Effect of mode of delivery of patient reported outcomes in patients with breast disease: a randomised controlled trial.

BACKGROUND: Patient reported outcomes (PROs) have an integral role on how to improve patients' overall experience. The optimal PROs delivery in patients with breast disease is an important issue since PROs are steadily integrated in routine care. METHODS: An institutional phase 3 randomised controlled, open-label trial. Eligible candidates were adult women with perceived or confirmed breast disease. Computer generated randomization was used to allocate interventions: collection of PROs in electronic or paper form. Our objective was the effectiveness of electronic versus paper form of PROs. The main outcome measures were: response rate, reported experience, administrative resources, and carbon dioxide emissions. RESULTS: Two hundred thirty-eight patients were randomised. After loss-to-follow-up and consent withdrawals, 218 participants (median age, IQR=55, 21; n =110/ n =108) were included in the per-intention-to-treat analysis. Response rate was 61.8% for electronic patient reported outcomes (ePROs) and 63.9% for paper patient reported outcomes (pPROs) (difference=-2.1%, 95% CI: -15.8-11.7%). Only known breast cancer at recruitment was predictive for response in multivariable analysis. ePROs were associated with a 57% reduction in administrative time required, a 95% reduction in incremental costs, and 84% reduction in carbon dioxide emissions, all differences being significant. No difference was detected in perception of PRO significance or ease of completion, but participants experienced that they needed less time to complete ePROs [median, (IQR) 10 (9) respectively 15(10)]. Finally, respondents would prefer ePROs over pPROs (difference 48.1%, 95% CI: 32.8-63.4%). CONCLUSION: ePROs do not increase the response rate in patients with perceived or confirmed breast disease. However, they can enhance patient experience, reduce incremental costs, facilitate administrative logistics, and are more sustainable. On the basis of these findings, both modalities should continue to be available.

Treatment utilization and effectiveness of neoadjuvant chemotherapy comparing men and women diagnosed with breast cancer: a Swedish retrospective cohort study.

PURPOSE: Evidence supporting the use of neoadjuvant chemotherapy (NAC) in early breast cancer is based on studies mainly including women, whereas the utilization and effectiveness of NAC in men is less studied. The present study aimed to investigate the utilization and effectiveness of NAC in men and women with early breast cancer. METHODS: Eligible patients were identified through the Swedish National Breast Cancer Quality Register, that includes all newly diagnosed breast cancer cases in Sweden from 2008 and onwards. For the treatment utilization analysis, all patients with stage I-III between 2008 and 2020 were included (n = 82,888), whereas for the effectiveness analysis the cohort was restricted to patients receiving NAC (n = 6487). For both analyses, multivariate logistic regression models were applied to investigate potential sex disparities in NAC utilization and effectiveness, adjusted for patient- and tumor characteristics. RESULTS: In the NAC utilization analysis, 487 men and 82,401 women with stage I-III were included. No statistically significant difference between sexes in terms of NAC utilization was observed (adjusted Odds Ratio (adjOR): 1.135; 95% Confidence Interval (CI) 0.606-2.128) with an overall utilization rate of 4.9% in men compared to 7.8% in women. Among the 24 men and 6463 women who received NAC, the pathologic complete response (pCR) rates were 16.7% and 21.2%, respectively (adjOR: 1.141; 95% CI 0.141-9.238). CONCLUSION: The present study did not find any sex disparities in NAC utilization or effectiveness in terms of pCR. This supports the current recommendations of treating men with breast cancer with the same indications for NAC as women.

De novo metastatic breast cancer in men vs women: a Swedish population-based cohort study.

Current evidence on de novo metastatic breast cancer is based on data from women. This Swedish population-based cohort study compared the incidence over time and prognosis of de novo metastatic breast cancer between sexes using data from the Swedish National Quality Register for Breast Cancer. Joinpoint regression analysis was used to compare incidence trends in all stages (104 733 women, 648 men) and multivariate Cox regression analysis to investigate potential sex disparities in de novo metastatic breast cancer prognosis (6005 women, 41 men). For both sexes, increased trends were evident for cancer stages I and II, with a stabilizing trend at the later years for women, while stage III incidence remained stable. An increased trend for de novo metastatic breast cancer in women, and to a lesser extent in men, was observed. No difference in de novo metastatic breast cancer overall survival between sexes was observed (hazard ratio = 1.24; 95% confidence interval = 0.85 to 1.81). The comparable features in terms of incidence and prognosis of de novo metastatic breast cancer between sexes imply similarities, supporting the adoption of common treatment strategies.

Tumour-infiltrating lymphocytes add prognostic information for patients with low-risk DCIS: findings from the SweDCIS randomised radiotherapy trial.

BACKGROUND: The immune microenvironment is an important modulator of tumour progression and treatment response. In invasive breast cancer, assessment of tumour-infiltrating lymphocytes (TILs) provides prognostic and predictive information. However, the clinical impact of TILs for ductal carcinoma in situ (DCIS) has not yet been demonstrated. PATIENTS AND METHODS: Post hoc analysis of the SweDCIS randomised radiotherapy trial including primary DCIS cases following breast-conserving surgery. TILs were assessed on haematoxylin-eosin sections (n = 711) according to the International Immuno-Oncology Biomarker Working Group guidelines. TILs-scores were analysed as continuous and dichotomised (≤5% versus >5%) variable regarding ipsilateral breast events (IBEs) as the predefined primary endpoint. RESULTS: Most women (61.9%) showed a TILs prevalence of ≤5%. High TILs-scores were associated with larger lesion size, human epidermal growth factor receptor 2 (HER2)-positivity, higher nuclear grade, and KI67-score. DCIS cases with high TILs prevalence had a significant increased cumulative IBE incidence at five years post-surgery (TILslow-versus TILshigh 9% versus 18%; p < 0.001). Among patients with HER2-negative DCIS, high TILs remained an independent poor prognosis marker for IBE risk in multivariable analysis with an adjusted hazard ratio of 2.41 [95%CI 1.17-4.95, p = 0.017]. Including TILs-status provided a refined stratification of patients with general low-risk DCIS (grade <3, size <25 mm, free margin). No interaction between TILs and radiotherapy benefits was detected. CONCLUSION: High TILs are associated with higher IBE risk over 5-years post-surgery, particularly for HER2-negative DCIS. Our data indicate that TILs should be integrated into the clinical workup to define patients with low-risk DCIS who can omit adjuvant therapy or patients with potential benefits from immunotherapy.

Neoadjuvant Trastuzumab, Pertuzumab, and Docetaxel vs Trastuzumab Emtansine in Patients With ERBB2-Positive Breast Cancer: A Phase 2 Randomized Clinical Trial.

Importance: Trastuzumab emtansine (T-DM1) is presently approved for treatment of advanced breast cancer and after incomplete response to neoadjuvant therapy, but the potential of T-DM1 as monotherapy is so far unknown. Objective: To assess pathologic complete response (pCR) to standard neoadjuvant therapy of combination docetaxel, trastuzumab, and pertuzumab (DTP) vs T-DM1 monotherapy in patients with ERBB2 (formerly HER2)-positive breast cancer. Design, Setting, and Participants: This randomized phase 2 trial, conducted at 9 sites in Sweden, enrolled 202 patients between December 1, 2014, and October 31, 2018. Participants were 18 years or older, with ERBB2-positive tumors larger than 20 mm and/or verified lymph node metastases. Analysis was performed on an intention-to-treat basis. Interventions: Patients were randomized to receive 6 cycles of DTP (standard group) or T-DM1 (investigational group). Crossover was recommended at lack of response or occurrence of intolerable toxic effects. Assessment with fluorine 18-labeled fluorodeoxyglucose (18F-FDG) positron emission tomography combined with computed tomography (PET-CT) was performed at baseline and after 2 and 6 treatment cycles. Main Outcome and Measures: Pathologic complete response, defined as ypT0 or Tis ypN0. Secondary end points were clinical and radiologic objective response; event-free survival, invasive disease-free survival, distant disease-free survival, and overall survival; safety; health-related quality of life (HRQoL); functional and biological tumor characteristics; and frequency of breast-conserving surgery. Results: Overall, 202 patients were randomized; 197 (99 women in the standard group [median age, 51 years (range, 26-73 years)] and 98 women in the investigational group [median age, 53 years (range, 28-74 years)]) were evaluable for the primary end point. Pathologic complete response was achieved in 45 patients in the standard group (45.5%; 95% CI 35.4%-55.8%) and 43 patients in the investigational group (43.9%; 95% CI 33.9%-54.3%). The difference was not statistically significant (P = .82). In a subgroup analysis, the pCR rate was higher in hormone receptor-negative tumors than in hormone receptor-positive tumors in both treatment groups (45 of 72 [62.5%] vs 45 of 125 [36.0%]). Three patients in the T-DM1 group experienced progression during therapy. In an exploratory analysis, tumor-infiltrating lymphocytes at 10% or more (median) estimated pCR significantly (odds ratio, 2.76; 95% CI, 1.42-5.36; P = .003). Response evaluation with 18F-FDG PET-CT revealed a relative decrease of maximum standardized uptake value by equal to or greater than 68.7% (median) was associated with pCR (odds ratio, 6.74, 95% CI, 2.75-16.51; P < .001). Conclusions and Relevance: In this study, treatment with standard neoadjuvant combination DTP was equal to T-DM1. Trial Registrations: ClinicalTrials.gov Identifier: NCT02568839; EudraCT number: 2014-000808-10.

High PDGFRb Expression Predicts Resistance to Radiotherapy in DCIS within the SweDCIS Randomized Trial.

PURPOSE: This study analyzes the potential of stromal platelet-derived growth factor receptor-beta (PDGFRb) expression as biomarker for radiotherapy (RT) benefit on ipsilateral breast events (IBE) in ductal carcinoma in situ (DCIS). Improved identification of DCIS patients refractory to adjuvant whole-breast RT is needed. Predictive biomarker studies in DCIS have focused on tumor cell features rather than the tumor-associated stroma, despite growing evidence of its influence on therapy efficiency. EXPERIMENTAL DESIGN: Samples from the Swedish randomized radiotherapy DCIS trial (SweDCIS) were subjected to IHC analysis for stromal PDGFRb expression. IBE incidence at 10 years after breast-conserving surgery was the primary endpoint. Interactions between marker and treatment were analyzed. RESULTS: PDGFRb score was predictive for RT benefit with regard to IBE (P interaction = 0.002 and P interaction = 0.008 adjusted multivariably). Patients of the PDGFRblow group had a strong benefit from RT regarding IBE risk [HR, 0.23; 95% confidence interval (CI), 0.12-0.45; P < 0.001] with an absolute risk reduction of 21% (cumulative risk 7% vs. 28%) at 10 years. No significant risk reduction by RT was observed for patients of the PDGFRbhigh group (HR, 0.83; 0.51-1.34; P = 0.444; cumulative risk 22% vs. 25%). The RT response-predictive effect of stromal PDGFRb was equally strong in analyses for in situ and invasive IBE when analyzed separately (in situ IBE: P = 0.029; invasive IBE: P = 0.044). CONCLUSIONS: Results suggest high stromal PDGFRb expression as a novel biomarker identifying DCIS patients who are refractory to standard whole-breast adjuvant RT. The data imply previously unrecognized fibroblast-mediated modulation of radiosensitivity of DCIS, which should be further explored from mechanistic and targeting perspectives.

Predictive role of HER2-status on the effectiveness of endocrine adjuvant treatment in postmenopausal breast cancer patients: a population-based cohort study.

PURPOSE: There are conflicting results on the potential role of HER2-status on the efficacy of aromatase inhibitors (AIs) and tamoxifen (TAM) in patients with hormone receptor (HR)-positive breast cancer (BC). The purpose of this population-based cohort study was to investigate the potential benefit of AIs compared to TAM as adjuvant therapy in postmenopausal BC patients by HER2-status in the era of modern therapy with HER2-blockade. METHODS: A population-based cohort study was performed including all postmenopausal women diagnosed with HR-positive BC without distant metastasis between 2007 and 2012 in three healthcare regions in Sweden. We analyzed the breast cancer-specific survival (BCSS) and overall survival (OS) in two distinct cohorts (HER2-negative, HER2-positive) based on the type of endocrine therapy (ET) used. A propensity score matching was performed separately in the HER2-negative and HER2-positive cohorts, respectively. RESULTS: After propensity score matching, 4368 patients with HER2-negative and 214 patients with HER2-positive BC were available for analysis. In the HER2-negative cohort, an improved BCSS [Hazard Ratio (HR): 0.51; 95% confidence interval (CI): 0.34-0.77, p value < 0.001] and a trend toward improved OS (HR: 0.66; 95% CI: 0.41-1.08, p value = 0.093) in favor of AI-based therapy was observed. In the HER2-positive cohort, no statistically significant difference between AI-based ET and TAM was found in terms of either BCSS or OS, although the direction of HR was similar as in the HER2-negative cohort (HR for BCSS: 0.84; 95% CI: 0.14-5.04, p = 0.849; HR for OS: 0.62; 95% CI: 0.10-3.38, p = 0.345). CONCLUSION: Our study results, based on propensity-matched cohorts, did not support any predictive value of HER2-status on endocrine therapy in postmenopausal BC patients. AI-based ET remains the treatment of choice for postmenopausal BC patients with HR-positive disease in the modern era of HER2-directed therapy irrespective of HER2-status.

Evaluation of Diffusion-Weighted MRI and FDG-PET/CT to Assess Response to AdCD40L treatment in Metastatic Melanoma Patients.

The purpose was to evaluate the potential of diffusion-weighted-magnetic resonance imaging (DW-MRI) and 18F-fludeoxy-glucose-positron emission tomography integrated with CT (FDG-PET/CT) for prediction of overall survival (OS) following AdCD40L-immunotherapy in patients with metastatic malignant melanoma (MMM). Twenty-four patients with refractory MMM were treated with immunostimulatory AdCD40L gene therapy in a phase I/IIa study. Pre-therapeutic DW-MRI and FDG-PET/CT were performed and then repeated at 5 and 9 weeks post-treatment. Evaluation was conducted according to RECIST 1.1 and EORTC criteria. Apparent diffusion coefficient (ADC), true diffusion coefficient (D), maximum standardized uptake value (SUVmax) were measured in the injected lesions. Fold changes (F) in ADC (F ADC), D (F D), SUVmax (F SUVmax) were statistically assessed. F D ≥ 1 and F ADC ≥ 1 were associated with better OS in scans at week 5 and 9 respectively. F SUVmax was not correlated to OS. F ADC ≥ 1 in both post-treatment scans and F D ≥ 1 at week 5 were related to a significant decrease of size of the injected lesions. These results suggest that in patients with MMM treated with AdCD40l, functional parameters of DW-MRI are better early predictors of OS than the established metabolic and morphologic criteria for FDG-PET/CT and MRI, respectively.

Local irradiation does not enhance the effect of immunostimulatory AdCD40L gene therapy combined with low dose cyclophosphamide in melanoma patients.

BACKGROUND: AdCD40L is an immunostimulatory gene therapy under evaluation for advanced melanoma, including ocular melanoma. Herein, we present the final data of a Phase I/IIa trial using AdCD40L alone or in combination with low dose cyclophosphamide +/- radiation therapy. METHODS: AdCD40L is a replication-deficient adenovirus carrying the gene for CD40 ligand (CD40L). Twenty-four patients with advanced melanoma were enrolled and treated with AdCD40L monotherapy, or combined with cyclophosphamide +/- single fraction radiotherapy. The patients were monitored for 10 weeks using immunological and radiological evaluations and thereafter for survival. RESULTS: AdCD40L treatment was safe and well tolerated both alone and in combination with cyclophosphamide as well as local radiotherapy. Four out of twenty-four patients had >1 year survival. Addition of cyclophosphamide was beneficial but adding radiotherapy did not further extend survival. High initial plasma levels of IL12 and MIP3b correlated to overall survival, whereas IL8 responses post-treatment correlated negatively with survival. Interestingly, antibody reactions to the virus correlated negatively with post IL6 and pre IL1b levels in blood. CONCLUSIONS: AdCD40L was safely administered to patients and effect was improved by cyclophosphamide but not by radiotherapy. Immune activation profile at baseline may predict responders better than shortly after treatment.