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Background Non-melanoma skin cancers (NMSC) are the most common malignancies worldwide. While early-stage lesions can be definitively treated with local therapies, advanced stage cutaneous squamous cell carcinoma (cSCC) often requires systemic treatments such as PD-1 inhibitors. These treatments may be administered for prolonged durations; this practice may lead to an unnecessary physical and financial toxicity. The purpose of this study was to evaluate the patterns of disease progression after anti-PD-1 therapy discontinuation in this group of patients. Methods This retrospective cohort study included patients diagnosed with advanced cSCC and treated with either cemiplimab or pembrolizumab from 2019 to 2024 at a single university-affiliated tertiary medical center. Results The cohort included 131 patients, with a 73% overall response rate. Among the 86 patients with either partial or complete response as the best response included in the final analysis, 40 (47%) patients had a treatment break for at least 3 months, and 46 (53%) continued without discontinuation to a maximal duration of 2 years. After a median follow-up of 29.9 months, 24 (60%) patients in the break group remained progression-free, systemic treatment-free, and alive throughout the follow-up. Four patients (10%) experienced disease progression. Among these, the best overall response was PR in three patients and CR in one patient. Nine (22.5%) patients died due to non-oncological reasons, two (5%) patients died from an unknown cause, and one (2.5%) due to treatment toxicity. The percentage of patients achieving CR was statistically significantly higher in the break group compared to the no-break group. Conclusions Our findings advocate for a more tailored approach to the duration of PD-1 inhibitor therapy in cSCC, potentially reducing burdens of overtreatment. Future studies regarding establishing robust predictors for safe treatment discontinuation are required to enhance decision-making in clinical practice.

Background Smoking is associated with an increased incidence of hormone receptor positive breast cancer. Data regarding worse breast cancer outcome in smokers are accumulating. Current literature regarding the impact of smoking on breast cancer characteristics is limited. We evaluated the impact of smoking on breast cancer characteristics and outcome. Methods This was a retrospective single center study. All women diagnosed from 4/2005 through 3/2012 and treated in our institute for early, estrogen receptor positive, human epidermal growth factor receptor 2 (HER2) negative breast cancer, whose tumors were sent for Oncotype DX analysis were included. Medical records were reviewed for demographics, clinico-pathological parameters, treatment and outcome. Data regarding smoking were retrieved according to patients’ history at the first visit in the oncology clinic. Patients were grouped and compared according to smoking history (ever smokers vs. never smokers), smoking status (current vs. former and never smokers) and smoking intensity (pack years ≥30 vs. the rest of the cohort). Outcomes were adjusted in multivariate analyses and included age, menopausal status, ethnicity, tumor size, nodal status and grade. Results A total of 662 women were included. 28.2% had a history of smoking, 16.6% were current smokers and 11.3% were heavy smokers. Smoking had no impact on tumor size, nodal involvement and Oncotype DX recurrence score. Angiolymphatic and perineural invasion rates were higher in current smokers than in the rest of the cohort (10.4% vs. 5.1%, p  = 0.045, 8.3% vs. 3.5%, p  = 0.031, respectively). Smoking had no other impact on histological characteristics. Five-year disease free survival and overall survival rates were 95.7% and 98.5%, respectively. Smoking had no impact on outcomes. Adjusted disease free survival and overall survival did not influence the results. Conclusions Smoking had no clinically significant influence on tumor characteristics and outcome among women with estrogen receptor positive, HER2 negative, early breast cancer. As the study was limited to a specific subgroup of the breast cancer population in this heterogeneous disease and since smoking is a modifiable risk factor for the disease, further research is required to clarify the possible impact of smoking on breast cancer.

Four cycles of docetaxel/cyclophosphamide (DC) resulted in superior survival than doxorubicin/cyclophosphamide in the treatment of early breast cancer. The original study reported a 5% incidence of febrile neutropenia (FN) recommending prophylactic antibiotics with no granulocyte colony-stimulating factor (G-CSF) support. The worldwide adoption of this protocol yielded several reports on substantially higher rates of FN events. We explored the use of growth factor (GF) support on days 8 and 12 of the cycle with the original DC protocol. Our study included all consecutive patients with stages I-II breast cancer who were treated with the DC protocol at the Institute of Oncology, Davidoff Center (Rabin Medical Center, Petah Tikva, Israel) from April, 2007 to March, 2012. Patient, tumor characteristics, and toxicity were reported. In total, 123 patients received the DC regimen. Median age was 60 years, (range, 25-81 years). Thirty-three patients (26.8%) were aged 65 years and older. Most of the women (87%) adhered to the planned G-CSF protocol (days 8 &12). 96% of the patients completed the 4 planned cycles of chemotherapy. Six patients (5%) had dose reductions, 6 (5%) had treatment delays due to non-medical reasons. Thirteen patients (10.6%) experienced at least one event of FN (3 patients had 2 events), all requiring hospitalization. Eight patients (6.5%) required additional support with G-CSF after the first chemotherapy cycle, 7 because of FN and one due to neutropenia and diarrhea. Primary prophylactic G-CSF support on days 8 and 12 of the cycle provides a tolerable option to deliver the DC protocol. Our results are in line with other retrospective protocols using longer schedules of GF support.

Purpose. To evaluate the associations between metformin, insulin, statins, and levothyroxine and breast cancer characteristics and outcome. Methods. Retrospective chart review of patients treated in our institute for early estrogen receptor (ER) positive, human epidermal growth factor receptor 2 negative breast cancer, whose tumors were sent to Oncotype DX (ODX) analysis. Patients were grouped according to medications usage during the time of breast cancer diagnosis. Each group was compared to the rest of the study population. Results. The study cohort included 671 patients. Sixty (9.1%) patients were treated with metformin, 9 (1.4%) with insulin, 208 (31.7%) with statins, and 62 (9.4%) with levothyroxine. Patients treated with metformin had more intense ER stain ( p = 0.032 ) and a lower ODX recurrence score (RS) ( p = 0.035 ). Diagnosis of diabetes mellitus was also associated with lower ODX RS ( p = 0.014 ). Insulin usage was associated with a higher rate of angiolymphatic invasion ( p = 0.041 ), but lower Ki67% ( p = 0.017 ). Levothyroxine usage was associated with different histological subtype distribution ( p = 0.02 ). Extended levothyroxine usage was associated with lower ODX RS ( p = 0.005 ). Statin usage had no impact on tumor characteristics. Outcome was comparable in the studied subgroups. Conclusions. Common medications for metabolic disorders might be associated with breast cancer characteristics.

BackgroundThe combination of a taxane with trastuzumab and pertuzumab is standard of care for first-line treatment of human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer. The combination of vinorelbine with trastuzumab and pertuzumab showed anti-tumor activity in a phase 2 trial.Patients and methodsThe databases of two tertiary medical centers were retrospectively searched for patients with HER2-positive metastatic breast cancer who underwent first-line treatment in 2013–2019 with a taxane or vinorelbine in combination with trastuzumab and pertuzumab. Groups were compared for progression-free survival (PFS), overall survival (OS), and toxicity profile.ResultsThe study included 87 patients in the taxane group and 65 in the vinorelbine group. Overall median PFS was significantly longer in the taxane group [HR 0.56 (0.36–0.88), P = 0.01], but on multivariate analysis the difference was not statistically significant [HR 0.68 (0.4–1.1, P = 0.11)]. PFS was comparable in both groups of patients with recurrent disease [HR 0.94 (0.5–1.79), P = 0.85]. However, in patients with de novo metastatic disease, the difference in favor of the taxane group was pronounced [HR 0.4 (0.2–0.78), P = 0.007] and maintained significance on multivariate analysis [HR 0.46 (0.2–0.97, P = 0.04)]. There was no statistical significant difference in OS in the whole cohort [HR 0.69 (0.39–1.23)] or the subgroups.ConclusionsPatients with HER2-positive metastatic breast cancer had similar survival with first-line treatment of taxane or vinorelbine combined with trastuzumab and pertuzumab. When the analysis was adjusted for prognostic factors, there was no PFS benefit for taxanes except in the subgroup with de novo disease.

PurposeThe purpose of this study is to explore differences in the pattern and outcome of central nervous system (CNS) involvement in breast cancer by age at diagnosis.MethodsA retrospective database of a tertiary cancer center yielded 174 consecutive patients with breast cancer who were diagnosed with CNS metastases in 2006–2019. Data on histopathology, characteristics of CNS involvement, treatments, and survival (at three time points during the disease course) were compared between patients aged ≤ 45 and > 45 years. Pearson Chi-square or Fisher exact test and Kaplan–Meier survival curves with log-rank test were used for statistical analyses.ResultsStudy population was divided according to age at diagnosis of breast cancer. 65 patients were ≤ 45 years old and 109 patients > 45 years old. The younger group was characterized by longer median overall survival (117.1 months vs 88 months, p = 0.017) and longer interval between breast cancer diagnosis to development of CNS metastases (97.4 months vs 75.9 months,p = 0.026). Median survival after development of CNS disease was not significantly different (18.7 months vs 11.1 months, p = 0.341), although it was significantly longer in younger patients within the subgroup of patients with triple-negative disease (22.5 vs 7.9 months, p = 0.033). There were no between-group differences in number, location, and clinical presentation of CNS metastases or in systemic and CNS-directed treatment approaches.ConclusionWhile the presentation of CNS involvement was similar between the different age groups, younger patients had significantly longer CNS-free interval and longer overall survival, and for the subgroups of triple-negative patients, younger age at breast cancer diagnosis was associated with longer survival after diagnosis of CNS disease.

Background. Our previous study of pulmonary function in 34 patients with early breast cancer without preexisting lung disease showed that anthracycline- and taxane-based adjuvant dose-dense chemotherapy (DDC) caused a significant 16.4% mean reduction in carbon monoxide diffusing capacity (DLCO). The present study reports the pulmonary and oncological outcomes of these patients on long-term follow-up. Patients and methods. The primary endpoint was DLCO measured by the pulmonary function test (PFT) performed at a median of 27 months after DDC (range, 8–97) in 25 patients without disease recurrence. DLCO values were recorded as a percentage of predicted values according to age, height, and hemoglobin level and analyzed relative to baseline pre-DDC DLCO values. The secondary endpoints were symptoms, additional therapies, and cancer outcomes during a median of 11 years’ follow-up (range, 4.4–11.4). Results. A longitudinal general linear model showed significant effects of time on DLCO and its trend (F(1, 87) = 14.68, p<0.001 and F(1, 87) = 10.26, p=0.002, respectively). Complementary descriptive analysis showed a significant recovery on the follow-up PFT (75.6% vs. 81.9%, p=0.002), but it was still significantly lower than the baseline DLCO (81.9% vs. 92.0%, p=0.003). Five patients (20%) still showed a >20% relative DLCO reduction from baseline. Patients with dyspnea or fatigue at later clinical follow-up had a significantly lower DLCO value on the follow-up PFT than nonsymptomatic patients (80.5% vs. 92.1%, p=0.02). DLCO recovery was inversely correlated with age (R = −0.39, p=0.05), but no significant correlation was found with the length of time until the follow-up PFT or additional therapies. There was no association of DDC-related DLCO reduction with cancer outcomes. Conclusions. The significant reduction in DLCO seen after DDC in patients with potentially curable breast cancer is evident years afterwards, especially in older patients. While most patients partly recover, some will have a lasting symptomatic DLCO impairment.

Systemic adjuvant treatment might mitigate the high risk of disease recurrence in patients with resected stage IIC–III melanoma. The BRIM8 study evaluated adjuvant vemurafenib monotherapy in patients with resected, BRAFV600 mutation-positive melanoma. BRIM8 was a phase 3, international, double-blind, randomised, placebo-controlled study that enrolled 498 adults (aged ≥18 years) with histologically confirmed stage IIC–IIIA–IIIB (cohort 1) or stage IIIC (cohort 2) BRAFV600 mutation-positive melanoma that was fully resected. Patients were randomly assigned (1:1) by an interactive voice or web response system to receive twice-daily adjuvant oral vemurafenib 960 mg tablets or matching placebo for 52 weeks (13 × 28-day cycles). Randomisation was done by permuted blocks (block size 6) and was stratified by pathological stage and region in cohort 1 and by region in cohort 2. The investigators, patients, and sponsor were masked to treatment assignment. The primary endpoint was disease-free survival in the intention-to-treat population, evaluated separately in each cohort. Hierarchical analysis of cohort 2 before cohort 1 was prespecified. This trial is registered with ClinicalTrials.gov, number NCT01667419. The study enrolled 184 patients in cohort 2 (93 were assigned to vemurafenib and 91 to placebo) and 314 patients in cohort 1 (157 were assigned to vemurafenib and 157 to placebo). At the time of data cutoff (April 17, 2017), median study follow-up was 33·5 months (IQR 25·9–41·6) in cohort 2 and 30·8 months (25·5–40·7) in cohort 1. In cohort 2 (patients with stage IIIC disease), median disease-free survival was 23·1 months (95% CI 18·6–26·5) in the vemurafenib group versus 15·4 months (11·1–35·9) in the placebo group (hazard ratio [HR] 0·80, 95% CI 0·54–1·18; log-rank p=0·026). In cohort 1 (patients with stage IIC–IIIA–IIIB disease) median disease-free survival was not reached (95% CI not estimable) in the vemurafenib group versus 36·9 months (21·4–not estimable) in the placebo group (HR 0·54 [95% CI 0·37–0·78]; log-rank p=0·0010); however, the result was not significant because of the prespecified hierarchical prerequisite for the primary disease-free survival analysis of cohort 2 to show a significant disease-free survival benefit. Grade 3–4 adverse events occurred in 141 (57%) of 247 patients in the vemurafenib group and 37 (15%) of 247 patients in the placebo group. The most common grade 3–4 adverse events in the vemurafenib group were keratoacanthoma (24 [10%] of 247 patients), arthralgia (17 [7%]), squamous cell carcinoma (17 [7%]), rash (14 [6%]), and elevated alanine aminotransferase (14 [6%]), although all keratoacanthoma events and most squamous cell carcinoma events were by default graded as grade 3. In the placebo group, grade 3–4 adverse events did not exceed 2% for any of the reported terms. Serious adverse events were reported in 40 (16%) of 247 patients in the vemurafenib group and 25 (10%) of 247 patients in the placebo group. The most common serious adverse event was basal cell carcinoma, which was reported in eight (3%) patients in each group. One patient in the vemurafenib group of cohort 2 died 2 months after admission to hospital for grade 3 hypertension; however, this death was not considered to be related to the study drug. The primary endpoint of disease-free survival was not met in cohort 2, and therefore the analysis of cohort 1 showing a numerical benefit in disease-free survival with vemurafenib versus placebo in patients with resected stage IIC–IIIA–IIIB BRAFV600 mutation-positive melanoma must be considered exploratory only. 1 year of adjuvant vemurafenib was well tolerated, but might not be an optimal treatment regimen in this patient population. F Hoffman–La Roche Ltd.

Systemic adjuvant treatment might mitigate the high risk of disease recurrence in patients with resected stage IIC-III melanoma. The BRIM8 study evaluated adjuvant vemurafenib monotherapy in patients with resected, BRAF mutation-positive melanoma. BRIM8 was a phase 3, international, double-blind, randomised, placebo-controlled study that enrolled 498 adults (aged ≥18 years) with histologically confirmed stage IIC-IIIA-IIIB (cohort 1) or stage IIIC (cohort 2) BRAF mutation-positive melanoma that was fully resected. Patients were randomly assigned (1:1) by an interactive voice or web response system to receive twice-daily adjuvant oral vemurafenib 960 mg tablets or matching placebo for 52 weeks (13 × 28-day cycles). Randomisation was done by permuted blocks (block size 6) and was stratified by pathological stage and region in cohort 1 and by region in cohort 2. The investigators, patients, and sponsor were masked to treatment assignment. The primary endpoint was disease-free survival in the intention-to-treat population, evaluated separately in each cohort. Hierarchical analysis of cohort 2 before cohort 1 was prespecified. This trial is registered with ClinicalTrials.gov, number NCT01667419. The study enrolled 184 patients in cohort 2 (93 were assigned to vemurafenib and 91 to placebo) and 314 patients in cohort 1 (157 were assigned to vemurafenib and 157 to placebo). At the time of data cutoff (April 17, 2017), median study follow-up was 33·5 months (IQR 25·9-41·6) in cohort 2 and 30·8 months (25·5-40·7) in cohort 1. In cohort 2 (patients with stage IIIC disease), median disease-free survival was 23·1 months (95% CI 18·6-26·5) in the vemurafenib group versus 15·4 months (11·1-35·9) in the placebo group (hazard ratio [HR] 0·80, 95% CI 0·54-1·18; log-rank p=0·26). In cohort 1 (patients with stage IIC-IIIA-IIIB disease) median disease-free survival was not reached (95% CI not estimable) in the vemurafenib group versus 36·9 months (21·4-not estimable) in the placebo group (HR 0·54 [95% CI 0·37-0·78]; log-rank p=0·0010); however, the result was not significant because of the prespecified hierarchical prerequisite for the primary disease-free survival analysis of cohort 2 to show a significant disease-free survival benefit. Grade 3-4 adverse events occurred in 141 (57%) of 247 patients in the vemurafenib group and 37 (15%) of 247 patients in the placebo group. The most common grade 3-4 adverse events in the vemurafenib group were keratoacanthoma (24 [10%] of 247 patients), arthralgia (17 [7%]), squamous cell carcinoma (17 [7%]), rash (14 [6%]), and elevated alanine aminotransferase (14 [6%]), although all keratoacanthoma events and most squamous cell carcinoma events were by default graded as grade 3. In the placebo group, grade 3-4 adverse events did not exceed 2% for any of the reported terms. Serious adverse events were reported in 40 (16%) of 247 patients in the vemurafenib group and 25 (10%) of 247 patients in the placebo group. The most common serious adverse event was basal cell carcinoma, which was reported in eight (3%) patients in each group. One patient in the vemurafenib group of cohort 2 died 2 months after admission to hospital for grade 3 hypertension; however, this death was not considered to be related to the study drug. The primary endpoint of disease-free survival was not met in cohort 2, and therefore the analysis of cohort 1 showing a numerical benefit in disease-free survival with vemurafenib versus placebo in patients with resected stage IIC-IIIA-IIIB BRAF mutation-positive melanoma must be considered exploratory only. 1 year of adjuvant vemurafenib was well tolerated, but might not be an optimal treatment regimen in this patient population. F Hoffman-La Roche Ltd.

Purpose Four cycles of docetaxel/cyclophosphamide (DC) resulted in superior survival than doxorubicin/cyclophosphamide in the treatment of early breast cancer. The original study reported a 5% incidence of febrile neutropenia (FN) recommending prophylactic antibiotics with no granulocyte colony-stimulating factor (G-CSF) support. The worldwide adoption of this protocol yielded several reports on substantially higher rates of FN events. We explored the use of growth factor (GF) support on days 8 and 12 of the cycle with the original DC protocol. Methods Our study included all consecutive patients with stages I-II breast cancer who were treated with the DC protocol at the Institute of Oncology, Davidoff Center (Rabin Medical Center, Petah Tikva, Israel) from April, 2007 to March, 2012. Patient, tumor characteristics, and toxicity were reported. Results: In total, 123 patients received the DC regimen. Median age was 60 years, (range, 25-81 years). Thirty-three patients (26.8%) were aged 65 years and older. Most of the women (87%) adhered to the planned G-CSF protocol (days 8 &12). 96% of the patients completed the 4 planned cycles of chemotherapy. Six patients (5%) had dose reductions, 6 (5%) had treatment delays due to non-medical reasons. Thirteen patients (10.6%) experienced at least one event of FN (3 patients had 2 events), all requiring hospitalization. Eight patients (6.5%) required additional support with G-CSF after the first chemotherapy cycle, 7 because of FN and one due to neutropenia and diarrhea. In Conclusion Primary prophylactic G-CSF support on days 8 and 12 of the cycle provides a tolerable option to deliver the DC protocol. Our results are in line with other retrospective protocols using longer schedules of GF support.