive of congestive cardiac failure, with a left ventricular ejection fraction of 15%. Gemcitabine administration was stopped and Furosemide with ACE-inhibitors and Beta-blocker agents were initiated. At that point the clinical situation improved: symptoms and findings disappeared with gemcitabine cessation. DISCUSSION: Our case demonstrated for the first time objective evidence for dilated cardiomyopathy induced by gemcitabine in a young patient with platinum-resistant ovarian cancer without pre-existing significant cardiac history. Although rare, gemcitabine-induced cardiotoxicity should be promptly recognized in order to take appropriate measures to manage it.