A multi-institutional prediction model to estimate the risk of recurrence and mortality after mastectomy for T1-2N1 breast cancer.

BACKGROUND: Post-mastectomy radiation therapy (PMRT) in women with pathologic stage T1-2N1M0 breast cancer is controversial. METHODS: Data from five North American institutions including women undergoing mastectomy without neoadjuvant therapy with pT1-2N1M0 breast cancer treated from 2006 to 2015 were pooled for analysis. Competing-risks regression was performed to identify factors associated with locoregional recurrence (LRR), distant metastasis (DM), overall recurrence (OR), and breast cancer mortality (BCM). RESULTS: A total of 3532 patients were included for analysis with a median follow-up time among survivors of 6.8 years (interquartile range [IQR], 4.5-9.5 years). The 2154 (61%) patients who received PMRT had significantly more adverse risk factors than those patients not receiving PMRT: younger age, larger tumors, more positive lymph nodes, lymphovascular invasion, extracapsular extension, and positive margins (p < .05 for all). On competing risk regression analysis, receipt of PMRT was significantly associated with a decreased risk of LRR (hazard ratio [HR], 0.21; 95% confidence interval [CI], 0.14-0.31; p < .001) and OR (HR, 0.76; 95% CI, 0.62-0.94; p = .011). Model performance metrics for each end point showed good discrimination and calibration. An online prediction model to estimate predicted risks for each outcome based on individual patient and tumor characteristics was created from the model. CONCLUSIONS: In a large multi-institutional cohort of patients, PMRT for T1-2N1 breast cancer was associated with a significant reduction in locoregional and overall recurrence after accounting for known prognostic factors. An online calculator was developed to aid in personalized decision-making regarding PMRT in this population.

Hypofractionated radiation treatment for breast cancer: The time is now.

While there is now Level I data with long-term follow-up supporting the routine use of hypofractionated (HF) whole-breast radiation therapy (WBRT) after breast-conserving surgery, its adoption has been slow and variable. This article will review the literature supporting the efficacy and safety of hypofractionated radiation for breast cancer, discuss the radiobiological rationale specific to breast tumors, and make an argument for justifying the routine adoption of shorter, HF-WBRT courses when delivering breast radiation. Data using HF with regional nodal irradiation and in the post-mastectomy setting will also be reviewed. The aim is to provide an in-depth understanding of the use of hypofractionated radiation therapy for breast cancer, its applicability, and topics warranting future research.

Locoregional recurrence and survival outcomes by type of local therapy and trastuzumab use among women with node-negative, HER2-positive breast cancer.

BACKGROUND: While human epidermal growth factor receptor 2 (HER2) overexpression is an adverse breast cancer prognostic factor, it is unclear whether there are differences in outcomes between types of local treatment in this population. This retrospective study examined locoregional recurrence and survival in women with node-negative, HER2+ breast cancer treated with breast-conserving therapy (BCT) versus mastectomy. METHODS: Subjects were 748 patients with pT1-2, N0, M0 HER2+ breast cancer, treated with BCT (n = 422) or mastectomy (n = 326). Trastuzumab was used in 54 % of subjects. The 5-year Kaplan-Meier locoregional recurrence free survival (LRRFS), breast cancer specific survival (BCSS), and overall survival (OS) were compared between cohorts treated with BCT versus mastectomy. Subgroup analyses of LRR and survival were performed separately among patients treated with BCT or mastectomy to examine the effect of trastuzumab on outcomes in each group. RESULTS: Median follow-up was 4.4 years. Patients treated with mastectomy had higher proportions of grade 3 histology (69 vs 60 %, p = 0.004) and lower rates of hormone therapy (51 vs 64 %, p < 0.001) and trastuzumab therapy (50 vs 57 %, p = 0.04). The 5-year outcomes in women treated with BCT compared with mastectomy were: LRRFS 98.0 versus 98.3 % (p = 0.88), BCSS 97.2 versus 96.1 % (p = 0.70), and OS 95.5 versus 93.4 % (p = 0.19). Trastuzumab was associated with similar LRRFS and improved OS in both local treatment groups. CONCLUSIONS: BCT is safe in the population of women with pT1-2, N0, HER2+ breast cancer, providing high rates of locoregional control and survival equivalent to mastectomy. Trastuzumab was associated with improved survival in both groups.

Advanced cutaneous squamous cell carcinoma: Impact of age on the safety and efficacy of cemiplimab and the prognostic significance of blood biomarkers.

INTRODUCTION: Age-related differences in the safety profile of cemiplimab for patients with locally advanced or metastatic cutaneous squamous cell carcinoma (cSCC) have not been well described. We investigated the association of increasing age with immune related adverse events (irAE) from cemiplimab, efficacy outcomes, and the prognostic significance of pre-treatment blood biomarkers in contemporary practice. MATERIALS AND METHODS: Patients starting first-line cemiplimab for locally advanced or metastatic cSCC at British Columbia Cancer between April 2019 and January 2023 were identified. Landmark four-month logistic regression analysis compared the odds of developing irAE or sequelae amongst patients aged <75 years to those aged 75-84 or ≥ 85. Objective responses were determined using Response Evaluation Criteria in Solid Tumors version 1.1. Univariable Cox proportional hazard (PH) regression modelling of factors associated with overall survival (OS) was performed. RESULTS: Of 106 patients, the proportions aged <75, 75-84, and ≥ 85 years were 34%, 45%, and 21%, respectively. Overall, the proportion of patients with irAE ≥ grade 3, cemiplimab discontinuation, and hospitalization for immune toxicity was 27.4%, 31.1%, and 11.3%, respectively. There was no clear association between age and the odds of high grade irAE. However, increased odds of cemiplimab discontinuation was observed in patients aged 75-84 years (p = 0.05). Patients ≥85 years had increased hospitalizations due to irAE (OR = 5.00, 95% CI = 0.97-37.52) with two treatment-related deaths. Objective responses were similar across age cohorts (50.0%, 60.4%, and 54.5%) but progressive disease was higher in the age ≥ 85 group (22.2%, 18.8%, and 31.8%). On Cox PH regression analysis, age ≥ 85 years (vs. <75), Eastern Cooperative Oncology Group performance status 2-3 (vs. 0-1), and neutrophil to lymphocyte ratio (NLR) ≥7.80 (vs. <7.80) were associated with shorter survival. DISCUSSION: While the odds of high grade irAE were similar across age groups, significant age-related differences in treatment discontinuation and hospitalization due to immune toxicity were observed. Despite a higher incidence of primary progression and shorter OS in the oldest cohort, cemiplimab yielded robust objective responses regardless of age. Higher pre-treatment NLR was associated with shorter survival and the cut-point identified requires further study.

Safety and efficacy of pembrolizumab for advanced nonsmall cell lung cancer: before and during the COVID-19 pandemic.

PURPOSE: The COVID-19 pandemic changed diagnostic and treatment pathways in oncology. We compared the safety and efficacy of pembrolizumab amongst advanced nonsmall cell lung cancer (NSCLC) patients with a PD-L1 tumor proportion score (TPS) ≥ 50% before and during the pandemic. METHODS: Advanced NSCLC patients initiating pembrolizumab between June 2015 and December 2019 ("pre-pandemic cohort") and between March 2020 and March 2021 ("pandemic cohort") at BC Cancer were identified retrospectively. Multivariable logistic regression evaluated risk factors for immune-related adverse events (irAE) ≥ grade 3 at the 6 week, 3 month, and 6 month landmarks. Cox regression models of overall survival (OS) were constructed. RESULTS: The study population comprised 417 patients in the pre-pandemic cohort and 111 patients in the pandemic cohort. Between March and May 2020, 48% fewer advanced NSCLC cases with PD-L1 TPS ≥ 50% were diagnosed compared to similar intervals in 2018-2019. Telemedicine assessment [new patient consultations (p < 0.001) and follow-up (p < 0.001)] and extended interval pembrolizumab dosing (p < 0.001) were more common in the pandemic cohort. Patients initiating pembrolizumab after February 2020 (vs. before January 2020) experienced similar odds of developing severe irAE. 2/111 (1.8%) patients receiving pembrolizumab during the pandemic tested positive for COVID-19. On multivariable analysis, no association between pembrolizumab treatment period (before vs. during the COVID-19 pandemic) and OS was observed (p = 0.18). CONCLUSION: Significant changes in healthcare delivery in response to the pandemic did not result in increased high grade toxicity or lower survival outcomes in patients with advanced NSCLC treated with pembrolizumab.

First-line osimertinib for patients with EGFR-mutated advanced non-small cell lung cancer: efficacy and safety during the COVID-19 pandemic.

Background: The FLAURA trial demonstrated improved overall survival (OS) with first-line osimertinib for patients with epidermal growth factor receptor (EGFR)-mutated advanced non-small cell lung cancer (NSCLC). We studied the efficacy and safety of osimertinib in a cohort treated during the coronavirus disease 2019 (COVID-19) pandemic. Methods: Patients diagnosed with EGFR-mutated advanced NSCLC between 11 March 2020 to 31 December 2021 who received first-line osimertinib in British Columbia, Canada were identified retrospectively. Kaplan-Meier curves of OS and progression-free survival (PFS) from the start of osimertinib were plotted. The associations of baseline characteristics with PFS, and development of pneumonitis or dose reductions due to toxicity with OS were evaluated with hazard ratios estimated using univariable and multivariable Cox models. Results: The cohort comprised 231 individuals. 58.7% of patients with de novo advanced NSCLC were initially diagnosed after presentation to the Emergency Room. At osimertinib initiation, 31.6% were aged ≥75 years and 45.5% had an Eastern Cooperative Oncology Group performance status (ECOG PS) ≥2. Median PFS and OS were 18.0 months [95% confidence interval (CI): 16.1-26.2] and 25.4 months (95% CI: 20.3-not reached), respectively. On multivariable analysis, age ≥75 years (vs. <75), ECOG PS 2/3 (vs. 0/1), ECOG PS 4 (vs. 0/1), current smokers (vs. never smokers), programmed death ligand 1 (PD-L1) expression ≥50% (vs. <1%), and L858R mutation (vs. exon 19 deletion) were associated with shorter PFS. Among 110 patients who progressed, 33.6% received subsequent therapy. A proportion of 16.5% of the cohort developed grade ≥3 adverse events. Pneumonitis from osimertinib (3.9% incidence) was weakly associated with shorter OS (hazard ratio: 2.59, 95% CI: 0.94-7.12, P=0.066); dose reductions were not associated with worse OS. 10.8% of patients developed COVID-19. Conclusions: In a cohort receiving first-line osimertinib during the COVID-19 pandemic, ECOG PS ≥2 was observed in nearly half of patients at treatment initiation contributing to a median OS shorter than in FLAURA. The incidence of severe adverse events was low and dose reduction for drug toxicity did not impact OS. Identifying and reducing barriers to the diagnosis of NSCLC during the COVID-19 pandemic are required.

Which prediction models best identify additional axillary disease after a positive sentinel node biopsy for breast cancer?

To determine which web-based model best identifies women at low risk of further axillary disease after a positive sentinel lymph node (SLN+) biopsy. 673 women with T1-2cN0M0 SNB+ breast cancer who underwent completion axillary dissection (AxD) were identified. A subgroup not eligible to avoid AxD as part of the Z0011 study was defined (Z0011 exclusion group). Predicted risk of further axillary disease was generated using seven web-based models. "Low risk" was defined as a ≤10% risk of further axillary disease. False negative ("low risk" prediction but AxD+) rates (FNRs), area under the receiver operating characteristic curve (AUC), and Brier score were determined for each model. 6 of 7 models identified "low risk" patients but FNRs ranged from 14 to 30%. The Stanford and Memorial Sloan-Kettering (MSKCC) models had the best FNRs. FNRs were lower with SLN micrometastasis (7-15%) and higher in the Z0011 exclusion group (21-41%). All models under-predicted further nodal disease in low risk patients and over-predicted in higher-risk patients. The Stanford and MSKCC models were able to identify women with SLN micrometastasis with a ≤10% FNR. Models were not able to accurately identify low risk women from a cohort that would have been excluded from Z0011.

Limited M1 disease: a significant prognostic factor for stage IV breast cancer.

PURPOSE: The prognosis of patients with breast cancer presenting with distant metastasis can vary depending on disease extent. This study evaluates a definition of limited M1 disease in association with survival in a cohort of women presenting with metastatic breast cancer. METHODS: The study cohort comprised 692 women referred to the BC Cancer Agency between 1996 and 2005 with M1 breast cancer at presentation. Limited M1 disease was defined as <5 metastatic lesions confined to one anatomic subsite. Extensive M1 disease was defined as ≥ 5 lesions or disease in more than one subsite. Clinicopathologic and treatment characteristics and overall survival (OS) were compared between subjects with limited (n = 233) versus extensive (n = 459) M1 disease. Multivariable analysis was performed by Cox regression modeling. RESULTS: Median follow-up time was 1.9 years. Five-year Kaplan-Meier OS was significantly higher in patients with limited compared to extensive M1 disease (29.7 vs. 13.1 %, p < 0.001). In the multivariable Cox regression analysis, limited M1 disease was significantly associated with OS (hazard ratio 0.51, 95 % confidence interval 0.40-0.66, p < 0.001). The only patient subsets with limited M1 disease with poor 5-year OS <15 % were patients with Eastern Cooperative Oncology Group performance status of ≥ 2 or estrogen receptor-negative status. CONCLUSIONS: Limited M1 disease, defined as <5 metastatic lesions confined to one anatomic subsite, is a relevant favorable prognostic factor in patients with stage IV breast cancer. This definition may be used in conjunction with other clinicopathologic factors to select patients for more aggressive systemic and locoregional treatments.

Coplanar versus noncoplanar intensity-modulated radiation therapy (IMRT) and volumetric-modulated arc therapy (VMAT) treatment planning for fronto-temporal high-grade glioma.

The purpose of this study was to compare dosimetric and radiobiological parameters of treatment plans using coplanar and noncoplanar beam arrangements in patients with fronto-temporal high-grade glioma (HGG) generated for intensity-modulated radiotherapy (IMRT) or volumetric-modulated arc therapy (VMAT). Ten cases of HGG overlapping the optic apparatus were selected. Four separate plans were created for each case: coplanar IMRT, noncoplanar IMRT (ncIMRT), VMAT, and noncoplanar VMAT (ncVMAT). The prescription dose was 60 Gy in 30 fractions. Dose-volume histograms and equivalent uniform doses (EUD) for planning target volumes (PTVs) and organs at risk (OARs) were generated. The four techniques resulted in comparable mean, minimum, maximum PTV doses, and PTV EUDs (p ≥ 0.33). The mean PTV dose and EUD averaged for all techniques were 59.98 Gy (Standard Deviation (SD) ± 0.15) and 59.86 Gy (SD ± 0.27). Non-coplanar IMRT significantly reduced contralateral anterior globe EUDs (6.7 Gy versus 8.2 Gy, p = 0.05), while both ncIMRT and ncVMAT reduced contralateral retina EUDs (16 Gy versus 18.8 Gy, p = 0.03). Noncoplanar techniques resulted in lower contralateral temporal lobe dose (22.2 Gy versus 24.7 Gy). Compared to IMRT, VMAT techniques required fewer monitor units (755 vs. 478, p ≤ 0.001) but longer optimization times. Treatment delivery times were 6.1 and 10.5 minutes for coplanar and ncIMRT versus 2.9 and 5.0 minutes for coplanar and ncVMAT. In this study, all techniques achieved comparable target coverage. Superior sparing of contralateral optic structures was seen with ncIMRT. The VMAT techniques reduced treatment delivery duration but prolonged plan optimization times, compared to IMRT techniques. Technique selection should be individualized, based on patient-specific clinical and dosimetric parameters.

Survival Outcomes in Metastatic Ewing Sarcoma Treated With Whole-Lung Radiation.

Background and objective There is a scarcity of research on outcomes in patients with metastatic Ewing sarcoma limited to pulmonary metastases who receive whole-lung radiotherapy (WLRT). In light of this, this study aimed to evaluate the use of WLRT and compare the survival outcomes between patients with metastatic Ewing sarcoma who received treatment with WLRT and those who did not. Materials and methods Patients of all ages with metastatic Ewing sarcoma restricted to the lung who were referred to the British Columbia (BC) Cancer from 1995 to 2017 were identified from the Sarcoma Outcomes Unit (SARCOU). Patient demographics and tumor and treatment characteristics were compared between cohorts treated with WLRT versus those who did not undergo WLRT. Five-year progression-free survival (PFS) and overall survival (OS) were evaluated using Kaplan-Meier (KM) estimates and compared between treatment groups with log-rank tests. Results The study cohort comprised 30 patients (median follow-up time: 6.8 years). Overall, the median age of the patients was 16 years (range: 4-86 years) and 60% were female; the primary disease sites were as follows: 27% axial skeleton, 53% appendicular skeleton, 20% visceral, 86% had ≥2 lung metastases, and 60% had bilateral disease. Fifteen (50%) patients received WLRT (median of 1500 cGy in 10 fractions). Chemotherapy was used in 97% of patients. The rate of surgery for lung metastases was 40%, which was similar between the WLRT and non-WLRT groups. The median size of the largest lung metastasis in the WLRT cohort was 1 cm (range: 0.3-1.8 cm), compared to 2 cm (range 0.5-6.7 cm) in the non-WLRT cohort (p=0.05). Demographics and tumor characteristics were otherwise not significantly different between the two treatment groups (all p>0.05). Among patients who received WLRT, 53% had complete response (CR), 7% partial response (PR), and 40% had disease progression. The five-year PFS was 86% vs. 59% (p=0.33) and OS was 78% vs. 54% (p=0.24) respectively for patients in the WLRT group vs. those in the non-WLRT group. The five-year PFS outcomes were higher on univariate analysis in patients with appendicular skeletal compared to axial skeletal and visceral primary sites (87.5% vs. 58% vs. 50%, respectively, p=0.02) and in patients with the size of the largest lung metastasis <2 cm vs. those with a size ≥2 cm (80% vs. 25%, p=0.04). Conclusions Patients treated with WLRT had a smaller-volume lung disease and over half of the patients who received WLRT had either complete or partial response. Trends of improved PFS and OS at five years were observed among patients who received WLRT compared to the non-WLRT group, but these were not statistically significant.

Immune related adverse events and treatment discontinuation in patients older and younger than 75 years with advanced melanoma receiving nivolumab or pembrolizumab.

BACKGROUND: Programmed cell-death 1 antibodies (PD-1 Ab) improve overall survival (OS) for patients with advanced melanoma in trials; however, safety data in patients ≥75 years are lacking. The prognostic significance of and risk factors for PD-1 Ab discontinuation due immune related adverse events (irAE) are also uncertain. METHODS: Patients with advanced melanoma receiving frontline PD-1 Ab at British Columbia Cancer outside of clinical trials between 10/2015-10/2019 were retrospectively analyzed. The incidence and subtypes of irAE were compared between age subgroups <75 and ≥ 75 years. Univariable logistic regression identified variables associated with treatment discontinuation within four months of PD-1 Ab initiation. Cox proportional hazard regression models were used to determine factors significantly associated with OS. RESULTS: 302 patients were identified, of whom 126 (41.7%) were ≥ 75 years. During all follow-up, 15.9% of patients experienced irAE grade 3/4 and 27.2% of the cohort stopped PD-1 Ab due to immune toxicity. irAE incidence, hospitalization, and need for steroids by the four-month landmark were similar amongst age groups. Advanced age was not associated with risk of PD-1 Ab discontinuation from irAE on logistic regression. For the entire cohort, pre-treatment factors associated with shorter OS on multivariable analysis were ECOG performance status ≥1, M1d stage, lactate dehydrogenase >224, and neutrophil/ lymphocyte ratio ≥ 5. On four-month landmark multivariable analysis, treatment discontinuation due to irAE was significantly associated with worse OS. CONCLUSION: Patients aged ≥75 years experienced similar irAE rates and treatment discontinuation for immune toxicity compared to younger patients. As PD-1 Ab discontinuation due to irAE was associated with shorter OS, efforts to treat irAE early are warranted to potentially avoid therapy cessation.

Locoregional Treatments for Metastatic Gastrointestinal Stromal Tumor in British Columbia: A Retrospective Cohort Study from January 2008 to December 2017.

INTRODUCTION: The role of surgery and non-surgical locoregional treatments (LRT) such as radiation therapy (RT) and local ablation techniques in patients with metastatic gastrointestinal stromal tumor (GIST) is unclear. This study examines LRT practice patterns in metastatic GIST and their clinical outcomes in British Columbia (BC). METHODS: Patients diagnosed with either recurrent or de novo metastatic GIST from January 2008 to December 2017 were identified. Clinical characteristics and outcomes were analyzed in patients who underwent LRT, including surgical resection of the primary tumor or metastectomy, RT, or other local ablative procedures. RESULTS: 127 patients were identified: 52 (41%) had de novo metastasis and 75 (59%) had recurrent metastasis. Median age was 67 (23-90 years), 58.2% were male, primary site was 33.1% stomach, 40.2% small intestine, 11% rectum/pelvis, and 15.7% others. 37 (29.1%) of patients received palliative surgery, the majority of which had either primary tumor removal only (43.3%) or both primary tumor removal and metastectomy (35.1%). A minority of patients underwent metastectomy only (21.6%). A total of 12 (9.5%) patients received palliative RT to metastatic sites only (58.3%) or primary tumors only (41.7%), mostly for symptomatic control (n = 9). A few patients (n = 3) received local ablation for liver metastatic deposits with 1 patient receiving microwave ablation (MWA) and 2 receiving radiofrequency ablation (RFA). Most patients (n = 120, 94.5%) received some type of systemic treatment. It is notable that prolonged progression free survival (PFS) was observed for the majority of patients who underwent surgery in the metastatic setting with a median PFS of 20.5 (95% confidence interval (CI): 14.29-40.74) months. In addition, significantly higher median overall survival (mOS) was observed in patients who underwent surgery (97.15 months; 95% CI: 77.7-not reached) and LRT (78.98 months; 95% CI: 65.58-not reached) versus no surgery (45.37 months; 95% CI: 38.7-64.69) and no LRT (45.27 months; 95% CI: 33.25-58.66). Almost all patients (8 out of 9) achieved symptomatic improvement after palliative RT. All 3 patients achieved partial response and 2 out of 3 patients had relatively durable responses of 1 year or more after local ablation. DISCUSSION: This study is among the first to systematically examine the use of various LRT in metastatic GIST management. Integration of LRT with systemic treatments may potentially provide promising durable response and prolonged survival for highly selected metastatic GIST patients with low volume disease, limited progression and otherwise well controlled on systemic treatments. These observations, consistent with others, add to the growing evidence that supports the judicious use of LRT in combination with systemic treatments to further optimize the care of metastatic GIST patients.

Tumor-infiltrating lymphocytes predict response to anthracycline-based chemotherapy in estrogen receptor-negative breast cancer.

INTRODUCTION: Infiltration of breast tumors by tumor-infiltrating lymphocytes (TIL) has been associated with sensitivity to anthracycline-based chemotherapy. However, it is unclear whether this is true within the estrogen receptor-alpha (ER)-negative subset of breast tumors that frequently manifest high TIL levels. METHODS: The association of TIL with short-term and long-term clinical response to anthracycline-based therapy was assessed in two independent ER-negative breast cancer cohorts in which patients were categorized as TIL-high or TIL-low. We defined an eight-gene lymphocyte mRNA expression signature (including CD19, CD3D, CD48, GZMB, LCK, MS4A1, PRF1, and SELL) and used unsupervised hierarchical clustering to examine the association between TIL and short-term response to neoadjuvant chemotherapy in a previously published cohort of ER-negative tumors (n = 113). We also examined the association between TIL and long-term chemotherapeutic efficacy in a second cohort of ER-negative tumors (n = 255) with longer than 6 years of median follow-up by using tissue microarrays and immunohistochemistry (IHC) for detection of CD3, CD8, CD4, CD20, and TIA-1. RESULTS: In patients with ER-negative tumors treated with neoadjuvant anthracycline-based chemotherapy, pathologic complete responses (pCRs) were achieved by 23 (74%) of 31 TIL-high patients and 25 (31%) of 80 TIL-low patients (odds ratio (OR), 6.33; 95% confidence interval (CI), 2.49 to 16.08; P < 0.0001). Multivariate logistic regression with standard clinicopathologic features demonstrated that only tumor size (P = 0.037) and TIL status (P = 0.001) were independent predictors of anthracycline response. In the second cohort, adjuvant anthracycline-based therapy was associated with increased disease-free survival (DFS) only in patients with high levels of intraepithelial CD3+ TIL (P = 0.0023). In contrast, outcomes after CMF treatment (cyclophosphamide, methotrexate, and fluorouracil) showed no association with CD3 status. In both cohorts, cytotoxic T-cells were the primary TIL subtype associated with anthracycline sensitivity. Finally, TIL significantly predicted anthracycline sensitivity for both the Her2-positive and triple-negative tumor phenotypes. CONCLUSIONS: ER-negative breast cancers with high levels of TIL have heightened sensitivity to anthracycline-based chemotherapy, as assessed by the immediate response to neoadjuvant therapy and long-term outcome following adjuvant therapy. Investigations of TIL-based predictive tests to identify patients likely to benefit from anthracycline-based treatments are warranted.

Predictors of local recurrence in a population-based cohort of women with ductal carcinoma in situ treated with breast conserving surgery alone.

BACKGROUND: To identify prognostic indicators of local recurrence (LR) in patients with ductal carcinoma in situ (DCIS) of the breast treated with breast conserving surgery (BCS) alone. METHODS: A retrospective study was conducted of all women with pure DCIS, diagnosed 1985-1999, referred for tertiary oncologic opinion in British Columbia, treated with BCS without adjuvant radiotherapy. Kaplan-Meier local control (LC) and breast cancer specific survival (BCSS) estimates for the entire group were plotted. Stratified analyses identified subgroups with high Kaplan-Meier 10-year LR. Cox multivariate modeling was used to assess predictors of LR. Kaplan-Meier BCSS rates were compared between two cohorts: those who experienced LR and those who did not have LR. RESULTS: A total of 460 women comprised the study cohort. Median follow-up was 9.4 years. The 15-year LC and BCSS rates were 82% and 97%, respectively. Stratified analyses of LR identified comedo histology, high nuclear grade, tumor size >4 cm or indeterminate size, and positive margins to be associated with significantly higher LR risk, with 10-year LR risks approximating 15-30%. The 10-year BCSS rates for the LR group were 94% compared with 99% for the NoLR group. On Cox regression modeling, high nuclear grade, the presence of comedocarcinoma, and positive margins were significant factors for higher risk of LR. CONCLUSIONS: Women with DCIS treated with BCS alone had higher LR risk, and those with a LR were more likely to die of breast cancer. Optimal local treatment is mandatory to minimize the risk of breast cancer death for women with this curable disease.

Time to Treatment With Nivolumab or Pembrolizumab for Patients With Advanced Melanoma in Everyday Practice.

Background The anti-programmed cell death one antibodies (Anti-PD-1 Ab) pembrolizumab or nivolumab are commonly prescribed to patients with advanced melanoma. The purpose of the current study is to identify baseline clinical characteristics associated with time to treatment initiation (TTI) of pembrolizumab or nivolumab for advanced melanoma and whether treatment delays are associated with differences in survival outcomes. Methods All patients receiving Anti-PD-1 Ab as a first-line treatment for advanced melanoma outside of clinical trials at British Columbia Cancer Agency between 10/2015 and 10/2019 were identified retrospectively. TTI was defined as the interval from pathologic diagnosis of advanced melanoma to first Anti-PD-1 Ab treatment. To determine the association between TTI and baseline characteristics, multivariable Cox proportional hazard regression analyses provided an estimate of the instantaneous relative risk of starting treatment at any time point (hazard ratio [HR] >1 indicates shorter TTI). To describe changes in overall survival (OS) observed for each four-week delay in treatment initiation, multivariable cox proportional hazard regression modelling was also performed. Results In a cohort of 302 patients, the median TTI was 52 days (interquartile range 30.2-99.0). Pulmonary metastases (M1b)/non-central nervous system visceral metastases (M1c) vs. metastases to skin or non-regional lymph nodes (M1a)(HR=1.50, 95% CI=1.12-2.02; p=0.007) and pre-treatment Eastern Cooperative Oncology Group Performance Status (ECOG PS) >1 (vs 0/1, HR=1.50, 95% CI= 1.11-2.01; p=0.008) were associated with earlier TTI. An association between treatment delay and improved OS was observed. Conclusion Patients having visceral metastases and poor baseline ECOG PS were more likely to initiate Anti-PD-1 Ab sooner. The association of shorter TTI with worse OS likely represents confounding by indication (urgent treatment offered to patients with aggressive disease).

Among women who experience a recurrence after postmastectomy radiation therapy irradiation is not associated with more aggressive local recurrence or reduced survival.

Recent pre-clinical models suggest that radiation can promote tumor aggressiveness. We hypothesized that if this were occurring clinically, locoregional recurrences (LRRs) after postmastectomy radiation therapy (PMRT) would lead to lower survival than LRR after mastectomy alone. This study used two independent datasets to compare survival after LRR in women treated with versus without PMRT. Data from 229 LRR cases among 1,500 patients enrolled on prospective trials at the MD Anderson Cancer Center (MDA), and 66 LRR cases among 318 patients enrolled in the British Columbia Cancer Agency (BCCA) PMRT randomized trial were analyzed. In the MDA non-randomized dataset, 189/1031 had LRR after mastectomy alone and 40/469 had LRR after PMRT. In the randomized BC trial dataset, 52/158 had LRR after mastectomy alone and 14/160 had LRR after PMRT. In both datasets, survival was calculated from the time of LRR to death. Analysis of MDA data shows that in all LRR cases regardless of distant metastasis (DM), 5/10-year OS were 50/34% without PMRT and 27/19% after PMRT (P = 0.006). However, PMRT-treated patients had increased risk factors for DM (advanced T and N stages) and more PMRT-treated patients developed DM prior to LRR (63 vs. 34%, P = 0.005). Analyzing only patients will an isolated LRR (without previous or simultaneous, DMV), there was no OS difference between groups (P = 0.33). Analysis of BCCA data shows that distributions of T and N stages were similar in patients with LRR after mastectomy alone versus after PMRT. DM free survival after any LRR and after isolated LRR were similar in mastectomy alone versus PMRT-treated patients (P = 0.75, P = 0.26, respectively). Overall survival after any LRR and after isolated LRR were also similar in the two groups (P = 0.93, P = 0.28, respectively). Patients who develop LRR after mastectomy alone have high rates of DM and poor OS but these rates are not affected by the use of PMRT at the time of primary treatment. These data do not support the hypothesis that irradiation promotes biologically aggressive local recurrences.

Micrometastatic node-positive breast cancer: long-term outcomes and identification of high-risk subsets in a large population-based series.

PURPOSE: The prognostic implication of breast cancer with nodal micrometastases measuring >0.2 mm but < or =2 mm (pNmic) is unclear. This study evaluates survival in pNmic relative to node-negative (N0) and macroscopic node-positive (pNmac) disease in a large population-based series. METHODS: Subjects were 9,637 women diagnosed between 1989 and 1999, referred to the British Columbia Cancer Agency with pT1-2, node-negative and node-positive, M0 breast cancer. Kaplan-Meier breast-cancer-specific survival (BCSS) and overall survival (OS) were compared between patients with pN0 (n = 7,988), pNmic (n = 491), and pNmac disease (n = 1,158), according to the number of positive nodes and the lymph node ratio (LNR) of positive to excised nodes. Cox regression and recursive partitioning analyses were performed to identify significant factors associated with survival. RESULTS: Median follow-up was 8.2 years. Patients with pNmic disease had significantly poorer outcomes compared with pN0 cancers, with progressively lower BCSS and OS with increasing number of positive nodes and with LNR > 0.25. On multivariable analysis, histologic subtype, T stage, number of positive nodes, LNR, grade, lymphovascular invasion, estrogen receptor status, and systemic therapy use were factors significantly associated with BCSS and OS. Recursive partitioning trees for BCSS and OS both selected the pN/LNR variable at the first split, indicating that this variable provided the strongest prognostic separation. CONCLUSION: Patients with nodal micrometastases are a heterogeneous population with varying breast cancer mortality risks. The number of positive nodes and the LNR should be considered in conjunction with tumor factors in risk estimates and treatment decisions for patients with nodal micrometastatic breast cancer.

Comparison of Nodal Target Volume Definition in Breast Cancer Radiation Therapy According to RTOG Versus ESTRO Atlases: A Practical Review From the TransAtlantic Radiation Oncology Network (TRONE).

Regional nodal irradiation has gained interest in recent years with the publication of several important randomized trials and the availability of more conformal techniques. Target volume delineation represents a critical step in the radiation planning process. Adequate coverage of the microscopic tumor spread to regional lymph nodes must be weighed against exposure of critical structures such as the heart and lungs. Among available guidelines for delineating the clinical target volume for the breast/chest wall and regional nodes, the Radiation Therapy Oncology Group and European Society for Radiotherapy and Oncology guidelines are the most widely used internationally. These guidelines have been formulated based on anatomic boundaries of areas historically covered in 2-dimensional field-based radiation therapy but have not been validated by patterns-of-failure studies. In recent years, an important body of data has emerged from mapping studies documenting patterns of local and regional recurrence. We aim to review, discuss, and compare contouring guidelines for breast cancer radiation therapy in the context of contemporary data on locoregional relapse to improve their implementation in modern practice.

Hypofractionated Adjuvant Radiation Therapy Is Effective for Patients With Lymph Node-Positive Breast Cancer: A Population-Based Analysis.

PURPOSE: This study evaluated long-term, population-based, breast cancer-specific outcomes in patients treated with radiation therapy (RT) to the breast/chest wall plus regional nodes using hypofractionated (HF) (40-42.5 Gy/16 fractions) versus conventionally fractionated (CF) regimens (50-50.4 Gy/25-28 fractions). METHODS AND MATERIALS: A prospective provincial database was used to identify patients with lymph node-positive breast cancer treated with curative-intent breast/chest wall + regional nodal RT from 1998 to 2010. The effect of RT fractionation on locoregional recurrence-free survival (LRRFS), distant recurrence-free survival (DRFS), and breast cancer-specific survival (BCSS) was assessed for the entire cohort and for high-risk subgroups: grade 3, ER-/HER2-, HER2+, and ≥4 positive nodes. Multivariable analysis and 2:1 case-match comparison of HF versus CF were also performed. RESULTS: A total of 5487 patients met the inclusion criteria (4006 HF and 1481 CF). Median age was 55 years, and median follow-up was 12.7 years. On multivariable analysis, no statistically significant differences were identified in 10-year LRRFS (hazard ratio [HR] 0.87; 95% confidence interval [CI], 0.59-1.27; P = .46), DRFS (HR 0.90; 95% CI, 0.76-1.06; P = .19), or BCSS (HR 0.92; 95% CI, 0.76-1.10; P = .36) between the HF and CF cohorts. There was no statistical difference in breast cancer-specific outcomes in the high-risk subgroups. On analysis of 2962 HF cases matched to 1481 CF controls, no statistical difference was observed in LRRFS (HR 0.98; 95% CI, 0.71-1.33; P = .87), DRFS (HR 0.97; 95% CI, 0.85-1.11; P = .68), or BCSS (HR 1.00; 95% CI, 0.87-1.16; P = .92). CONCLUSIONS: This large, population-based analysis with long-term follow-up after locoregional RT demonstrated that modest HF provides similar breast cancer-specific outcomes compared with CF. HF is an effective option for patients with stage I to III breast cancer receiving nodal RT.

Treatment and outcomes in adult patients with primary cardiac sarcoma: the British Columbia Cancer Agency experience.

BACKGROUND: To evaluate treatment and survival in a cohort of patients referred to a Canadian institution with newly diagnosed primary cardiac sarcoma. METHODS: Between 1990 and 2006, 16 patients were referred to the British Columbia Cancer Agency with pathologically confirmed sarcoma of cardiac origin. Retrospective chart review was performed to document patient, tumor, and treatment characteristics. Disease-free survival and overall survival (OS) were calculated by Kaplan-Meier methods and compared in different subgroups by log rank statistics. RESULTS: The cohort comprised 10 female and 6 male patients. The mean age was 51 years (range, 27-81 years). The most common histologic subtype was angiosarcoma. Surgical resection, alone or in combination with chemotherapy or radiotherapy, was undertaken in 10 of 12 patients with localized and 3 of 4 patients with metastatic disease. At a median follow-up of 8 months, all patients had died of disease. In the entire cohort, mean disease-free survival and OS were 6 months and 14 months, respectively. Patients with localized disease had significantly longer survival compared to metastatic disease (mean OS 18 months vs. 2 months, P = 0.001). Patients treated with complete resection had improved OS compared to incompletely resected disease (25 months vs. 6 months, P = 0.042). Age, sex, tumor grade, location, and subtype were not associated with statistically significant survival differences. CONCLUSIONS: Patients with nonmetastatic cardiac sarcoma amenable to complete resection experienced improved survival. However, the high overall rates of disease progression and mortality highlight the need for more effective local and systemic treatments that may be used in conjunction with surgery to improve patient outcomes.