Breast metastasis and lung large-cell neuroendocrine carcinoma: first clinical observation

The lung Large-cell neuroendocrine carcinoma (LCNEC) is a very rare aggressive neuroendocrine tumor with a high propensy to metastasize and very poor prognosis. We report an atypical presentation of lung large-cell neuroendocrine carcinoma was diagnosed from a metastatic nodule on the breast. Our patient is a 59 years-old woman that presented in March 2014 non productive cough. A CT scan showed multiple brain, lung, adrenal gland and liver secondary lesions; moreover, it revealed a breast right nodule near the chest measuring 1.8 cm. The breast nodule and a lung lesions were biopsied and their histology and molecular diagnosis were LCNEC of the lung. To our knowledge, this is the first documented case of breast metastasis from LCNEC of the lung. Furthermore, breast metastasis from extramammary malignancy is uncommon and its diagnosis is difficult but important for proper management and prediction of prognosis. Therefore, a careful clinical history with a thorough clinical examination is needed to make the correct diagnosis. Moreover, metastasis to the breast should be considered in any patient with a known primary malignant tumor history who presents with a breast lump. Anyhow, pathological examination should be performed to differentiate the primary breast cancer from metastatic tumor. Therefore, an accurate diagnosis of breast metastases may not only avoid unnecessary breast resection, more importantly it is crucial to determine an appropriate and systemic treatment

Effect of concomitant medications with immune-modulatory properties on the outcomes of patients with advanced cancer treated with immune checkpoint inhibitors: development and validation of a novel prognostic index

Background: Concomitant medications are known to impact on clinical outcomes of patients treated with immune checkpoint inhibitors (ICIs). We aimed weighing the role of different concomitant baseline medications to create a drug-based prognostic score. Methods: We evaluated concomitant baseline medications at immunotherapy initiation for their impact on objective response rate (ORR), progression-free survival (PFS) and overall survival (OS) in a single-institution cohort of patients with advanced cancer treated with ICIs (training cohort, N = 217), and a drug-based prognostic score with the drugs resulting significantly impacting the OS was computed. Secondly, we externally validated the score in a large multicenter external cohort (n = 1012). Results: In the training cohort (n = 217), the median age was 69 years (range: 32–89), and the primary tumours were non–small-cell lung cancer (70%), melanoma (14.7%), renal cell carcinoma (9.2%) and others (6%). Among baseline medications, corticosteroids (hazard ratio [HR] = 2.3; 95% confidence interval [CI]: 1.60–3.30), systemic antibiotics (HR = 2.07; 95% CI: 1.31–3.25) and proton-pump inhibitors (PPIs) (HR = 1.57; 95% CI: 1.13–2.18) were significantly associated with OS. The prognostic score was calculated using these three drug classes, defining good, intermediate and poor prognosis patients. Within the training cohort, OS (p < 0.0001), PFS (p < 0.0001) and ORR (p = 0.0297) were significantly distinguished by the score stratification. The prognostic value of the score was also demonstrated in terms of OS (p < 0.0001), PFS (p < 0.0001) and ORR (p = 0.0006) within the external cohort. Conclusion: Cumulative exposure to corticosteroids, antibiotics and PPIs (three likely microbiota-modulating drugs) leads to progressively worse outcomes after ICI therapy. We propose a simple score that can help stratifying patients in routine practice and clinical trials of ICIs

High familial burden of cancer correlates with improved outcome from immunotherapy in patients with NSCLC independent of somatic DNA damage response gene status

Family history of cancer (FHC) is a hallmark of cancer risk and an independent predictor of outcome, albeit with uncertain biologic foundations. We previously showed that FHC-high patients experienced prolonged overall (OS) and progression-free survival (PFS) following PD-1/PD-L1 checkpoint inhibitors. To validate our findings in patients with NSCLC, we evaluated two multicenter cohorts of patients with metastatic NSCLC receiving either first-line pembrolizumab or chemotherapy. From each cohort, 607 patients were randomly case–control matched accounting for FHC, age, performance status, and disease burden. Compared to FHC-low/negative, FHC-high patients experienced longer OS (HR 0.67 [95% CI 0.46–0.95], p = 0.0281), PFS (HR 0.65 [95% CI 0.48–0.89]; p = 0.0074) and higher disease control rates (DCR, 86.4% vs 67.5%, p = 0.0096), within the pembrolizumab cohort. No significant associations were found between FHC and OS/PFS/DCR within the chemotherapy cohort. We explored the association between FHC and somatic DNA damage response (DDR) gene alterations as underlying mechanism to our findings in a parallel cohort of 118 NSCLC, 16.9% of whom were FHC-high. The prevalence of ≥ 1 somatic DDR gene mutation was 20% and 24.5% (p = 0.6684) in FHC-high vs. FHC-low/negative, with no differences in tumor mutational burden (6.0 vs. 7.6 Mut/Mb, p = 0.6018) and tumor cell PD-L1 expression. FHC-high status identifies NSCLC patients with improved outcomes from pembrolizumab but not chemotherapy, independent of somatic DDR gene status. Prospective studies evaluating FHC alongside germline genetic testing are warranted

Adjuvant capecitabine in triple negative breast cancer patients with residual disease after neoadjuvant treatment: real-world evidence from CaRe, a multicentric, observational study

Background: In triple negative breast cancer patients treated with neoadjuvant chemotherapy, residual disease at surgery is the most relevant unfavorable prognostic factor. Current guidelines consider the use of adjuvant capecitabine, based on the results of the randomized CREATE-X study, carried out in Asian patients and including a small subset of triple negative tumors. Thus far, evidence on Caucasian patients is limited, and no real-world data are available. Methods: We carried out a multicenter, observational study, involving 44 oncologic centres. Triple negative breast cancer patients with residual disease, treated with adjuvant capecitabine from January 2017 through June 2021, were recruited. We primarily focused on treatment tolerability, with toxicity being reported as potential cause of treatment discontinuation. Secondarily, we assessed effectiveness in the overall study population and in a subset having a minimum follow-up of 2 years. Results: Overall, 270 patients were retrospectively identified. The 50.4% of the patients had residual node positive disease, 7.8% and 81.9% had large or G3 residual tumor, respectively, and 80.4% a Ki-67 >20%. Toxicity-related treatment discontinuation was observed only in 10.4% of the patients. In the whole population, at a median follow-up of 15 months, 2-year disease-free survival was 62%, 2 and 3-year overall survival 84.0% and 76.2%, respectively. In 129 patients with a median follow-up of 25 months, 2-year disease-free survival was 43.4%, 2 and 3-year overall survival 78.0% and 70.8%, respectively. Six or more cycles of capecitabine were associated with more favourable outcomes compared with less than six cycles. Conclusion: The CaRe study shows an unexpectedly good tolerance of adjuvant capecitabine in a real-world setting, although effectiveness appears to be lower than that observed in the CREATE-X study. Methodological differences between the two studies impose significant limits to comparability concerning effectiveness, and strongly invite further research

SARS-CoV-2 omicron (B.1.1.529)-related COVID-19 sequelae in vaccinated and unvaccinated patients with cancer: results from the OnCovid registry

BACKGROUND: COVID-19 sequelae can affect about 15% of patients with cancer who survive the acute phase of SARS-CoV-2 infection and can substantially impair their survival and continuity of oncological care. We aimed to investigate whether previous immunisation affects long-term sequelae in the context of evolving variants of concern of SARS-CoV-2. METHODS: OnCovid is an active registry that includes patients aged 18 years or older from 37 institutions across Belgium, France, Germany, Italy, Spain, and the UK with a laboratory-confirmed diagnosis of COVID-19 and a history of solid or haematological malignancy, either active or in remission, followed up from COVID-19 diagnosis until death. We evaluated the prevalence of COVID-19 sequelae in patients who survived COVID-19 and underwent a formal clinical reassessment, categorising infection according to the date of diagnosis as the omicron (B.1.1.529) phase from Dec 15, 2021, to Jan 31, 2022; the alpha (B.1.1.7)-delta (B.1.617.2) phase from Dec 1, 2020, to Dec 14, 2021; and the pre-vaccination phase from Feb 27 to Nov 30, 2020. The prevalence of overall COVID-19 sequelae was compared according to SARS-CoV-2 immunisation status and in relation to post-COVID-19 survival and resumption of systemic anticancer therapy. This study is registered with ClinicalTrials.gov, NCT04393974. FINDINGS: At the follow-up update on June 20, 2022, 1909 eligible patients, evaluated after a median of 39 days (IQR 24-68) from COVID-19 diagnosis, were included (964 [50·7%] of 1902 patients with sex data were female and 938 [49·3%] were male). Overall, 317 (16·6%; 95% CI 14·8-18·5) of 1909 patients had at least one sequela from COVID-19 at the first oncological reassessment. The prevalence of COVID-19 sequelae was highest in the pre-vaccination phase (191 [19·1%; 95% CI 16·4-22·0] of 1000 patients). The prevalence was similar in the alpha-delta phase (110 [16·8%; 13·8-20·3] of 653 patients, p=0·24), but significantly lower in the omicron phase (16 [6·2%; 3·5-10·2] of 256 patients, p<0·0001). In the alpha-delta phase, 84 (18·3%; 95% CI 14·6-22·7) of 458 unvaccinated patients and three (9·4%; 1·9-27·3) of 32 unvaccinated patients in the omicron phase had sequelae. Patients who received a booster and those who received two vaccine doses had a significantly lower prevalence of overall COVID-19 sequelae than unvaccinated or partially vaccinated patients (ten [7·4%; 95% CI 3·5-13·5] of 136 boosted patients, 18 [9·8%; 5·8-15·5] of 183 patients who had two vaccine doses vs 277 [18·5%; 16·5-20·9] of 1489 unvaccinated patients, p=0·0001), respiratory sequelae (six [4·4%; 1·6-9·6], 11 [6·0%; 3·0-10·7] vs 148 [9·9%; 8·4-11·6], p=0·030), and prolonged fatigue (three [2·2%; 0·1-6·4], ten [5·4%; 2·6-10·0] vs 115 [7·7%; 6·3-9·3], p=0·037). INTERPRETATION: Unvaccinated patients with cancer remain highly vulnerable to COVID-19 sequelae irrespective of viral strain. This study confirms the role of previous SARS-CoV-2 immunisation as an effective measure to protect patients from COVID-19 sequelae, disruption of therapy, and ensuing mortality. FUNDING: UK National Institute for Health and Care Research Imperial Biomedical Research Centre and the Cancer Treatment and Research Trust

Time-Dependent COVID-19 Mortality in Patients with Cancer: An Updated Analysis of the OnCovid Registry

Importance: Whether the severity and mortality of COVID-19 in patients with cancer have improved in terms of disease management and capacity is yet to be defined. Objective: To test whether severity and mortality from COVID-19 among patients with cancer have improved during the course of the pandemic. Design, Setting, and Participants: OnCovid is a European registry that collects data on consecutive patients with solid or hematologic cancer and COVID-19. This multicenter case series study included real-world data from 35 institutions across 6 countries (UK, Italy, Spain, France, Belgium, and Germany). This update included patients diagnosed between February 27, 2020, and February, 14, 2021. Inclusion criteria were confirmed diagnosis of SARS-CoV-2 infection and a history of solid or hematologic cancer. Exposures: SARS-CoV-2 infection. Main Outcomes and Measures: Deaths were differentiated at 14 days and 3 months as the 2 landmark end points. Patient characteristics and outcomes were compared by stratifying patients across 5 phases (February to March 2020, April to June 2020, July to September 2020, October to December 2020, and January to February 2021) and across 2 major outbreaks (February to June 2020 and July 2020 to February 2021). Results: At data cutoff, 2795 consecutive patients were included, with 2634 patients eligible for analysis (median [IQR] age, 68 [18-77] years; 52.8% men). Eligible patients demonstrated significant time-dependent improvement in 14-day case-fatality rate (CFR) with estimates of 29.8% (95% CI, 0.26-0.33) for February to March 2020; 20.3% (95% CI, 0.17-0.23) for April to June 2020; 12.5% (95% CI, 0.06-22.90) for July to September 2020; 17.2% (95% CI, 0.15-0.21) for October to December 2020; and 14.5% (95% CI, 0.09-0.21) for January to February 2021 (all P &lt;.001) across the predefined phases. Compared with the second major outbreak, patients diagnosed in the first outbreak were more likely to be 65 years or older (974 of 1626 [60.3%] vs 564 of 1008 [56.1%]; P =.03), have at least 2 comorbidities (793 of 1626 [48.8%] vs 427 of 1008 [42.4%]; P =.001), and have advanced tumors (708 of 1626 [46.4%] vs 536 of 1008 [56.1%]; P &lt;.001). Complications of COVID-19 were more likely to be seen (738 of 1626 [45.4%] vs 342 of 1008 [33.9%]; P &lt;.001) and require hospitalization (969 of 1626 [59.8%] vs 418 of 1008 [42.1%]; P &lt;.001) and anti-COVID-19 therapy (1004 of 1626 [61.7%] vs 501 of 1008 [49.7%]; P &lt;.001) during the first major outbreak. The 14-day CFRs for the first and second major outbreaks were 25.6% (95% CI, 0.23-0.28) vs 16.2% (95% CI, 0.13-0.19; P &lt;.001), respectively. After adjusting for country, sex, age, comorbidities, tumor stage and status, anti-COVID-19 and anticancer therapy, and COVID-19 complications, patients diagnosed in the first outbreak had an increased risk of death at 14 days (hazard ratio [HR], 1.85; 95% CI, 1.47-2.32) and 3 months (HR, 1.28; 95% CI, 1.08-1.51) compared with those diagnosed in the second outbreak. Conclusions and Relevance: The findings of this registry-based study suggest that mortality in patients with cancer diagnosed with COVID-19 has improved in Europe; this improvement may be associated with earlier diagnosis, improved management, and dynamic changes in community transmission over time.

COVID-19 in breast cancer patients: a subanalysis of the OnCovid registry

BACKGROUND: Cancer patients are at higher risk of COVID-19 complications and mortality than the rest of the population. Breast cancer patients seem to have better prognosis when infected by SARS-CoV-2 than other cancer patients. METHODS: We report a subanalysis of the OnCovid study providing more detailed information in the breast cancer population. RESULTS: We included 495 breast cancer patients with a SARS-CoV-2 infection. Mean age was 62.6 years; 31.5% presented more than one comorbidity. The most frequent breast cancer subtype was luminal-like (n = 245, 49.5%) and 177 (35.8%) had metastatic disease. A total of 332 (67.1%) patients were receiving active treatment, with radical intent in 232 (47.6%) of them. Hospitalization rate was 58.2% and all-cause mortality rate was 20.3%. One hundred twenty-nine (26.1%) patients developed one COVID-19 complication, being acute respiratory failure the most common (n = 74, 15.0%). In the multivariable analysis, age older than 70 years, presence of COVID-19 complications, and metastatic disease were factors correlated with worse outcomes, while ongoing anticancer therapy at time of COVID-19 diagnosis appeared to be a protective factor. No particular oncological treatment was related to higher risk of complications. In the context of SARS-CoV-2 infection, 73 (18.3%) patients had some kind of modification on their oncologic treatment. At the first oncological reassessment (median time: 46.9 days ± 36.7), 255 (51.6%) patients reported to be fully recovered from the infection. There were 39 patients (7.9%) with long-term SARS-CoV-2-related complications. CONCLUSION: In the context of COVID-19, our data confirm that breast cancer patients appear to have lower complications and mortality rate than expected in other cancer populations. Most breast cancer patients can be safely treated for their neoplasm during SARS-CoV-2 pandemic. Oncological treatment has no impact on the risk of SARS-CoV-2 complications, and, especially in the curative setting, the treatment should be modified as little as possible