Palma Fedele

Recent advances in the treatment of hormone receptor positive HER2 negative metastatic breast cancer

Endocrine therapy is the recommended systemic therapy for hormone receptor (HR) positive metastatic breast cancer (MBC). However so far the limited number of endocrine agents and the onset of endocrine resistance have severely limited the therapeutic options for this patients. In the last years many targeted agents have been investigated to prevent or overcome endocrine resistance; only a few of them have been found effective in HR positive MBC, such as everolimus, CK4/6 inhibitors and HDAC inhibitors. Furthermore, translational medicine studies using next generation sequencing technologies have evaluated genetic variations of a broad panel of cancer-related genes and explored their correlations with targeted agents benefit. In some studies predictive biomarkers have been identified and many ongoing studies are evaluating the efficacy of targeted drugs in HR positive MBC patients selected for biomarkers or stratified by pathways amplification.

Targeting triple negative breast cancer with histone deacetylase inhibitors

ABSTRACT Introduction: Triple negative breast cancer (TNBC) is a heterogeneous disease characterized by poor outcomes, higher rates of relapse, lack of biomarkers for rational use of targeted treatments and insensitivity to current available treatments. Histone deacetylase inhibitors (HDACis) perform multiple cytotoxic actions and are emerging as promising multifunctional agents in TNBC. Areas covered: This review focuses on the challenges so far addressed in the targeted treatment of TNBC and explores the various mechanisms by which HDACis control cancer cell growth, tumor progression and metastases. Pivotal preclinical trials on HDACis like panobinostat, vorinostat, and entinostat show that these epigenetic agents exert an anti-proliferative effect on TNBC cells and control tumor growth by multiple mechanisms of action, including apoptosis and regulation of the epithelial to mesenchimal transition (EMT). Combination studies have reported the synergism of HDACis with other anticancer agents. Expert opinion: In recent years, treatment of TNBC has recorded a high number of failures in the development of targeted agents. HDACis alone or in combination strategies show promising activity in TNBC and could have implications for the future targeted treatment of TNBC patients. Future research should identify which agent synergizes better with HDACis and which patient will benefit more from these epigenetic agents.

Discordance in pathology report after central pathology review: Implications for breast cancer adjuvant treatment

AIMnPathological predictive factors are the most important markers when selecting early breast cancer adjuvant therapy. In randomized clinical trials the variability in pathology report after central pathology review is noteworthy. We evaluated the discordance rate (DR) and inter-rater agreement between local and central histopathological report and the clinical implication on treatment decision.nnnMETHODSnA retrospective analysis was conducted in a series of consecutive early breast cancer tumors diagnosed by local pathologists and subsequently reviewed at the Pathology Division of European Institute of Oncology. The inter-rater agreement (k) between local and central pathology was calculated for Ki-67, grading, hormone receptors (ER/PgR) and HER2/neu. The Bland-Altman plots were derived to determine discrepancies in Ki-67, ER and PgR. DR was calculated for ER/PgR and HER2.nnnRESULTSnFrom 2007 to 2013, 187 pathology specimens from 10 Cancer Centers were reviewed. Substantial agreement was observed for ER (k0.612; 95% CI, 0538-0.686), PgR (k0.659; 95% CI, 0580-0.737), Ki-67 (k0.609; 95% CI, 0.534-0.684) and grading (k0.669; 95% CI, 0.569-0.769). Moderate agreement was found for HER2 (k0.546; 95% CI, 0444-0.649). DR was 9.5% (negativity to positivity) and 31.7% (positivity to negativity) for HER2 and 26.2% (negativity to positivity) and 12.5% (positivity to negativity) for ER/PgR. According to changes in Her2 and ER/PgR status, 23 (12.2%) and 33 (17.6%) systemic prescription were respectively modified.nnnCONCLUSIONSnIn our retrospective analysis, central pathological review has a significant impact in the decision-making process in early breast cancer, as shown in clinical trials. Further studies are warranted to confirm these provocative results.

An update on first line therapies for metastatic breast cancer

ABSTRACT Introduction: In recent years, outcomes of patients with metastatic breast cancer (MBC) have improved due to a greater understanding of the mechanisms of carcinogenesis in the development of newer molecularly targeted drugs, especially those as a front-line therapy. Remarkable improvements have been made in the treatment of hormone receptor positive (HR+) and Her2 positive MBC and currently targeted treatment strategies represent a valid first line treatment. Areas covered: Herein, the authors provide an overview of the first-line pharmacotherapies currently available for the treatment of MBC and provide their expert perspectives on the area. Expert opinion: Decisions on the first-line treatment of MBC should consider the clinical features of the disease, but also the biological mechanisms that regulate tumor cell growth. New and effective therapeutic agents have recently been introduced in the first-line therapy of MBC. However, to optimize the treatment of patients with metastatic disease, clinicians need biomarkers of resistance or sensitivity to targeted therapies. Efforts must also be made in developing strategies to personalize treatments of MBC patients and to identify those patients who might gain the most benefit from new treatment interventions, to save costs and limit toxicity.

Panitumumab after progression on cetuximab in KRAS wild-type metastatic colorectal cancer patients: a single institution experience

Aims and background Few data describe the activity of panitumumab after cetuximab-irinotecan-based regimen failure in patients with KRAS wild-type metastatic colorectal cancer (WT MCRC). Methods The aim of this study is to assess if panitumumab has some activity in this setting. Results We retrospectively analyzed 25 patients with KRAS WT MCRC who received panitumumab from July 2009 to January 2013 after progression on cetuximab. All patients had previously received cetuximab and irinotecan (20 patients) or oxaliplatin (5 patients). We withdrew cetuximab for intolerance in 4 patients (16%). Twenty-one patients (84%) who had previously responded to cetuximab (overall response rate [ORR] plus stable disease ≥5 months) received panitumumab off-label after progression on cetuximab because they were strongly motivated to continue treatment without chemotherapy. The median number of cycles of panitumumab was 7 (range 1-54). Only 20 patients were evaluable for ORR (5 patients received 1-2 cycles and then died). We observed 1 (5%) partial response, 5 (25%) stable disease, median duration 9 months. Median progression-free survival (PFS) and overall survival (OS) were 5 (3-28) and 8 (5-41) months, respectively. All patients were evaluable for toxicity. No patients developed anemia or neutropenia. One patient (4%) developed grade 2 thrombocytopenia, 8 patients (32%) grade 2-3 dry skin or rash, and 2 patients (8%) grade 2 nausea-vomiting (Common Terminology Criteria for Adverse Events version 4.03). Conclusions Our data, with all the limits of a retrospective analysis, show longer PFS and OS as compared to other series in the same setting, demonstrating that panitumumab has treatment effectiveness in patients with KRAS WT MCRC who progressed on prior cetuximab. Further confirmatory prospective studies with a larger series of patients are necessary.

Response of Extensive Breast Cancer Skin Metastases to Rechallenge with Trastuzumab Together with Low-Dose Chemotherapy and Insulin:

Introduction Cutaneous metastasis occurs in about 29% of breast cancer patients and has a deep impact on patient quality of life. Methods A 60-year-old woman with cutaneous metastases from heavily pretreated HER2-positive breast cancer received CMFVP (oral cyclophosphamide 100 mg daily; oral prednisone 12.5 mg daily for 2 weeks, then 7.5 mg daily; intravenous weekly methotrexate 25 mg/m2, 5-5-fluorouracil 400 mg/m2 and vincristine 0.5 mg) with weekly trastuzumab and subcutaneous insulin until disease progression. Results From March 2009 to November 2009 the patient was treated with the described regimen. At the best response, we observed the disappearance of some lesions and cessation of bleeding and thoracic pain. Time to progression was 8 months. Conclusions Our patient had clinical benefit from reintroduction of trastuzumab, low-dose chemotherapy and insulin. The explanation of this prolonged response is only speculative and requires further clinical confirmation in the treatment strategy of HER2-positive breast cancer.

Updating data about a first-line modified schedule of gemcitabine with a lower dose than standard in very elderly or PS 2 patients with advanced non-small cell lung cancer.

e18031 Background: Monochemotherapy with gemcitabine (Gem) is often the treatment of choice in elderly or poor performance status (PS) patients with advanced non-small cell lung cancer (NSCLC). Our study was aimed to assess the efficacy and tolerability of a modified schedule of Gem using a lower dose than standard.nnnMETHODSnFrom May 2009 through December 2010, fifty patients (43 males and 7 females with a median age of 76 years (64 to 85) with advanced NSCLC (stage IIIB 34,0% and IV 66,0%) were enrolled. Histology were: squamous 39,6%, adenocarcinoma 31,2%, large cell 6,2 %, undifferentiated 4,2 %, undetermined 18,8%. Only eight patients (16,0%) had a WHO PS 0 whereas nineteen (38,0%) were PS 1 and eleven (46,0%) PS 2. All patients received first-line chemotherapy with 6 cycles of Gem 1000 mg/sq on days 1 and 8 every 4 weeks.nnnRESULTSnAt the time of analysis 35 patients were evaluable for response. Partial response (PR) was achieved in 7 patients (20,0%), stable disease > 12 weeks (SD) in 16 (45,7%) whereas 12 had progressive disease (34,3%). Importantly, the clinical benefit rate (PR + SD) was 65,7%. Quality of life was mesured with EORTC QoL 3.0 Questionary. Both pain and PS improved in 6 patients (17,1%) whereas 19 (54,2%) had an improvement in pain with no worsening of PS. We observed only grade 2 NCCTs version 3 haematological toxicities including anemia, leucopenia, neutropenia and trombocytopenia. Not febrile neutropenia occurred in 4 patients (11,4%). Overall, we did not observe any not-haematological treatment-related event.nnnCONCLUSIONSnOur data show that a modified schedule of Gem with a lower dose intensity than standard may be beneficial in terms of both disease control and tolerability when employed in elderly or PS 2 patients with advanced NSCLC. These data are similar to published data in elderly. At ASCO meeting we present all data about 50 pts enrolled.

Optimizing outcomes in patients (pts) with HER2+ metastatic breast cancer (MBC) through continuous inhibition of HER2 activity: A single institution study.

e11067 Background: Anti-HER2 therapies are effective in HER2+ breast cancer; even if resistance occurs, continued HER2 inhibition is required for antitumor effect. There are no definitive data on the clinical benefit of continued trastuzumab (T) beyond progression in MBC and the optimal duration of T in pts with long-term control of disease. This study explores outcomes of MBC pts treated with T in multiple sequential lines.nnnMETHODSnFrom 2001 to 2009 we evaluated OS and cardiac toxicity in 50 pts with HER2+ (ASCO/CAP criteria) MBC who received T-based therapy for ≥ 12 months. OS was measured from the beginning of T-based CT to the last follow up visit or death. Cardiac event was any decline in LVEF by >10% from baseline or drop to <50%, III/IV NYHA CHF, new onset angina myocardial infarction, significant arrhytmias or sudden cardiac death.nnnRESULTSnMedian age was 59 (33-79), visceral disease in 60% and multiple site in 34%; 8 (16%) pts developed brain metastasis during T. All had overexpression of HER2 by IHC, FISH was centrally assessed in 78% and not amplified in 8%. T was administered for a median duration of 23 months (12-120). All pts received a median of 2 CT regimens (1-8); 9 out of 25 pts with endocrine responsive disease received endocrine therapy plus T after at least 1 CT regimen; 20 pts (40%) experienced CR and received T alone as maintenance for a median duration of 9 months (3-46); 23 (46%) pts received lapatinib, when the drug was licensed in Italy, after failure of at least two T-based CT lines. Median OS was 34 months (12-120). There were 3 cardiac events (6%) and consisted in asymptomatic decrease in LVEF to less than 50%; T-based CT was interrupted in 1 patient because of LVEF decrease to ≤ 40%.nnnCONCLUSIONSnT in multiple sequential lines demonstrated highly favorable outcomes in MBC pts. Overall the incidence of cardiac dysfunction was low.

P.26 Adjuvant treatment for elderly patients with colon cancer in ten Italian medical oncology units

Background: Palliative chemotherapy significantly reducesmortalityinpatientswithstageIVcoloncancer,butis less prescribed with rising age. In this paper, we highlight the pattern of palliative treatment and possible effects on survival among elderly patients. Patients and Methods: From January to December 2004, 78 files on the management of stage IV colorectalcancer(CRC)patientsover70years,collectedfrom