Nicola Calvani

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.

BMI variation increases recurrence risk in women with early-stage breast cancer

AIMS The prognostic role of BMI variation during and/or after treatments for early-stage breast cancer is still unknown. PATIENTS & METHODS The χ(2) test was conducted to explore the correlation between breast cancer recurrence and BMI changes in 520 early-stage breast cancer patients. Cox proportional hazard models were used to analyze the association of BMI changes, baseline BMI, known prognostic factors and recurrences. RESULTS BMI gain was significant determinant of recurrences (p = 0.0008). In multivariate analyses, BMI variation more than 5.71% was associated with higher rates of recurrences, as well as age less than 55 years, stage disease and molecular subtype. CONCLUSION Women who experience BMI gain after breast cancer may be at increased risk of poor outcomes.

Sorafenib as first- or second-line therapy in patients with metastatic renal cell carcinoma in a community setting

AIM The Italian Retrospective Analysis of Sorafenib as First or Second Target Therapy study assessed the efficacy and safety of sorafenib in metastatic renal cell carcinoma patients treated in the community. PATIENTS & METHODS Patients receiving first- or second-line single-agent sorafenib between January 2008 and December 2010 were eligible. Retrospective data collection started in 2012 and covers at least 1-year follow-up. The primary end point was overall survival (OS). RESULTS Median OS was 17.2 months (95% CI: 15.5-19.6): 19.9 months (95% CI: 15.9-25.3) in patients treated with first-line sorafenib and 16.3 months (95% CI: 13.1-18.2) with second-line sorafenib. Overall median (95% CI) progression-free survival was 5.9 months (95% CI: 4.9-6.7): 6.6 (95% CI: 4.9-9.3) and 5.3 months (95% CI: 4.3-6.0) in first- and second-line patients, respectively. CONCLUSION The efficacy and safety of sorafenib in routine community practice was generally good, especially in relation to OS in patients treated in the second line, where results were similar to those seen in recent prospective clinical trials.

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

AIM Pathological 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. METHODS A 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. RESULTS From 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. CONCLUSIONS In 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.

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.

Bone metastases affect prognosis but not effectiveness of third-line targeted therapies in patients with metastatic renal cell carcinoma.

INTRODUCTION Treatment of metastatic renal cell carcinoma (mRCC) has improved with the use of targeted therapies, but bone metastases continue to be negative prognostic factor. METHODS Patients with mRCC treated with everolimus (EV) or sorafenib (SO) after two previous lines of targeted therapies were included in the analysis. Overall survival (OS) and progression-free survival (PFS) were assessed based on the presence of bone metastases and type of therapy; they were also adjusted based on prognostic criteria. RESULTS Of the 233 patients with mRCC, 76 had bone metastases. Of the 233 patients, EV and SO were administered in 143 and 90 patients, respectively. Median OS was 10.4 months in patients with BMs and 17.4 months in patients without bone metastases (p = 0.002). EV decreased the risk of death by 18% compared to SO (adjusted hazard ratio [HR] 0.82, 95% confidence interval [CI] 0.74-0.91; p < 0.001), with comparable effects in patients with or without bone metastases. In the same manner, EV decreased the risk of progression by 12% compared to SO (adjusted HR 0.88, 95% CI 0.82-0.96; p = 0.002), but this difference was not significant in patients without bone metastases. The major limitations of the study are its retrospective nature, the heterogeneity of the methods to detect bone metastases, and the lack of data about patients treated with bisphosphonates. CONCLUSIONS The relative benefit of targeted therapies in mRCC is not affected by the presence of bone metastases, but patients without bone metastases have longer response to therapy and overall survival.

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.

Retrospective analysis of sorafenib as first- or second-line targeted therapy in patients with mRCC: Three-year Italian experience.

415 Background: The Retrospective analysis of Sorafenib (So) as the first- or second- target therapy (RESET) study in metastatic renal cell carcinoma (mRCC) patients assessed the use and safety of sorafenib under daily-life treatment conditions in a community-based patient population in Italian centers. METHODS RESET was a retrospective, observational, non-interventional field study in mRCC patients. Treatment decisions were determined by each physician according to local prescribing guidelines and clinical practice. Patients for whom a decision to treat with sorafenib single agent as first- or second- target therapy (TT) for mRCC has been made, were eligible for inclusion. Patients that started So treatment between January 1, 2008 and December 31, 2010 were included. Data collection started retrospectively in 2012, in order to have a period of observation of at least 1 year up to 31st Dec 2011. Endpoints included safety, overall survival (OS), progression-free survival (PFS), response rate (RR), and treatment duration. Subgroup analyses included age, Eastern Cooperative Oncology Group performance status, prior therapy, number of metastases, and line of TT with So. RESULTS From February to Jululy 2012, 358 pts from 37 Italian centers were enrolled. The most common ≥ grade 3 drug-related adverse events were hand-foot skin reaction (6.3%), rash (2.3%), hypertension, fatigue, and diarrhea (1.7% each). In the overall population, median OS was 17.2 months (mos) (95% CI 15.5 - 19.6 mos) and median PFS was 5.9 mos (95% CI 5.0-6.8 mos). Median duration of treatment with So was 5.09 mos. Complete response was observed in 3 (0.8%) pts, partial response in 53(15.0%) pts and stable disease in 139(39.4%) pts. In pts receiving So as first- or second- TT, median OS was 19.9 mos (95% CI 15.4-25.3 mos) and 16.6 mos (95% CI 13.1-18.4 mos) respectively, and median PFS was 6.6 mos (95% CI 4.9-9.3 mos) and 5.3 mos (95% CI 4.4-6.2 mos) respectively. CONCLUSIONS The efficacy and safety of So under routine clinical practice conditions in the setting of community-based practice in Italy were similar to that reported in prospective clinical trials. The efficacy of So was observed in the subgroup of pts receiving So as either the first or second TT for mRCC.

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. METHODS From 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. RESULTS At 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. CONCLUSIONS Our 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. METHODS From 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. RESULTS Median 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%. CONCLUSIONS T in multiple sequential lines demonstrated highly favorable outcomes in MBC pts. Overall the incidence of cardiac dysfunction was low.