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In January 2022, our institution launched a comprehensive cancer genome profiling program on 10 cancer types using a non-IVD solution named the TruSight Oncology 500 Assay provided by Illumina®. The assay analyzes both DNA and RNA, identifying Single-Nucleotide Variants (SNV)s and Insertion–Deletion (InDel) in 523 genes, as well as known and unknown fusions and splicing variants in 55 genes and Copy Number Alterations (CNVs), Mutational Tumor Burden (MTB) and Microsatellite Instability (MSI). According to the current European IVD Directive 98/79/EC, an internal validation was performed before running the test. A dedicated open-source bioinformatics pipeline was developed for data postprocessing, panel assessment and embedding in high-performance computing framework using the container technology to ensure scalability and reproducibility. Our protocols, applied to 71 DNA and 64 RNA samples, showed full agreement between the TruSight Oncology 500 assay and standard approaches, with only minor limitations, allowing to routinely perform our protocol in patient screening.

The implementation of cancer molecular characterization in clinical practice has improved prognostic re-definition, extending the eligibility to a continuously increasing number of targeted treatments. Broad molecular profiling technologies better than organ-based approaches are believed to serve such dynamic purposes. We here present the workflow our institution adopted to run a comprehensive cancer genome profiling in clinical practice. This article describes the workflow designed to make a comprehensive cancer genome profiling program feasible and sustainable in a large-volume referral hospital.

(1) Background: Drug development in oncology is changing rapidly. The aim of the present study was to provide an insight into the features of anti-tumor drugs approved in Europe; (2) Methods: We included all the indications for solid tumors issued by the European Medicines Agency (EMA) between 2015 and 2020. We extracted data from European Public Assessments Reports (EPAR), including drug name, mechanism of action, setting, features of pivotal clinical trials, primary end-points, quality of life (QoL); (3) Results: In the explored period, EMA issued 132 new indications (81 indications’ extensions) for 62 oncology drugs. In about half of indications (47%), the approval was biomarker-based. Immune check point inhibitors (ICIs) and signal transduction inhibitors were the two most representative drug categories (62%). Most of the indications were for the advanced setting (91%) and front-line therapy (66%). The most common tumor types were non-small cell lung cancer (24%), breast (16%), and melanoma (10%). Two thirds of the indications (73%) were approved based on phase III trials. Overall survival (OS) represented the primary end-point only in 39% of indications, mainly limited to advanced setting (98%) and ICI trials (80%). Almost all (94%) cell cycle and DNA repair mechanism inhibitors were approved based on progression free survival (PFS) data. In pivotal trials with signal transduction inhibitors, objective response rate (ORR) was the prevalent (45%) primary end-point. QoL was never considered as primary end-point; (4) Conclusions: In this analysis, we intended to offer an updated picture of the recent drug development in oncology. Most of the efforts led to broadening indications of pre-existing molecules, with signal transduction inhibitor and ICIs contending the leadership. Twenty-seven percent of the indication were approved without a phase III trial. The majority of drugs entered the market without evidence of OS or QoL benefit but based on surrogate outcomes.

Breast cancer is the leading cause of death in the female population and despite significant efforts made in diagnostic approaches and treatment strategies adopted for advanced breast cancer, the disease still remains incurable. Therefore, development of more effective systemic treatments constitutes a crucial need. Recently, several clinical trials were performed to find innovative predictive biomarkers and to improve the outcome of metastatic breast cancer through innovative therapeutic algorithms. In the pathogenesis of breast cancer, the phosphatidylinositol 3-kinase (PI3K)-protein kinase B (PKB/AKT)-mammalian target of rapamycin (mTOR) axis is a key regulator of cell proliferation, growth, survival, metabolism, and motility, making it an interest and therapeutic target. Nevertheless, the PI3K/AKT/mTOR cascade includes a complex network of biological events, needing more sophisticated approaches for their use in cancer treatment. In this review, we described the rationale for targeting the PI3K pathway, the development of PI3K inhibitors and the future treatment directions of different breast cancer subtypes in the metastatic setting.

This review provides a comprehensive update on recent evidence regarding gynecologic tumors associated with Lynch Syndrome (LS). Endometrial cancer (EC) and ovarian cancer (OC) are the first and second most common gynecologic malignancies in developed countries, respectively, and LS is estimated to be the hereditary cause in 3% of both EC and OC. Despite the increasing evidence on LS-related tumors, few studies have analyzed the outcomes of LS-related EC and OC stratified by mutational variant. This review aims to provide a comprehensive overview of the literature and comparison between updated international guidelines, to help outline a shared pathway for the diagnosis, prevention, and management of LS. Through the widespread adoption of the immunohistochemistry-based Universal Screening, LS diagnosis and identification of mutational variants could be standardized and recognized by international guidelines as a feasible, reproducible, and cost-effective method. Furthermore, the development of a better understanding of LS and its mutational variants will support our ability to better tailor EC and OC management in terms of prophylactic surgery and systemic treatment in the light of the promising results shown by immunotherapy.

Simple Summary Cervical cancer represents one of the main leading causes of cancer-related mortality in women worldwide. In contrast to patients with early-stage disease, those with advanced, recurrent, or metastatic cervical cancer have a poor prognosis and new treatment strategies are needed. Immunotherapy has recently modified the natural course of different tumors, such as melanoma and lung cancer. The aim of this review is to evaluate the possible role of immune checkpoint inhibitors in cervical cancer treatment. Abstract Human papillomavirus (HPV) infection is the recognized cause of almost all cervical cancers. Despite the reduction in incidence due to a wide use of screening programs and a specific vaccine, the prognosis of cervical cancer remains poor, especially for late-stage and relapsed disease. Considering the elevated rates of PD-L1 expression in up to 80% of cervical cancers, a strong rationale supports the use of immunotherapy to restore the immune response against tumor. The aim of this review is to analyze the possible role of immune checkpoint inhibitors in cervical cancer treatment, with a particular focus on the rationale and on the results of phase I and II clinical trials. An overview of ongoing phase III studies with possible future areas of development is also provided.

Introduction: Ovarian cancer (OC) represents the leading cause of death among gynecological cancers. Despite novel compound classes like vascular endothelial growth factor (VEGF) inhibitors or poly-ADP ribose polymerase (PARP) inhibitors are available, which improve significantly efficacy of platinum-based chemotherapy, OC prognosis remains poor and innovative strategies are needed. The induction of tumor specific immune response with a therapeutic intent is a very challenging approach. Oregovomab is a murine monoclonal antibody direct to the tumor-associated antigen CA125 that stimulate a host cytotoxic immune response against tumor cells expressing CA125. Areas covered: This paper reviews the preclinical and clinical published data underlying the use of oregovomab in advanced OC. A literature search was performed in PubMed for oregovomab, ovarian cancer, anti-CA125, and on ClinicalTrials.gov for currently ongoing trials. Expert opinion: Oregovomab demonstrated a significant improvement in progression-free and overall survival in advanced OC treatment when administered simultaneously with first-line chemotherapy. This promising schedule is currently investigated in a phase III trial. Since oral treatments as PARP-inhibitors have recently been approved in the OC first-line setting, the possible role of oregovomab needs still to be defined, also considering the intravenous route of administration. The easy to manage toxicity profile makes oregovomab an ideal candidate for association strategies.

Simple Summary Ovarian cancer treatment is the deadliest of gynecological cancers but the introduction of target therapies in its therapeutic algorithm has significantly improved outcomes. The aim of this article was to provide a review of completed and ongoing clinical trials involving the use of PARP inhibitors and/or immune checkpoint inhibitors for the treatment of ovarian cancer in front line and relapse settings. We confirmed the role of bevacizumab and PARP inhibitors which have transformed OC into a chronic disease while almost all trials involving immunotherapy were disappointing. Abstract Ovarian cancer treatment strategy is mainly based on three pillars: cytoreductive surgery, platinum-based chemotherapy, and targeted therapies. The latter in the last decade has provided a remarkable improvement in progression free patients and, hopefully, in overall survival. In particular, poly(adenosine diphosphate-ribose) polymerase (PARP) inhibitors exploit BRCA 1/2 mutations and DNA damage response deficiencies, which are believed to concern up to 50% of high grade epithelial ovarian cancer cases. While these agents have an established role in ovarian cancer treatment strategy in BRCA mutated and homologous recombination deficient patients, an appropriate predictive molecular test to select patients is lacking in clinical practice. At the same time, the impressive results of immunotherapy in other malignancies, have opened the space for the introduction of immune-stimulatory drugs in ovarian cancer. Despite immune checkpoint inhibitors as a monotherapy bringing only modest efficacy when assessed in pretreated ovarian cancer patients, the combination with chemotherapy, anti-angiogenetics, PARP inhibitors, and radiotherapy is believed to warrant further investigation. We reviewed literature evidence on PARP inhibitors and immunotherapy in ovarian cancer treatment.

Background. The management of small (≤ 1 cm), node-negative, HER2+ve BC is controversial, since data from randomized clinical trials specifically addressing the benefit of adjuvant systemic treatment with or without Trastuzumab in this setting are still lacking. The aims of this retrospective study are to assess how pts are managed in routinary clinical practice in Italy, whether clinical or biological features may influence the choice of adjuvant systemic therapy and if there is any difference in the outcome between treated and not treated pts. Patients and methods. Data of 268 consecutive pts who underwent surgery from January 2007 to December 2012 for HER2+ve, pT1a-b pN0 BC, were collected from 25 Italian centres. Descriptive statistical analyses and multivariate logistic regression models were used, with the aim of investigating the relationship between the baseline clinical and biological features and the adjuvant treatment strategy. Results. Pts characteristics were: median age 57, 69% postmenopausal status, 77% had conservative surgery, 32% pT1a, 68% pT1b, 48% G3, 66% ER+ve, 75% Ki67 ≥14%. Ninety percent of pts received adjuvant systemic therapy: 19% hormone therapy (HT) alone, 3% chemotherapy (CT) +/- HT, 64% Trastuzumab + CT +/- HT and 4% Trastuzumab + HT. At the multivariate analysis, the odds of being treated with adjuvant systemic therapy with or without Trastuzumab, resulted higher in presence of conservative surgery (p=0.002), pT1b (p Conclusion. This preliminary analysis shows that in Italy the majority of these pts received systemic adjuvant treatment and about 2/3 were treated with Trastuzumab. Pathological tumor size (pT1b) and negative hormone receptor status represent the main factors influencing the choice of including Trastuzumab in the adjuvant treatment. Survival data are still not mature to drive definitive conclusions about outcome. Citation Format: Stefania Gori, Monica Turazza, Simona Duranti, Elena Fiorio, Jennifer Foglietta, Marcella Gulisano, Ilaria Marcon, Marta Gubbiotti, Maria Giovanna Cavazzini, Simon Spazzapan, Valeria De Simone, Giancarlo Bisagni, Chiara Saggia, Luigi Cavanna, Emilio Bria, Laura Iezzi, Elisabetta Cretella, Patrizia Vici, Daniele Santini, Alessandra Fabi, Ornella Garrone, Antonella Ferro, Silvana Saracchini, Lucia Evangelisti, Sandro Barni, Lucia Mentuccia, Lucio Laudadio, Alessandro Inno, Gianluigi Lunardi, Francesca Coati, Luca Boni. The Promher Study: An observational Italian study on HER2+ve, pT1a-b, pN0, M0 breast cancer (BC) patients (pts) [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P5-18-05.

Background The combination of the dual HER1/HER2 inhibitor lapatinib (L) and capecitabine (C) is a therapeutic option for patients (pts) with HER2+MBC whose disease progresses after treatment with the monoclonal antibody trastuzumab. At present time, no clinical or pathological factors except HER2 status are clearly recognized as predictors of the activity of LC. We conducted a retrospective analysis of pts with HER2-positive metastatic breast cancer receiving LC after trastuzumab failure to identify factors associated with resistance to LC. Materials and methods We collected clinical and pathological data from 151 pts with HER2+ MBC receiving LC after failing a prior trastuzumab-based treatment (either adjuvant or for metastatic disease) treated at 13 Italian Institutions between March 2007 and December 2013. Time to progression (TTP) and overall survival (OS), calculated by the Kaplan Meier (KM) method, were from LC treatment beginning to disease progression or to death in the absence of progression (TTP), and to the date of death or to the date of last follow-up (OS), respectively. LC resistance was defined as TTP from treatment initiation lower or equal to the median TTP for the overall population. KM curves were compared by the Log-rank test. Logistic regression analysis was used to study predictors of TTP below the median value for patients receiving LC. Analyses were performed using SPSS version 17.0 (SPSS Inc., Chicago, IL). Results At a median follow-up of 41 months (IQR 23-62), median TTP to LC therapy was 7 months (IQR 5.5-8.5) and median OS was 18 months (IQR 10-28). Fifteen pts were excluded because of short follow-up (i.e. on LC treatment and Conclusions A short time to progression during capecitabine and lapatinib (LC-R) is associated with reduced OS in patients failing prior trastuzumab based therapy for HER2+ MBC. Patients who had modest clinical benefit from previous trastuzumab-based therapy could experience LC-R indicating the possibility of primary resistance to anti HER2-treatment. For these patients, alternative targeting strategies are urgently needed. Citation Format: Stefania Gori, Valentina Rossi, Monica Turazza, Elena Fiorio, Alessandra Fabi, Giancarlo Bisagni, Jennifer Foglietta, Daniele Santini, Ida Pavese, Alberto Zambelli, Patrizia Vici, Vita Leonardi, Sandro Barni, Silvana Saracchini, Giuseppe Bogina, Simona Duranti, Alessandro Inno, Gianluigi Lunardi, Filippo Montemurro. Multi-institutional retrospective analysis of clinical and pathological factors predicting resistance to lapatinib-based therapy in HER2 positive metastatic breast cancer (HER2+ MBC) [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P5-19-25.

Small (pT1a-b), node-negative (pN0) breast cancer generally has a good prognosis. However, HER2-positive status is associated with an increased risk of relapse and decreased survival even in these tumors. Although there are only few data from prospective randomized trials, results of retrospective studies suggest adjuvant chemotherapy plus trastuzumab may improve outcomes of patients with pT1a-b pN0 HER2-positive breast cancer. On the other hand, trastuzumab is potentially associated with increased cardiac toxicity, especially when combined with anthracycline-based chemotherapy. A valid strategy for improving cardiac safety is the addition of trastuzumab to non-anthracycline chemotherapy, whereas a shorter duration of trastuzumab should be not routinely considered although might represent an option for selected patients at low risk of relapse and very high risk of cardiac events. Therefore, the choice of adjuvant treatment for patients with pT1a-b pN0 HER2-positive breast cancer should be done on individual basis, carefully weighing benefits and risks.

Aromatase inhibitors represent an effective endocrine treatment for patients with hormone receptor-positive breast cancer, in early stage and in metastatic disease. However, by decreasing levels of serum estrogens they also potentially reduce the protective effect of estrogens on the cardiovascular system. Patients treated with aromatase inhibitors, in fact, compared with those who receive tamoxifen, more often develop hyperlipidemia, hypercholesterolemia, and hypertension, which are recognized risk factors for cardiovascular disease. This might raise some concerns especially in the adjuvant setting where the aim of treatment is the cure, and for postmenopausal patients who are already at risk for cardiovascular disease. However, whether the relative higher incidence of cardiac adverse events reported with aromatase inhibitors compared with tamoxifen is related to an actual cardiac toxicity of aromatase inhibitors rather than a cardioprotective effect of tamoxifen is still unclear. In this article we review the available literature on cardiotoxicity of aromatase inhibitors and provide some practical advice to improve the cardiovascular safety profile of these drugs.

Introduction This retrospective study was undertaken to investigate the impact of specific mutant KRAS on clinical outcome to either gefitinib or erlotinib (EGFR tyrosine kinase inhibitor, EGFR-TKI) in patients with EGFR wild type (WT) advanced non-small cell lung cancer (NSCLC). Methods Patients with an EGFR WT genotype who were treated with an EGFR-TKI for advanced disease at our Institution were identified. Simultaneous availability of KRAS mutation status was required for study inclusion. Results Sixty-seven patients were eligible. Median age was 60 years (39–84), and 10 patients (14.9%) had received an EGFR-TKI as upfront therapy. Overall, the median progression-free survival (PFS) and overall survival (OS) were 2.9 months and 18.0 months, respectively. KRAS mutant patients ( n =18) experienced a significantly shorter PFS compared with those carrying a KRAS WT genotype ( n =49) (1.6 months vs 3.0 months, respectively, P =0.04; HR=1.92). However, within the KRAS mutant group a great variability in terms of sensitivity to treatment was noted (PFS ranging from 0.7 months to 38.7 months). KRAS codon 13 mutant patients ( n =4) experienced the worse outcome when compared with KRAS codon 12 mutants ( n =14) and KRAS WT patients ( P P =0.01 for PFS and OS, respectively). Conclusions Though we found that EGFR WT/ KRAS mutant advanced NSCLC patients are associated with an increased resistance to treatment, specific mutant KRAS may account for differential sensitivity to an EGFR-TKI. KRAS codon 13 mutants are those who seem to experience the worse clinical outcome.

Background There are no validated predictive markers for lapatinib and capecitabine in patients with trastuzumab-resistant HER2 positive metastatic breast cancer. Methods Data of 148 consecutive patients treated with lapatinib and capecitabine from March 2007 to December 2013 were collected from 13 Italian institutions. Estimates of progression-free survival (PFS) and overall survival (OS) were obtained with the Kaplan-Meier method and compared with logrank test. The association of clinicopathological variables and the outcome was studied by binary logistic regression analysis and Cox proportional hazard analysis. Results At a median follow-up of 41 months, median PFS and OS were 7 and 21 months, respectively. Patents with a PFS longer than 7 months had a significantly longer OS, compared with patients with a PFS equal to or shorter than 7 months (36 vs 15 months; p

The management of pT1a-b pN0 HER2-positive breast cancer is controversial and no data about the efficacy of trastuzumab in this setting are available from randomized clinical trials. The aims of this retrospective study were to assess how patients are managed in clinical practice in Italy, which clinical or biological characteristics influenced the choice of adjuvant systemic therapy and the outcome of patients.Data of consecutive patients who underwent surgery from January 2007 to December 2012 for HER2-positive, pT1a-b pN0 M0 breast cancer were retrospectively collected from 28 Italian centres. Analysis of contingency tables and multivariate generalized logit models were used to investigate the association between the baseline clinical and biological features and the treatment strategy adopted.Among 303 enrolled patients, 204 received adjuvant systemic therapy with trastuzumab, 65 adjuvant systemic therapy without trastuzumab and 34 did not receive adjuvant systemic therapy. At the multivariate analysis age, tumor size, proliferation index and hormone receptor status were significantly associated with the treatment choice. Five-year disease-free survival (DFS) probability was 95%, 94.3% and 69.6% for patients treated with adjuvant systemic therapy and trastuzumab, with adjuvant systemic therapy without trastuzumab and for patients who did not receive adjuvant systemic therapy, respectively (p

UNLABELLED : Neuroendocrine carcinoma of the breast is considered a rare entity, and for this reason there are no data from prospective clinical trials on its optimal management. Early stage tumors are usually treated with the same strategy used for the other types of invasive breast cancer. Anthracycline- and taxane-based regimens represent the most frequently administered chemotherapy in neoadjuvant and adjuvant setting, as well as for metastatic disease, although combinations of platinum compounds and etoposide have been widely used, in particular for small-cell histology and tumors with a high proliferation index. For metastatic disease, a multimodality therapeutic strategy can be considered on an individual basis, with chemotherapy, endocrine therapy, peptide receptor radionuclide therapy, radiation therapy, surgery, or a combination of the above. In the near future, a better knowledge of the biology of these tumors will hopefully provide new therapeutic targets for personalized treatment. In this review, we discuss the current evidence and the future perspectives on diagnosis and treatment of neuroendocrine carcinoma of the breast. IMPLICATIONS FOR PRACTICE Neuroendocrine carcinoma of the breast (NECB) is a distinct entity of breast cancer. Clinical features and morphology are not helpful to distinguish NECB from other subtypes of breast cancer; therefore, immunohistochemistry markers for neuroendocrine differentiation, mainly chromogranin and synaptophysin, should be routinely used to confirm the diagnosis, especially in cases of mucinous or solid papillary carcinoma in which the suspicion of NECB may be relevant. Adjuvant treatment should be offered according to the same recommendations given for the other types of invasive breast cancer. An accurate diagnosis of NECB is also important in the metastatic setting, in which a multimodality approach including specific therapies such as peptide receptor radionuclide therapy can be considered.

Small cell lung cancer (SCLC) is a biologically complex tumor whose medical treatment has remained largely unchanged over the last 30 years. The frustration for the invariably negative results reported in the early 2000s in clinical studies investigating new agents for this disease have contributed to the little interest shown by pharmaceutical industries in funding SCLC research. However, recent advances in the molecular understanding of the oncogenic mechanisms underlying SCLC have renewed the attraction for the clinical development of novel active drugs for the treatment of this challenging disease.The authors briefly touch on the most promising agents under clinical development for the treatment of SCLC, either chemotherapeutic or targeted drugs. Relevant and recent (2 years) studies obtained through Pubmed literature research or released at International scientific meetings are presented.The data discussed herein provide evidence in support of the fact that only rationally designed clinical trials including relevant translational research may lead to successful results. Therefore, a thoughtful change in trial construction is crucial for the approval of new active drugs for this orphan disease.

e18023 Background: Treatment with a reversible EGFR-TKI may benefit pts with EGFR WT advanced NSCLC, though to a much lesser extent than pts carrying an activating mutation in the EGFR gene. We assessed whether KRAS mutational status would help predict sensitivity to gefitinib or erlotinib in EGFR WT advanced NSCLC pts. Methods: Sixty-seven EGFR WT, advanced NSCLC pts treated with a reversible EGFR-TKI in any line setting were included. Pts were treated from May 2005 to March 2011 at the Medical Oncology of the Perugia Hospital. EGFR (exons 18 to 21) and KRAS (codons 12, 13 and 61) genes were amplified by nested PCR and sequenced in both sense and antisense directions. Results: Median age was 60 years (39-84); 52 pts (77.6%) were PS 0 or 1; 58 pts (86.6%) belonged to the non-squamous subtype and 22 pts (32.8%) were never-smokers. Eighteen pts (26.8%) were KRAS mutant (MUT), of which 14 pts at codon 12 (COD 12 MUT) and 4 pts at codon 13 (COD 13 MUT). Overall, 11 pts (16.4%) responded to treatment and 8 pts (11.9%) achieved stable disease, for a disease control rate of 28.3%. At a median follow-up of 25.2 months, median progression-free survival (PFS) and overall survival (OS) were 2.9 and 29.5 months, respectively. When analyzed according to KRAS status, a significantly shorter PFS was noted for the EGFR WT/KRAS MUT subgroup (N=18) compared with the EGFR WT/KRAS WT population (N=49) (1.6 vs. 3.0 months, respectively, p=0.04). However, no significant difference was observed between the two groups in terms of OS (18.0 vs. 34.8 months, respectively, p=0.42). Within the EGFR WT/KRAS MUT subrgoup a significantly longer PFS was reported for COD 12 MUT pts compared with COD 13 MUT pts (1.7 vs 0.7 months, respectively, p=0.04). Similarly, KRAS COD 12 MUT pts experienced a statistically significant superior OS compared with COD 13 MUT pts (36.2 vs 7.4 months, respectively, p=0.003). Conclusions: EGFR WT/KRAS MUT pts appear to be more resistant to treatment with a reversible EGFR-TKI, the greatest resistance occurring in COD 13 MUT pts. KRAS COD 12 MUT pts may represent a clinically distinct subgroup of KRAS mutants with a particularly favorable prognosis.

e18101 Background: All mutated non-small cell lung cancer (NSCLC) patients (pts) previously treated with an EGFR reversibile inhibitor, develop, soon or later, resistance. Afatinib is a potent irreversible HER family inhibitor, with preclinical data suggesting activity against the resistance mutation EGFR T790M. From August 2005 to January 2011, in a retrospective observational study at our Division of Medical Oncology, we have evaluated 22 advanced NSCLC pts, who have been treated with Afatinib, after disease progression with Erlotinib or Gefitinib. Methods: 22 advanced NSCLC pts who have previously received a reversible EGFR-TKI (gefitinib or erlotinib), and subsequently have been treated with Afatinib in a different setting of their medical history, were included in the analysis. Afatinib was provided in an expanded access program by Boehringer. Results: Patients characteristics: median age 64 ys (34-85); PS 0-1; most of pts were never smokers (82%) with non-squamous histology. 12 pts (54%) had multi-metastatic sites at diagnosis, 4 of which (33%) had brain lesions. Nineteen pts (86%) were found to be EGFR mutated (15 patients with EGFR-sensitizing mutations at exon 19 and 21). No one was K-RAS mutated. Eighteen pts (82%) received Afatinib in a second line TKI setting and 4 pts (18%) in a third line. Overall, 4 pts (18%), 2 of which had a multi-metastatic disease at diagnosis, had a partial response to Afatinib and 11 pts (50%) achieved a stable disease. Of the 16 pts evaluable for response in the second line setting, median progression-free survival (PFS) was 5,2 months. Diarrhea and skin rash were the most common adverse events but a dose-limiting toxicity was observed in only three patients. Conclusions: Our experience confirmed Afatinib clinical activity in patients with acquired resistance to prior reversible TKI. The treatment has been well tolerated and there were no new or unexpected safety findings.

7580 Background: In the present analysis we evaluated the clinical outcome of KRAS mutated advanced non-small cell lung cancer (NSCLC) patients (pts) treated at a single Institution from April 2007...

Background In this retrospective analysis we assessed whether KRAS mutation would affect the clinical outcome of EGFR WT advanced NSCLC pts treated with a first-line platinum-based chemotherapy. Moreover, the effect of specific mutant KRAS was evaluated. Methods One hundred and ninety-five EGFR WT, advanced NSCLC pts were included in the analysis. Study pts were treated at the Medical Oncology of the Perugia Hospital from Jan 2005 to March 2012. EGFR (exons 18 to 21) and KRAS (codons 12, 13 and 61) genes were amplified by nested PCR and sequenced in both sense and antisense directions. Results Median age was 60 years (29-81); 181 pts (92.8%) were PS 0 or 1; 155 pts (79.4%) belonged to the non-squamous subtype and 39 pts (20.0%) were never-smokers. Treatment was as follows: platinum + a third generation agent in 103 pts (52.8%); platinum + pemetrexed in 81 pts (41.6%); platinum-based doublet + bevacizumab in 11 pts (5.6%). Seventy-five pts (38.4%) were KRAS mutant (MUT), of which 60 pts at codon 12 (COD 12 MUT), 12 pts at codon 13 (COD 13 MUT) and 3 pts at codon 61 (COD 61 MUT). The most common amino acid changes found were: Gly12Cys (29 pts), Gly12Val (11 pts) and Gly13Cys (10 pts). In the whole study population, 69 pts (35.3%) responded to treatment and 62 pts (31.7%) achieved stable disease, for a disease control rate of 67.0%. At a median follow-up of 14 months (2-102), median progression-free survival (PFS) and overall survival (OS) were 6.2 and 21.6 months, respectively. When analyzed according to KRAS mutation status, a significantly shorter PFS was noted for the EGFR WT/KRAS MUT subgroup (n = 75) compared with the EGFR WT/KRAS WT population (n = 120) [5.1 vs 6.6 months, respectively, P = 0.02; HR = 1.43 (95% CI, 1.05 to 1.95)]. Similarly, a significant difference was observed between the two groups in terms of OS [13.7 vs 26.1 months, respectively, P = 0.02; HR = 1.56 (95% CI, 1.06 to 2.30)]. In the EGFR WT/KRAS MUT subrgoup, OS for COD 12 MUT, COD 13 MUT and COD 61 MUT was 17.2, 10.2 and 8.0 months, respectively, P = 0.17. Multivariate analysis for PFS and OS confirmed that KRAS mutation was an independent predictor of poorer oucome. Conclusions EGFR WT/KRAS MUT pts appear to experience a less favorable prognosis compared with the EGFR WT/KRAS WT genotype, with a significant difference in clinical outcome according to the mutant codon of KRAS. Disclosure All authors have declared no conflicts of interest.

Simple Summary Considering the high incidence and mortality of breast cancer, a lot of trials evaluating new drugs for the treatment of this disease are currently ongoing. However, few drugs show a statistically and clinically significant improvement in the outcomes leading to the Competent Authority approval. In this review we analyzed the European Medicines Agency breast cancer drug indications issued between January 2015 and June 2021 and we evaluated the clinical trials results leading to the approval and their update. Abstract Breast cancer represents the first cause of cancer worldwide and the leading cause of cancer mortality for women. Therefore, new therapies are needed to improve the prognosis of women diagnosed with this disease. In this review, we summarize the new drug indications for the treatment of breast cancer approved by European Medicines Agency between January 2015 and June 2021. In particular, we analyzed the clinical trials results leading to approvals and their update (when available), according to setting (localized and locally advanced or metastatic) and clinical features (hormone receptor positive, HER2 positive, triple negative, BRCA 1/2 mutation). The aim of this paper is to describe the clinical benefit obtained with the new indications.