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Supplemental material, sj-docx-1-tam-10.1177_17588359211059873 for PANHER study: a 20-year treatment outcome analysis from a multicentre observational study of HER2-positive advanced breast cancer patients from the real-world setting by Laura Pizzuti, Eriseld Krasniqi, Isabella Sperduti, Maddalena Barba, Teresa Gamucci, Maria Mauri, Enzo Maria Veltri, Icro Meattini, Rossana Berardi, Francesca Sofia Di Lisa, Clara Natoli, Mirco Pistelli, Laura Iezzi, Emanuela Risi, Nicola D���Ostilio, Silverio Tomao, Corrado Ficorella, Katia Cannita, Ferdinando Riccardi, Alessandra Cassano, Emilio Bria, Maria Agnese Fabbri, Marco Mazzotta, Giacomo Barchiesi, Andrea Botticelli, Giuliana D���Auria, Anna Ceribelli, Andrea Michelotti, Antonio Russo, Beatrice Taurelli Salimbeni, Giuseppina Sarobba, Francesco Giotta, Ida Paris, Rosa Saltarelli, Daniele Marinelli, Domenico Corsi, Elisabetta Maria Capomolla, Valentina Sini, Luca Moscetti, Lucia Mentuccia, Giuseppe Tonini, Mimma Raffaele, Luca Marchetti, Mauro Minelli, Enzo Maria Ruggeri, Paola Scavina, Olivia Bacciu, Nello Salesi, Lorenzo Livi, Nicola Tinari, Antonino Grassadonia, Angelo Fedele Scinto, Rosalinda Rossi, Maria Rosaria Valerio, Elisabetta Landucci, Simonetta Stani, Beatrice Fratini, Marcello Maugeri-Sacc��, Michele De Tursi, Angela Maione, Daniele Santini, Armando Orlandi, Vito Lorusso, Enrico Cortesi, Giuseppe Sanguineti, Paola Pinnar��, Federico Cappuzzo, Lorenza Landi, Claudio Botti, Federica Tomao, Sonia Cappelli, Giulia Bon, Fabio Pelle, Flavia Cavicchi, Elena Fiorio, Jennifer Foglietta, Simone Scagnoli, Paolo Marchetti, Gennaro Ciliberto and Patrizia Vici in Therapeutic Advances in Medical Oncology

Additional File 2: Supplementary Table 2 (S2). Distribution of CTCAE G2-3 fatigue and neurotoxicity by age and arm of treatment. Reported as N (%) unless otherwise indicated. Abbreviations: CTCAE, Common Terminology Criteria for Adverse Events.

Additional File 1: Supplementary Table 1 (S1). Distribution of AEs by arm in patients aged ≥75 years. Abbreviations: CTCAE, Common Terminology Criteria for Adverse Events; /, grade does not exist for this adverse event; ° grade 5 n=1.

The present analysis focuses on real-world data of Everolimus-Exemestane in advanced HR+ve, HER2-ve elderly breast cancer patients (aged 65 years) included in the EVA study, with unique findings in those aged 70 years.Data are collected from clinical records and analysed according to age cut-off (65 years; 65 - 69 years and {greater than or equal to} 70 years). Relationship of analyzed variables with response were tested by mean of a Mantel-Haenszel chi square test. Time to event analysis was described by Kaplan Meier approach and association with baseline characteristics was analysed by stratified log-rank test and proportional hazard model.From July 2013 to December 2015, the EVA study enrolled overall 404 pts. 154 patients out of 404 (38,1%) were aged {greater than or equal to} 65 years, of whom 87 were {greater than or equal to} 70 years. Median duration of EVE treatment was 28.5 weeks (95% CI 19.0 - 33.8) in patients aged 65-69 years and 24,4 weeks (95% CI 19,2 - 33,2) in those aged {greater than or equal to} 70 years. Fewer patients aged 65 years received the highest EVE Dose-Intensity (7.5 mg/day) in comparison to younger patients (49,6% vs. 66,8%). Grade 3-4 toxicities occurred to 55 patients (35,7%), mainly stomatitis (10,9%), rash (5,8%) and non-infectious pneumonitis (NIP) (3,6%). Some toxicities, such as weight loss and anaemia were peculiarly observed in patients aged {greater than or equal to} 70 years. Five treatment-related deaths were collected (3,2%).EVE-EXE combination remains one of the potential treatments in HR+ patients also for elderly ones.

Background: Angiogenesis is essential for tumor growth and development of metastases in human breast cancer. Randomized studies have shown that bevacizumab (inhibitor of VEGF) combined with taxane-based regimens increases response rates and prolongs Progression-Free Survival (PFS) of patients with Metastatic Breast Cancer (MBC). However predictive or prognostic markers that identify the appropriate target population, thus improving the cost-effectiveness ratio of this treatment, are still needed. In this retrospective analysis, we investigated the impact of traditional clinical and pathological features in order to identify the subgroups of patients who derive the greatest benefit from antiangiogenic-agents. Patients and methods: Retrospectively, we included consecutive patients treated with bevacizumab (10 mg/Kg on days 1 and 15) and paclitaxel (90 mg/m2, on days 1, 8 and 15) as first-line treatment for HER2-negative MBC at our Institution between June 2007 and December 2012. Results: 33 patients were included. Median age was 50 years (31-68). 78. 8%, 12.1% and 9.1% of patients had luminal B, triple negative and luminal A breast cancer, respectively. 66. 6% of patients had visceral disease. The overall response rate was 31.2%. Median PFS and overall survival (OS) were 7.7 months (range 1. 9-14.0 months) and 95.2 months (range 11.6-205.8 months), respectively. Univariate analysis highlighted a statistically significant relationship between PFS to the first line and the following factors: relapse-free survival (RFS 12 months; p

Rossana Berardi, Matteo Santoni, Francesca Morgese, Zelmira Ballatore, Agnese Savini, Azzurra Onofri, Paola Mazzanti, Mirco Pistelli, Chiara Pierantoni, Mariagrazia De Lisa, Miriam Caramanti, Silvia Pagliaretta, Chiara Pellei, Stefano CascinuMedical Oncology Unit, Universita Politecnica delle Marche, Azienda Ospedaliero-Universitaria Ospedali Riuniti Umberto I – GM Lancisi – G Salesi, Ancona, ItalyAbstract: In the last decade, better understanding of the role of epidermal growth factor receptor in the pathogenesis and progression of non-small cell lung cancer has led to a revolution in the work-up of these neoplasms. Tyrosine kinase inhibitors, such as erlotinib and gefitinib, have been approved for the treatment of non-small cell lung cancer, demonstrating an improvement in progression-free and overall survival, particularly in patients harboring activating EGFR mutations. Nevertheless, despite initial responses and long-lasting remissions, resistance to tyrosine kinase inhibitors invariably develops, most commonly due to the emergence of secondary T790M mutations or to the amplification of mesenchymal–epithelial transition factor (c-Met), which inevitably leads to treatment failure. Several clinical studies are ongoing (http://www.clinicaltrials.gov/), aimed to evaluate the efficacy and toxicity of combined approaches and to develop novel irreversible or multitargeted tyrosine kinase inhibitors and mutant-selective inhibitors to overcome such resistance. This review is an overview of ongoing Phase I, II, and III trials of novel small molecule epidermal growth factor receptor inhibitors and combinations in non-small cell lung cancer patients.Keywords: clinical trials, combined targeted therapy, epidermal growth factor receptor, non-small cell lung cancer, novel targeted agents, tyrosine kinase inhibitors

Breast cancer (BC) heterogeneity is composite in nature, with a wide variety of factors concurring to define several pathological entities, which differ by clinical presentation, pathologic features, therapy administered, and inherent outcomes1. Additional sources of breast cancer heterogeneity may raise during the disease course. In BC patients whose disease was initially diagnosed in the early stage and subsequently progressed with metastatic involvement of one single or multiple site/s, the molecular characteristics of metastatic lesions do not necessary mimic those of the disease initially diagnosed. A well-depicted molecular landscape is crucial for subtype definition, prognostic evaluation and appropriate therapeutic decisions. Accordingly, current guidelines suggest repeating the immunohistochemical (IHC) assessment in patients with metastatic spread and at least one secondary lesion amenable to biopsy2. Discordance in human epidermal growth factor receptor 2 (HER2) status between the tumor and metastatic lesions is widely acknowledged, and not yet completely unraveled in their biologic meaning and prognostic relevance3–11. The overexpression of HER2 or amplification of the related gene is extensively recognized as a feature associated with more aggressive biological behavior12,13. However, the extent to which changes in HER2 status may affect patients’ prognosis is still a matter of debate14. We herein propose an observational study of HER2-positive metastatic breast cancer (mBC) patients treated with the anti-HER2 targeted agents pertuzumab and/or trastuzumab emtansine (T-DM1). Our research question is whether relevant differences exist in long-term outcomes of patients with concordant HER2 status between the primary tumor and its secondary lesion/s compared to patients whose disease revealed HER2-positivity gain at the IHC assessment of metastatic lesions. In our historical cohorts, we also sought to identify factors associated with HER2-positivity gain at the IHC reassessment, for which an impact on prognosis may be foreseen.

Background Limited data are available regarding the use of nab-paclitaxel in older patients with breast cancer. A weekly schedule is recommended, but there is a paucity of evidence regarding the optimal dose. We evaluated the efficacy of two different doses of weekly nab-paclitaxel, with a specific focus on their corresponding impact on patient function, in order to address the lack of data specifically relating to the older population. Methods EFFECT is an open-label, phase II trial wherein 160 women with advanced breast cancer aged ≥ 65 years were enrolled from 15 institutions within Italy. Patients were randomly assigned 1:1 to receive nab-paclitaxel 100 mg/m2 (arm A) or 125 mg/m2 (arm B) on days 1, 8, and 15 on a 28-day cycle, as first-line treatment for advanced disease. The primary endpoint was event-free survival (EFS), wherein an event was defined as disease progression (PD), functional decline (FD), or death. In each arm, the null hypothesis that the median EFS would be ≤ 7 months was tested against a one-sided alternative according to the Brookmeyer Crowley test. Secondary endpoints included objective response rate (ORR), clinical benefit rate (CBR), progression-free survival (PFS), overall survival (OS), and safety. Results After a median follow-up of 32.6 months, 140 events were observed in 158 evaluable patients. Median EFS was 8.2 months (90% CI, 5.9–8.9; p = 0.188) in arm A vs 8.3 months (90% CI, 6.2–9.7, p = 0.078) in arm B. Progression-free survival, overall survival, and response rates were similar in both groups. A higher percentage of dose reductions and discontinuations due to adverse events (AEs) was noted in arm B. The most frequently reported non-haematological AEs were fatigue (grade [G] 2–3 toxicity occurrence in arm A vs B, 43% and 51%, respectively) and peripheral neuropathy (G2–3 arm A vs B, 19% and 38%, respectively). Conclusion Pre-specified outcomes were similar in both treatment arms. However, 100 mg/m2 was significantly better tolerated with fewer neurotoxicity-related events, representing a more feasible dose to be recommended for older patients with advanced disease. Trial registration EudraCT, 2012-002707-18. Registered on June 4, 2012. NIH ClinicalTrials.gov, NCT02783222. Retrospectively registered on May 26, 2016.

Data from 423 human epidermal growth factor receptor 2-negative (HER2−), hormone receptor-positive (HR+) advanced breast cancer (aBC) patients treated with palbociclib and endocrine therapy (ET) were provided by 35 Italian cancer centers and analyzed for treatment outcomes. Overall, 158 patients were treated in first line and 265 in second/later lines. We observed 19 complete responses and 112 partial responses. The overall response rate (ORR) was 31% (95% confidence interval [CI], 26.6–35.4) and clinical benefit was 52.7% (95% CI, 48–57.5). ORR was negatively affected by prior exposure to everolimus/exemestane (p = 0.002) and favorably influenced by early line-treatment (p < 0.0001). At 6 months, median progression-free survival was 12 months (95% CI, 8–16) and median overall survival was 24 months (95% CI, 17–30). More favorable outcomes were associated with palbociclib in early lines, no visceral metastases and no prior everolimus/exemestane. The main toxicity reported was neutropenia. Our results provide further support to the use of palbociclib with ET in HER2−, HR+ aBC. Differences in outcomes across patients subsets remain largely unexplained.

[This corrects the article DOI: 10.18632/oncotarget.25874.].

BACKGROUND: The present analysis focuses on real-world data of Everolimus- Exemestane in advanced HR+ve, HER2-ve elderly breast cancer patients (aged 65 years) included in the EVA study, with unique findings in those aged 70 years. METHODS: Data are collected from clinical records and analysed according to age cut-off (< 65 years; 65 - 69 years and [greater than or equal to] 70 years). Relationship of analyzed variables with response were tested by mean of a Mantel- Haenszel chi square test. Time to event analysis was described by Kaplan Meier approach and association with baseline characteristics was analysed by stratified log-rank test and proportional hazard model. RESULTS: From July 2013 to December 2015, the EVA study enrolled overall 404 pts. 154 patients out of 404 (38,1%) were aged [greater than or equal to] 65 years, of whom 87 were [greater than or equal to] 70 years. Median duration of EVE treatment was 28.5 weeks (95% CI 19.0 - 33.8) in patients aged 65-69 years and 24,4 weeks (95% CI 19,2 - 33,2) in those aged [greater than or equal to] 70 years. Fewer patients aged 65 years received the highest EVE Dose-Intensity (> 7.5 mg/day) in comparison to younger patients (49,6% vs. 66,8%). Grade 3-4 toxicities occurred to 55 patients (35,7%), mainly stomatitis (10,9%), rash (5,8%) and non-infectious pneumonitis (NIP) (3,6%). Some toxicities, such as weight loss and anaemia were peculiarly observed in patients aged [greater than or equal to] 70 years. Five treatment-related deaths were collected (3,2%). CONCLUSIONS: EVE-EXE combination remains one of the potential treatments in HR+ patients also for elderly ones.

The aim of the study was to determine the potential role of occupational exposures to chromium (Cr) in the onset of extragonadal germinal embryonal carcinoma. The first two cases of workers in a company with Cr exposure are reported. The published scientific literature regarding the topic in peer-reviewed journals including MEDLINE and CancerLit databases was extensively reviewed. Two young patients who were coworkers in the same company, exposed to Cr, developed extragonadal germinal embryonal carcinomas. One of them also developed angiosarcoma of the mediastinum. To the best of our knowledge these are the first two cases of germinal embryonal carcinoma in patients with occupational exposure to Cr The aim of the study was to determine the potential role of occupational exposures to chromium (Cr) in the onset of extragonadal germinal embryonal carcinoma. The first two cases of workers in a company with Cr exposure are reported. The published scientific literature regarding the topic in peer-reviewed journals including MEDLINE and CancerLit databases was extensively reviewed. Two young patients who were coworkers in the same company, exposed to Cr, developed extragonadal germinal embryonal carcinomas. One of them also developed angiosarcoma of the mediastinum. To the best of our knowledge these are the first two cases of germinal embryonal carcinoma in patients with occupational exposure to Cr.

Background/aims Breast cancer is the most common tumor in women and the first cause of death for malignancy in the female population. Bile ducts are not among the common sites of metastasis from breast cancer; few cases of obstructive jaundice due to metastatic breast cancer have been described in the literature and they mostly resulted from widespread liver metastases that eventually involved the bile ducts. We report an exceptional case of metastatic infiltration of the extrahepatic bile ducts in absence of liver metastases. Case presentation A 56-year-old woman who had undergone a right mastectomy 13 years earlier due to infiltrating ductal breast cancer and had remained tumor free, presented at a follow-up examination with obstructive jaundice. Imaging (computed tomography, magnetic resonance and endoscopic retrograde cholangiopancreatography) scans showed features that were suggestive of a primary tumor of the extrahepatic bile duct. At surgery, the intraoperative findings were also those of a tumor of the bile duct, however, an histological examination showed no evidence of malignancy in the mucosa, but did shown an infiltration of the external wall from adenocarcinoma. Immunohistochemistry analysis demonstrated that the tumor was metastatic breast cancer. Conclusions Indeterminate stenosis of the extrahepatic bile ducts should be examined with suspicion in women with a history of breast cancer, and bile duct metastases are to be considered among the possible diagnoses. A differential diagnosis from cholangiocarcinoma is of paramount importance and mainly relies on pathology.