The treatment of epidermal growth factor receptor (EGFR)-mutant non-small-cell lung cancer (NSCLC) patients was dramatically revolutionized by the introduction of EGFR tyrosine kinase inhibitors in clinical practice, both in advanced and locally advanced/early stages. The present work focuses on osimertinib use in locally advanced and early NSCLC stages. Phase 3 clinical trials have supported the use of osimertinib as the new standard of care, both in the adjuvant setting and in locally advanced disease. The ADAURA study reported an overall survival (OS) advantage for adjuvant osimertinib in completely resected stage II-IIIA EGFR-mutant tumors, while the LAURA study proved a statistically significant benefit in progression-free survival (PFS) and a delay of central nervous system metastasis development in EGFR-mutant patients treated with osimertinib maintenance after concurrent chemoradiotherapy for locally advanced disease. In the neoadjuvant setting, data on osimertinib’s efficacy are conflicting; therefore, the Neo-ADAURA study is evaluating the efficacy and safety of neoadjuvant osimertinib alone or in combination with chemotherapy in patients with stage II-IIIB NSCLC and common EGFR mutations. We discuss several issues that need to be clarified, such as the efficacy of the drug on uncommon mutations, the long-term impact on survival, and the management of resistance mechanisms. Moreover, we report the studies that are trying to identify potential biomarkers of response, such as the circulating tumor DNA (ctDNA), with the aim of selecting patients who will benefit most from osimertinib.

Estrogen receptor (ER)-positive breast cancer (BC) is the most common BC subtype. Endocrine therapy (ET) targeting ER signaling still remains the mainstay treatment option for hormone receptor (HR)-positive BC either in the early or in advanced setting, including different strategies, such as the suppression of estrogen production or directly blocking the ER pathway through SERMs—selective estrogen receptor modulators—or SERDs—selective estrogen receptor degraders. Nevertheless, the development of de novo or acquired endocrine resistance still remains challenging for oncologists. The use of novel ET combined with targeted drugs, such as cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitors, has significantly improved long-term outcome rates, thus changing the therapeutic algorithm for metastatic BC (MBC) and recently the therapeutic strategy in the adjuvant setting for early high-risk BC. Eluding the resistance to CDK4/6 inhibitors combined with ET is currently an unmet medical need, and there is disagreement concerning the best course of action for patients who continue to progress after this combination approach. Genetic changes in the tumor along its growth uncovered by genomic profiling of recurrent and/or metastatic lesions through tumor and/or liquid biopsies may predict the response or resistance to specific agents, suggesting the best therapeutic strategy for each patient by targeting the altered ER-dependent pathway (novel oral SERDs and a new generation of anti-estrogen agents) or alternative ER-independent signaling pathways such as PI3K/AKT/mTOR or tyrosine kinase receptors (HER2 mutations or HER2 low status) or by inhibiting pathways weakened through germline BRCA1/2 mutations. These agents are being investigated as single molecules and in combination with other target therapies, offering promising weapons to overcome or avoid treatment failure and propose increasingly more personalized treatment approaches. This review presents novel insights into ET and other targeted therapies for managing metastatic HR+/HER2− BC by exploring potential strategies based on clinical evidence and genomic profiling following the failure of the CDK4/6i and ET combination.

Introduction: In recent years, several inflammation-related factors and nutritional parameters have been evaluated to develop prognostic scores as potential biomarkers in non-small-cell lung cancer (NSCLC) patients receiving immune checkpoint inhibitors (ICIs). The aim of this study was to retrospectively investigate the prognostic role of the advanced lung cancer inflammation (ALI) index, lung immune prognostic index (LIPI), prognostic nutritional index (PNI) and systemic inflammation score (SIS) in metastatic NSCLC patients receiving ICI alone or in combination with chemotherapy. Methods and patients: We retrospectively included 191 patients with advanced NSCLC who received first-line ICI with or without chemotherapy from 2017 to 2024. The association between pretreatment ALI, LIPI, PNI, and SIS and overall survival (OS) was evaluated using the Kaplan-Meier method and Cox regression models. Results: After a median follow-up of 27.7 months, significantly longer OS was associated with an ALI score > 18 vs. <= 18 (18.0 vs. 7.3 months; p = 0.00111), LIPI score 0 vs. 1 and 2 [18.9 vs. 8.2 and 4.2 months; (p = 0.001)], PNI >= 45 vs. <45 (22.7 vs. 9.6 months; p = 0.002), and SIS score 0 vs. 1 and 2 (27.4 vs. 7.1 and 8.6 months, respectively; p < 0.001). The OS benefit was independent of treatment (ICI vs. ICI + chemotherapy). At multivariate analysis, pretreatment albumin was positively associated with OS, while ECOG PS 1 and liver metastases were negatively associated with OS. Conclusions: Inflammatory and nutritional biomarkers such as the ALI, LIPI, PNI, and SIS represent useful tools to prognosticate survival in metastatic lung cancer patients treated with ICI alone or in combination with chemotherapy as first-line.

Endocrine therapy (ET) targeting estrogen receptor (ER) signaling is still the mainstay treatment option for early or advanced ER-positive breast cancer (BC) and may involve suppressing estrogen production by means of aromatase inhibitors or directly blocking the ER pathway through selective estrogen receptor modulators such as tamoxifen or selective estrogen receptor degraders such as fulvestrant. However, despite the availability of this armamentarium in clinical practice, de novo or acquired resistance to ET is the main cause of endocrine-based treatment failure leading to the progression of the BC. Recent advances in targeting, modulating, and degrading ERs have led to the development of new drugs capable of overcoming intrinsic or acquired ET resistance related to alterations in the ESR1 gene. The new oral selective estrogen receptor degraders, which are capable of reducing ER protein expression and blocking estrogen-dependent and -independent ER signaling, have a broader spectrum of activity against ESR1 mutations and seem to be a promising means of overcoming the failure of standard ET. The aim of this review is to summarize the development of oral selective estrogen receptor degraders, their current status, and their future perspectives.

OBJECTIVES:We aimed to analyze rheumatic immune-related (ir) and nonimmune-related adverse events (AEs) due to immune-checkpoint inhibitors (ICIs) targeting programmed cell death-1 or its ligand PD-(L)1 in lung cancer patients from the available literature. METHODS:We performed a systematic review and meta-analysis of phase III randomized clinical trials (RCTs) assessing PD-(L)1-ICIs in lung cancer patients, from inception until January 12th, 2021. We extracted data of each trial to estimate odds ratio (OR) for rheumatic ir or non-irAE as classified in RCTs safety data. Sensitivity analyses (by ICI, treatment group and histology) were performed. RESULTS:Eighteen RCTs met the inclusion criteria (n=12172 subjects). The OR [95%IC] for rheumatic irAE in ICIs versus controls (either placebo or chemotherapy) was 2.20 [0.85,5.72]. Among rheumatic non-irAEs, both overall and severe (grade≥3) back pain were significantly more frequent in ICIs versus controls, 2.01 [1.09;3.73] and 2.90 [1.18;7.08], respectively. The overall frequency of arthralgia was similar between ICIs and controls; by sensitivity analysis RCTs assessing ICIs in combination with chemotherapy showed a significant association with arthralgia (1.55 [1.15;2.10]). Similarly, the frequency of myalgia was significantly lower in RCTs assessing ICIs alone versus chemotherapy (OR 0.32 [0.24;0.42]). Muscular pain was not significantly increased with ICI. CONCLUSION:Rheumatic irAEs are not increased in RCTs assessing PD-(L)1 inhibitors, not reflecting the real-life incidence, therefore likely underreported or misclassified. Back pain is significantly associated with them regardless its severity, while arthralgia only when ICIs are added on conventional chemotherapy.

Background Several adverse events (AEs) occurring during immune checkpoint inhibitors (ICIs) therapy are clearly related to their mechanisms of action, and in this case they are indicated as immune-related AEs (irAEs). Every organ may be affected, including the musculoskeletal system; myositis, polymyalgia rheumatica, arthritis or arthritis have been reported in several retrospective and prospective case series and cohorts, with an incidence between 1.5% and 22%. While arthritis, vasculitis, myositis, and polymyalgia rheumatica are usually defined as “irAE” in RCTs, other rheumatic musculoskeletal conditions such as arthralgia, myalgia, back pain and muscular pain are often reported under the umbrella of “general” AEs. Objectives We aimed to analyze rheumatic irAE and non-irAE due to immune-checkpoint inhibitors (ICIs) targeting programmed cell death-1 or its ligand PD-(L)1 in lung cancer patients from the available literature. Methods We performed a systematic review and meta-analysis of phase III randomized clinical trials (RCTs) assessing PD-(L)1 -ICIs in lung cancer patients, from inception until January 12 th , 2021. We extracted data of each trial to estimate odds ratio (OR) for rheumatic ir or non-irAE as classified in RCTs safety data. Sensitivity analyses (by ICI, treatment group and histology) were performed. Results Eighteen RCTs met the inclusion criteria (n=12172 subjects). The OR [95%IC] for rheumatic irAE in ICIs versus controls (either placebo or chemotherapy) was 2.20 [0.85,5.72]. Among rheumatic non-irAEs, both overall (any grade, Figure 1A) and severe (grade≥3, Figure 1B) back pain were significantly more frequent in ICIs versus controls (2.01 [1.09;3.73] and 2.90 [1.18;7.08], respectively). Figure 1. Forest plot showing pooled odds ratio (OR) for back pain (5 phase III trials) (A) and severe back pain (4 phase III trials) (B), respectively. The overall frequency of arthralgia and severe arthralgia was similar between ICIs and controls (1.13 [0.86, 1.47] and 1.69 [0.68, 4.20], respectively). By sensitivity analysis RCTs assessing ICIs in combination with chemotherapy versus chemotherapy alone showed a significant association with arthralgia (1.55 [1.15;2.10]). Similarly, the frequency of myalgia did not differ between ICIs and controls, but was significantly lower in RCTs assessing ICIs alone versus chemotherapy (OR 0.32 [0.24;0.42]). Muscular pain was not significantly increased with ICI. Conclusion Rheumatic irAEs are not increased in RCTs assessing PD-(L)1 inhibitors, not reflecting the real-life incidence, therefore likely underreported or misclassified. Back pain is significantly associated with PD-(L)1-ICIs regardless its severity, suggesting a possible implication of the PD-(L)1 axis in the development of inflammatory back pain in some patients. In addition, PD-(L)1-ICIs added on conventional chemotherapy are associated with a significantly higher frequency of arthralgia than ICI alone. This trend was seen in the other rheumatic AEs, suggesting that conventional chemotherapy might be a confounder in the interpretation of the occurrence of rheumatic AEs. Disclosure of Interests Antonello Veccia: None declared, Marie Kostine: None declared, Alice Tison: None declared, Mariachiara Dipasquale: None declared, Stefania Kingspergher: None declared, Guido Grandi: None declared, Orazio Caffo: None declared, Sandro Inchiostro: None declared, Giuseppe Paolazzi: None declared, Roberto Bortolotti: None declared, Divi Cornec: None declared, Alvise Berti Consultant of: GSK

KRAS is the most frequently mutated gene in non-small cell lung cancer (NSCLC), however conflicting data are available on its role as a biomarker. The aim of our work was to investigate the impact of KRAS mutations on response and survival outcomes in advanced non-squamous NSCLC patients treated with immune checkpoint inhibitors alone or in combination with chemotherapy. We retrospectively identified 119 patients, most of whom (58

Analyser les effets indésirables (EI) immunomédiés (IM) et non immunomédiés des inhibiteurs de point de contrôle immunitaire (IPCI) ou « inhibiteurs d’immune check point » ciblant la protéine « Programmed-cell Death » (PD)-1 ou son ligand PD-(L)1 chez des patients présentant un cancer du poumon à partir des données disponibles dans la littérature. Nous avons effectué une revue systématique et une méta-analyse des essais cliniques randomisés (ECR) de phase III évaluant les IPCI ciblant le PD-(L)1 chez des patients atteints de cancer du poumon, publiés jusqu’au 12 janvier 2021. Nous avons extrait les données de chacun des essais afin d’estimer l’Odds Ratio (OR) des EI rhumatologiques IM et non IM classés dans les données de sécurité des ECR. Des analyses de sensibilité (par IPCI, groupe de traitement et type histologique) ont été réalisées. Dix-huit ECR remplissaient les critères d’inclusion (n = 12 172 patients). L’OR (IC 95 %) des EI rhumatologiques IM dans les groupes IPCI comparés aux groupes témoins (placebo ou chimiothérapie) était de 2,20 (0,85–5,72). Parmi les EI rhumatologiques non IM, les rachialgies modérées et sévères (grade ≥ 3) étaient significativement plus fréquentes sous IPCI que chez les témoins (2,01 [1,09–3,73] et 2,90 [1,18–7,08] respectivement). La fréquence globale de des arthralgies était similaire dans les deux groupes ; les analyses de sensibilité des ECR évaluant les IPCI combinés à la chimiothérapie ont montré une association significative avec les arthralgies (1,55 [1,15–2,10]). De même, la fréquence des myalgies était significativement plus faible dans les ECR évaluant les IPCI seuls par comparaison avec la chimiothérapie (0,32 [0,24–0,42]). Les douleurs musculaires n’étaient pas plus fréquentes sous IPCI. Les EI rhumatologiques IM sont plus fréquents mais de façon non significative dans les ECR évaluant les inhibiteurs de PD-(L)1, ce qui ne reflète probablement pas leur incidence réelle, suggérant que ces EI sont probablement sous-rapportés ou mal classifiés. Les rachialgies, quelle que soit leur sévérité, sont significativement associées aux IPCI anti-PD-(L)1, tandis que les arthralgies ne sont associées aux IPCI que lorsqu’ils sont ajoutés à une chimiothérapie conventionnelle.

Introduction: The introduction in clinical practice of the immune checkpoint inhibitors (ICIs) radically changed the treatment algorithm of lung cancers. To characterize the toxicity of ICIs (atezolizumab, durvalumab, nivolumab, pembrolizumab) is important for personalizing treatment. Patients and Methods: We performed a systematic review and meta-analysis of phase III randomized controlled trials assessing ICIs, from inception until April 23rd, 2020. We extracted the data from the ICI arm of each trial for indirect comparisons to estimate relative risk for immune-related adverse events (irAEs), severe (grade >= 3) irAEs, drug discontinuation due to irAEs or toxic death. Results: Sixteen trials included a total of 6226 subjects randomized to the experimental immunotherapy arm. Immunotherapy was administered in monotherapy (8 trials), in combination with chemotherapy (6 trials) or other ICI (2 trials). Any grade irAEs and severe irAEs for ICI were 37.1% and 18.5%, respectively. Discontinuations due to any grade irAEs and severe irAEs were 13.8% and 9.2%, respectively; toxic deaths were 2.9% in the immunotherapy arm. Pooled data on any, severe and organ-specific irAEs showed that immunotherapy has a significantly lower risk of irAEs compared to immuno-chemotherapy, especially when analysis was restricted to monoimmunotherapy, like drug discontinuation and toxic death (all p < 0.05). Detailed comparisons between different ICIs provided treatment-related risk profiles for organ-specific irAEs. Conclusions: Our findings contribute to clarifying frequency and features of immune-related toxicities between different ICIs in lung cancer patients, including any grade irAEs, severe irAEs, drug discontinuation and toxic deaths, and may be useful to inform the selection of treatment.

Lay abstract In recent years, immunotherapy has become a milestone in the treatment of non-small-cell lung cancer, but clinicians need clinical and/or laboratory factors able to predict the benefit of immunotherapy. Therefore, we investigated the role of pretreatment lung immune prognostic index (LIPI) as biomarker in advanced non-small-cell lung cancer patients with high PD-L1 expression levels and receiving pembrolizumab as first line. We retrospectively identified 117 patients divided into 3 prognostic groups (good, intermediate and poor) according to LIPI score. We found that patients belonging to good prognostic group (LIPI score 0) lived longer and responded better than those of intermediate and poor prognostic groups (LIPI score 1 or 2), confirming the correlation between LIPI score and survival and response outcomes. Background: To investigate the role of pretreatment lung immune prognostic index (LIPI) as biomarker in PD-L1 >= 50% non-small-cell lung cancer patients receiving pembrolizumab. Patients & methods: We retrospectively identified 117 patients, divided into 3 prognostic groups according to LIPI score. For each patient, we evaluated 1-year overall survival (OS) and progression-free survival rate. C-statistic and survival receiver operating characteristic curves were used to study discrimination of LIPI. Results: After a median follow-up of 11.7 months, 1-year OS rate was 60.1%, 35.3% and 28.6%, while 1-year progression-free survival rate was 39.1%, 20.6% and 14.3% in good, intermediate and poor LIPI groups, respectively (p < 0.001). The c-statistic and area under the curve of LIPI were 0.63 and 0.662 for OS and 1-year OS, respectively. Conclusions: Higher LIPI score is related to worse survival in advanced non-small-cell lung cancer patients treated with first-line pembrolizumab. However, based on c-statistic and area under the curve, LIPI does not represent a good prognostic survival model.

The brain is one of the most frequent sites of metastases in lung cancer patients, whose prognosis is related to the histological, biomolecular and clinical features of the disease. Over the years, the survival has improved significantly with the introduction of immune checkpoint inhibitors (ICIs), but there are limited data concerning their efficacy in patients with brain metastases. The aim of this review is to describe the biological mechanisms supporting the use of immunotherapy for brain metastases and the outcomes experienced by lung cancer patients with brain involvement enrolled in Phase III registration trials of ICIs. We also review retrospective data on ICIs alone or combined with brain radiotherapy, and indicate future directions for preclinical and clinical research.

PURPOSE:The EGFR (Epidermal Growth Factor Receptor) mutations may predict sensitivity and resistance to EGFR-TKIs (Tyrosine Kinases Inhibitors) in metastatic lung adenocarcinoma. The detection of these mutations is usually performed on tumor tissue samples. However, when a biopsy is not feasible or the amount of tissue is limited, circulating tumor DNA (ctDNA) may represent an alternative source for genotyping the tumor.METHODS:In the first phase of the study, the liquid biopsy was performed in newly diagnosed metastatic lung adenocarcinoma patients with and without EGFR mutations to evaluate the concordance between EGFR mutational analysis on ctDNA by real time PCR and on tissue. In the second phase it was performed in EGFR positive patients progressing after first or second generation TKIs in order to detect the T790M mutation.RESULTS:In the first phase, a 100% concordance between EGFR on ctDNA and tissue was revealed, leading to validation of the test. In the second phase, 44.8% of patients showed T790M positive result at liquid biopsy. Considering the re-biopsies performed in 31% of the cases, the overall positivity rate of T790M was 58.6%. Sensitivity and specificity were 76% and 75%, respectively. The median time to development of T790M mutation from the start of first line EGFR TKI was 244 days.CONCLUSIONS:Our experience confirms that liquid biopsy is a valid method to detect sensitizing and resistant EGFR mutations in patients with metastatic lung adenocarcinoma. Nevertheless, in the presence of negative ctDNA analysis, a rebiopsy should be performed whenever possible to confirm this result.

Future OncologyVol. 16, No. 19 EditorialFree AccessNasopharyngeal swab or clinical-radiological evidence: the dark side of the moon for cancer patients in the COVID-19 eraAntonello Veccia, Stefania Kinspergher, Mariachiara Dipasquale & Orazio CaffoAntonello Veccia *Author for correspondence: Tel.: +39 0461 902478; Fax: +39 0461 903364; E-mail Address: antonello.veccia@apss.tn.ithttps://orcid.org/0000-0002-8804-7094Medical Oncology Department, Santa Chiara Hospital, Largo Medaglie d'Oro 1, Trento, 38122, Italy, Stefania KinspergherMedical Oncology Department, Santa Chiara Hospital, Largo Medaglie d'Oro 1, Trento, 38122, Italy, Mariachiara DipasqualeMedical Oncology Department, Santa Chiara Hospital, Largo Medaglie d'Oro 1, Trento, 38122, Italy & Orazio CaffoMedical Oncology Department, Santa Chiara Hospital, Largo Medaglie d'Oro 1, Trento, 38122, ItalyPublished Online:26 May 2020https://doi.org/10.2217/fon-2020-0372AboutSectionsPDF/EPUB ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareShare onFacebookTwitterLinkedInRedditEmail Keywords: clinical diagnosisCOVID-19lung cancernasopharyngeal swabCoronavirus disease 2019 (COVID-19) has become a serious public health problem worldwide [1]. It is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), but little is known about its mechanisms of action or possible treatments [2].SARS-CoV-2 positivity is currently confirmed by means of a nasopharyngeal swab, but there is increasing evidence that clinical manifestations of the disease may appear even when a swab is negative, and the presence of the disease may not be demonstrated if the patient dies before it is diagnosed. Cancer patients with COVID-19 have a poorer prognosis than patients without cancer [3], and oncologists frequently observe the dramatic clinical course of the disease in patients without proven infection.All these issues emerged from a clinical case we have recently observed. A 73-year-old male patient that received an immune checkpoint inhibitor as first line treatment for metastatic non-small-cell lung cancer was hospitalized due to asthenia, fever, dry cough and dyspnea. Nevertheless, the nasopharyngeal swab was negative. Laboratory tests showed hypoxemia, lymphopenia with normal leukocytes, acute renal failure and increased inflammation indexes. Multiple frosted glass thickenings compatible with bilateral interstitial pneumonitis were described at the chest CT scan. Despite the intensive cares, the patient died of acute respiratory failure 3 days after being hospitalized and after a second negative nasopharyngeal swab.The clinical history, symptom onset and dramatic disease course of this patient clearly suggested the presence of SARS-CoV-2 infection. First of all, like all cancer patients, he was at higher risk of developing the disease: a recent study of 18 cancer patients, including six with lung cancer, found that they were older, more likely to have a history of smoking, polypnea and more severe computed tomography manifestations, and experienced a significantly shorter time to deterioration than patients without cancer [3]. Second, he was a former smoker with chronic obstructive pulmonary disease, and it has been shown that this clinical condition is an independent risk factor for severe COVID-19 [4]. Third, as a strong inflammatory response can be elicited during immune checkpoint treatment, immunotherapy may increase the risk of COVID-19 with a poorer prognosis [5].Nevertheless, this diagnosis was not supported by the nasopharyngeal swab results, which should therefore be considered a false negative. Several factors have been hypothesized to be responsible for the high rate of false negative swabs, that represents a serious problem when it comes to defining the extent and severity of the COVID-19 pandemic. A factor is the different quality, sensitivity and specificity of the kits used for the real-time polymerase chain reaction (RT-PCR), that is the standard method to detect SARS-CoV-2. Inappropriate collection, transportation and handling of samples may also affect the results of the test. Mutations in the primer and probe target regions of the SARS-CoV-2 genome can compromise the assay performance in the detection of the virus. Moreover, the false negativity may depend on the considered sample type [6]. A retrospective analysis of specimens from multiple sites taken from 205 patients has found that nasal swabs have a lower positivity rate (63%) than bronchoalveolar lavage fluid (93%) [7], and it is likely that tests of multiple sites would reduce the number of falsely negative patients. Therefore, clinical, radiological and laboratory parameters pathognomonic of COVID-19 play a crucial role in the identification of infected patients.Multiple subsegmental or segmental ground glass opacities and areas of consolidation on chest computed tomography imaging are typical of COVID-19 [8]. A retrospective study including 36 patients with COVID-19 pneumonia, who were examined with both CT scan and RT-PCR at initial presentation, reported a higher sensitivity for chest imaging (97.2 vs 83.3%) [9].A final consideration comes from the clinical case we considered and concerns the management of cancer patients in the COVID-19 era. There are a number of specific guidelines for managing cancer patients during the pandemic [10–12], and some recently published suggestions for lung cancer patients [13]. Before starting oncological treatment, a careful evaluation of the risk/benefit ratio should be made, particularly in the case of elderly patients with co-morbidities who are candidates for immune checkpoint inhibitor treatment.Thus, in conclusion, regardless of exposure to infected subjects, any patient (mainly if affected by cancer) with flu-like symptoms, severe breathing problems, acute renal failure, laboratory tests indicative of infection and radiological signs of pneumonia should be treated as having COVID-19, even when nasopharyngeal swabs are repeatedly negative. This is essential in order to avoid underestimating the number of positive patients who may continue to spread the infection and to improve our ability to identify COVID-19 infection in cancer patients.Financial & competing interests disclosureThe authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.No writing assistance was utilized in the production of this manuscript.References1. Jiang S, Shi Z, Shu Y et al. A distinct name is needed for the new coronavirus. Lancet 395(10228), 949 (2020).Medline CASGoogle Scholar2. Stebbing J, Phelan A, Griffin I et al. COVID-19: combining antiviral and anti-inflammatory treatments. Lancet Infect. Dis. 20(4), 400–402 (2020).Medline CASGoogle Scholar3. Liang W, Guan W, Chen R et al. Cancer patients in SARS-CoV-2 infection: a nationwide analysis in China. Lancet Oncol. 21(3), 335–337 (2020).Medline CASGoogle Scholar4. Guan WJ, Ni ZY, Hu Y et al. Clinical characteristics of coronavirus disease 2019 in China. N. Engl. J. Med. 382(18), 1708–1720 (2020).Medline CASGoogle Scholar5. Bonomi L, Ghilardi L, Arnoldi E, Tondini CA, Bettini AC. A rapid fatal evolution of coronavirus disease-19 (COVID-19) in an advanced lung cancer patient with a long time response to nivolumab. J. Thorac. Oncol. 15(6) e83–e85 (2020).Medline CASGoogle Scholar6. Tahamtan A, Ardebili A. Real-time RT-PCR in COVID-19 detection: issues affecting the results. Expert Rev. Mol. Diagn. 20(5), 1–2 (2020).MedlineGoogle Scholar7. Wang W, Xu Y, Gao R et al. Detection of SARS-CoV-2 in different types of clinical specimens. JAMA 323(18), 1843–1844 (2020) .Medline CASGoogle Scholar8. Yang W, Sirajuddin A, Zhang X et al. The role of imaging in 2019 novel coronavirus pneumonia (COVID-19). Eur. Radiol. doi: 10.1007/s00330-020-06827-4 (2020) (Epub ahead of print).Google Scholar9. Long C, Xu H, Shen Q et al. Diagnosis of the Coronavirus disease (COVID-19): rRT-PCR or CT? Eur. J. Radiol. 126, 108961 (2020).MedlineGoogle Scholar10. European Association of Medical Oncology. COVID-19 and cancer. (2020). www.esmo.org/covid-19-and-cancerGoogle Scholar11. ASCO coronavirus resources. (2020). www.asco.org/asco-coronavirus-informationGoogle Scholar12. Ueda M, Martins R, Hendrie PC et al. Managing cancer care during the COVID-19 pandemic: agility and collaboration toward a common goal. J. Natl Compr. Canc. Netw. doi: 10.6004/jnccn.2020.7560 (2020) (Epub ahead of print).MedlineGoogle Scholar13. Banna G, Curioni-Fontecedro A, Friedlaender A, Addeo A. How we treat patients with lung cancer during the SARS-CoV-2 pandemic: primum non nocere. ESMO Open. 5(2), pii:e000765 (2020).MedlineGoogle ScholarFiguresReferencesRelatedDetailsCited ByCancerona: Challenges of Cancer Management in Times of COVID-19 Pandemic30 September 2020 | SN Comprehensive Clinical Medicine, Vol. 2, No. 11 Vol. 16, No. 19 STAY CONNECTED Metrics History Received 19 April 2020 Accepted 4 May 2020 Published online 26 May 2020 Published in print July 2020 Information© 2020 Future Medicine LtdKeywordsclinical diagnosisCOVID-19lung cancernasopharyngeal swabFinancial & competing interests disclosureThe authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.No writing assistance was utilized in the production of this manuscript.PDF download

PURPOSE Gemcitabine-cisplatin combination is one of the most used schedules for non small cell lung cancer (NSCLC). Aiming to enhance dose intensity and reduce toxicity, the original 4-week schedule was modified or transformed into a 3-week schedule. The purpose of this study was to report the efficacy and tolerability of a modified 3-week regimen of gemcitabine-cisplatin. METHODS Our patients were treated with gemcitabine (1000 mg7sol;m2) on days 1, 8 and cisplatin on day 8 (75-100 mg/m2). The toxicity was recorded according to the NCIC criteria. RESULTS From October 2000 to December 2009 a consecutive series of 196 patients with a median age of 62 years and III-IV stage NSCLC received gemcitabine-cisplatin as induction therapy (76 patients) or palliative treatment (120 patients). The median dose intensity was 89%. In relation to day 8 of chemotherapy, 16.2% of the treatments were delayed due to hematologic toxicities. Grade 3-4 anaemia, neutropenia and thrombocytopenia was reported in 3.5, 43.8 and 4.6%, respectively. Response rate (RR) and median overall survival (OS) were 74% and 11 months in patients with locally advanced disease, and 46.7% and 9 months in metastatic patients, respectively. CONCLUSIONS In comparison with standard or modified schedules of literature, our modified 3-week regimen of gemcitabine- cisplatin demonstrated to be equally active, similar for dose intensity and well tolerated, with better hematologic toxicity profile in terms of anaemia and thrombocytopenia.

Background: The correlation between EGFR mutation subtype and efficacy of TKIs in patients with aNSCLC is uncertain. Therefore, TKIs are used regardless of mutation subtype. However, data of literature suggests better outcomes for patients with exon 19 deletions (19del) in comparison with exon 21 point mutations (L858R). Methods: Patients with EGFR-positive aNSCLC receiving TKIs as first line treatment were included in the analysis. Mutational status at diagnosis was detected on tumor tissue or on circulating free tumor DNA (cft-DNA). The association between mutation subtype and clinical factors was assessed by Pearson chi square test, while differences in progression free survival (PFS) and overall survival (OS) according to mutation subtype were evaluated by Log-rank test. Results: Between January 2011 and December 2016 a consecutive series of 39 EGFR-positive patients (all with adenocarcinoma) received a first line TKI: Gefitinib (21 pts), Erlotinib (14 pts) or Afatinib (4 pts). Most of patients, whose median age was 70 years (range 35-84), were female (67%), never smokers (74%) and with stage IV (97%). EGFR mutations were detected on tumor tissue in 37 pts and on cft-DNA in 2 pts. No correlation was found between mutation subtype and site of metastases (lung, lymph nodes, liver, adrenal, bone and brain). After a median follow up of 11.2 mos, the mutation subtype did not influence PFS (median 9.6 mos, 95% CI 3.3– 15.9 for 19del group vs 8.3 mos, 95% CI 6.6 - 9.9 for L858R group) and OS (median 17.4 mos, 95% CI .00 - 34.7 for 19del group vs 18 mos, 95% CI 12.3 - 23.8 for L858R group). Anyway, it is noteworthy that 2-y PFS and OS rates were quite different according to mutation subtype being 24.8% and 36.4% in 19del pts, compared to 0% and 14.8% in L858R pts, respectively. Conclusions: Our analysis showed that TKIs may be used for treating EGFR-positive lung adenocarcinoma regardless of mutation subtype. Despite the small sample size, the mutation subtype did not correlate with site of metastases, and no statistically significant difference was found in terms of PFS and OS between two mutation subtypes.

The identification of T790M mutation in EGFR exon 20 predicts sensitivity to third generation EGFR Tyrosine Kinases Inhibitors (TKIs) in patients (pts) with advanced non-small cell lung cancer (aNSCLC). However, its detection as part of a complete molecular analysis may be hampered by limited amount of tumor tissue available both before and after treatment with first or second generation EGFR TKIs. Therefore, circulating free tumor DNA (cftDNA) may represent an alternative source to assess T790M mutation. We considered as eligible patients with cytologically confirmed EGFR positive aNSCLC progressing after first or second generation TKIs. All patients were evaluated by a liquid biopsy assay to detect EGFR mutations in cftDNA. Plasma was analyzed by Real Time PCR (RT PCR). The degree of concordance between EGFR mutational analysis in blood and on tissue was evaluated. The T790M detection rate and the percentage of rebiopsy performed at disease progression following first line treatment were also reported. Between April 2015 and May 2017, a consecutive series of 20 patients underwent liquid biopsies before and/or after treatment with EGFR TKIs (erlotinib, gefitinib or afatinib). All pts had a diagnosis of adenocarcinoma and stage IV disease, and the median age was 69 years; most of them were female (70%) and never smokers (80%). Before starting first line treatment, 16 pts underwent liquid biopsy: the concordance of cftDNA with tissue was 100% for negative T790M mutational status. After disease progression, 12 pts underwent liquid biopsy: T790M was positive in 7 pts (58.3%). A rebiopsy was performed only in 4 out of 12 pts (33.4%): contrary to plasma analysis, one of them was found positive for T790M on tissue. Therefore, sensitivity and specificity of cftDNA in detection of T790M were 87.5% and 100%, respectively. The overall frequency of T790M detection after first line treatment was 66.7%. The third generation TKI osimertinib was administered to seven of eight T790M positive pts (87.5%); the remaining patient received best supportive care due to poor performance status. Liquid biopsy confirmed to be a valid method to detect the T790M mutation in pts with aNSCLC, both before and after treatment with first and second generation EGFR TKIs. In particular, RT PCR showed high sensitivity and specificity in detection of T790M at disease progression, when T790M positive pts may be offered third generation TKIs treatment. Nevertheless, a rebiopsy need to be performed whenever possible to avoid T790M false negative at cftDNA analysis.

To assess the activity of weekly paclitaxel (wPCT) in pretreated patients with advanced non-small-cell lung cancer (aNSCLC). In 2005, we included wPCT 80 mg/m(2) for 6 consecutive weeks, followed by a 2-week interval in our department's everyday clinical practice guidelines for the second-line (or subsequent) treatment of patients with nonsquamous histologies who have previously received pemetrexed-based treatments and patients with squamous histology. In the absence of clinical evidence of disease progression, patients repeat the pretreatment staging procedures after 16 weeks (two cycles) and, in the absence of disease progression or severe toxicity, continue treatment for a maximum of four courses. Between May 2005 and December 2013, we treated 60 patients (47 in second-line and 13 in third/fourth line), who received a median of two courses (range: 1-4). The most frequent toxicity was grade 1-2 neutropaenia (five patients); only four patients experienced grade 3-4 toxicity. When used as a second-line treatment, wPCT led to a disease control rate of 36.2%, with a median progression-free survival of 3.7 months and a median overall survival of 9.0 months; when used in the third/fourth line, the disease control rate was 41.7%, the median progression-free survival was 5.0 months and the median overall survival was 10.3 months. Our data confirm that wPCT is active and well tolerated in an unselected patient population with aNSCLC and can be considered a valuable alternative to docetaxel in a second-line treatment. Copyright (C) 2017 Wolters Kluwer Health, Inc. All rights reserved.

Background: Optimal follow up modalities for patients with melanoma after primary surgery is not unanimously defined by major scientific societies (AIOM, ASCO, NCCN). We have evaluated when and how recurrence was detected among 200 pts with melanoma followed in our institution. Material and methods: We have retrospectively reviewed the clinical records of 200 consecutive pts, diagnosed with melanoma stage IA to III C in 2009-2010 and followed for 5 years with physical examination and ultrasound of the loco-regional lymph nodes every 4 months. Chest Rx and abdomen ultrasound were done every year for pts with stage IB to IIC and CT scan was done yearly for stage III. The follow-up was updated on March 2016. Results: Pts were 87 males (43.5 %) and 113 females (56.5 %), with a median age of 56 years (15- 95) staged IA (16, 8%), IB (112, 56%), IIA (18, 9%), IIB (13, 6.5%), IIC (8, 4%), III A (9, 4.5%), IIIB (6, 3%), IIIC (4, 2%) and not defined (7, 3.5 %). The latter were excluded. Among the remaining 193 pts, we observed 32 recurrences (16%) and 3 second primary melanoma, all stage IB. The recurrence rate was 0% in stage IA, 7.1 % in stage IB, 33.3% in stage IIA, 46% in stage IIB, 37.5 % in stage IIC, 55.5 % in stage IIIA, 0% in stage IIIB and 100% in stage IIIC. Recurrences were loco-regional only in 21 pts (63.7 %), distant only in 7 (21.2 %) and loco-regional and distant in 5(15.1 %). Metastatic sites were lung (9 pts), brain (6), bone (3), liver(2), adrenal gland (1) and paraortic lymph node (1). Overall, median time to recurrence was 25 mos: 33 in stage IB pts, 28 in IIA, 23 in IIB, 17 in IIC, 27 in IIIA, 9 in III B pts. In 12 cases (37%) the recurrence was first detected by the patient, in 9 (28 %) by clinical examination and in 11 (35 %) by imaging (2 chest x-ray, 7 node ultrasound, 2 scar ultrasound). Conclusion: In spite of our intensive follow up, the recurrence was detected between visits by one third of the pts and at clinical examination in an additional 28%. This may rise also the problem of instrumental follow up, as the detection of recurrence was instrumental in 11 pts only, and none with CT scan, while all pts received all these test for at least 5 years. No correlation is possible yet with time and site of recurrence and with stage of disease and pts prognosis. We are looking to a larger number and a longer follow up in our pts series.

The detection of EGFR mutations may predict sensitivity to EGFR-TKIs (Tyrosine Kinases Inhibitors) in mLA. However, small biopsies or cytological samples often provide limited or insufficient tumor tissue for molecular analysis. Moreover, a re-biopsy is not always technically feasible to identify emerging mechanisms of resistance at disease progression. Therefore, cftDNA represents an alternative source of DNA for genotyping the tumor. Patients (pts) with newly diagnosed mLA were included in the study and treated with EGFR-TKIs or chemotherapy as first-line treatment according to the EGFR mutational status. EGFR and K-ras mutations were detected on tumor tissue by Pyrosequencing (Pyr) or Sequenom MassArray (SMA) before starting treatment; N-ras, B-Raf, DDR2 and PK3CA mutations were identified by SMA, too. Only EGFR mutations were found on cftDNA by a Real Time PCR (RT PCR) before starting therapy, during the treatment and at disease progression. The degree of concordance between EGFR mutational analysis on tissue and in blood was evaluated. Between April and November 2015, analysis of tumor tissue was performed in 17 pts (M/F = 8/9) with a median age of 65 years, while it was not possible in 3 cases due to insufficient material. EGFR mutations were detected in 9/17 patients: 6 cases of exon 19 deletions (five E746-A750 del, one E747-T751 del) and 3 cases of exon 21 substitution (L858R). All mutated pts, whose high percentage (53%) was due to selection bias of the study, received gefitinib or erlotinib as first line treatment; wild type pts underwent platinum-based chemotherapy. Analysis of EGFR mutations on cftDNA showed a 100% concordance with tissue detection. Moreover, pts with poor histological tissue appeared wild type on cftDNA analysis. RT PCR confirmed to be a valid method to detect EGFR mutations in blood, in particular when histological tissue is insufficient to molecular analysis and a re-biopsy is difficult to perform. It showed a 100% concordance with tissue analysis methods. Moreover, cftDNA better mirrors the heterogeneity of mLA and could be useful to monitor disease during the treatment.

Background: The detection of EGFR mutations may predict sensitivity to EGFR-TKIs (Tyrosine Kinases Inhibitors) in mLA. This analysis is usually performed on tumor samples obtained by small biopsies or fine needle aspirations, that often provide insufficient tissue for molecular analysis. Moreover, a re-biopsy, that should be proposed to identify emerging mechanisms of resistance at disease progression, is not always feasible due to poor compliance of the patients. Therefore, cftDNA represents an alternative source of DNA for genotyping the tumor. Methods: We evaluated a consecutive series of patients (pts) with newly diagnosed mLA treated with EGFR-TKIs or chemotherapy as first-line treatment according to the EGFR mutational status. EGFR and K-ras mutations were detected on tumor tissue by Pyrosequencing (Pyr) or Sequenom MassArray (SMA) before starting treatment; N-ras, B-Raf, DDR2 and PI3KA mutations were identified by SMA, too. Only EGFR mutations were assessed on cftDNA by a Real Time PCR (RT PCR) before starting therapy, during the treatment and at disease progression. The degree of concordance between EGFR mutational analysis on tissue and in blood was evaluated. Results: Between April 2015 and April 2016, analysis of tumor tissue was performed in 18 pts (M/F = 9/9) with a median age of 65 years (range 42-78), while it was not possible in 4 cases due to insufficient material. EGFR mutations were detected in 9/18 patients: 6 cases of exon 19 deletions (five E746-A750 del, one E747-T751 del) and 3 cases of exon 21 substitution (L858R). All mutated pts, whose high percentage (50%) was due to selection bias of the study, received gefitinib or erlotinib as first line treatment; wild type pts underwent platinum-based chemotherapy. Analysis of EGFR mutations on cftDNA showed a 100% concordance with tissue detection. Moreover, RT PCR identified 4 cases of T790M mutations: 1 at baseline, 3 at progression disease. Finally, pts with poor histological tissue appeared wild type on cftDNA analysis. Conclusions: RT PCR performed on cftDNA confirmed to be a valid method to detect EGFR mutations in blood, in particular when histological tissue is insufficient for molecular analysis and a re-biopsy is difficult to perform. It showed a 100% concordance with tissue analysis methods. Moreover, cftDNA better mirrors the heterogeneity of mLA and could be useful to monitor disease during the treatment.