Impact of TAILORx on chemotherapy prescribing and 21-gene recurrence score-guided treatment costs in a population-based cohort of patients with breast cancer.

BACKGROUND: The trial assigning individualized options for treatment (Rx) (TAILORx) confirmed the predictive value of the 21-gene recurrence score (RS) assay in hormone receptor (HR)-positive, HER2-negative, node-negative breast cancer and established thresholds for chemotherapy benefit in younger and older patients. Real-world chemotherapy use and RS-guided treatment costs in British Columbia post-TAILORx were examined. METHODS: The authors assembled 3 cohorts of HR-positive, HER2-negative, node-negative patients with breast cancer defined by diagnosis: before RS funding (cohort 1 [C1]: January 2013-December 2013), after introduction of public RS funding (cohort 2 [C2]: July 2015-June 2016), and after TAILORx results (cohort 3 [C3]: July 2018-June 2019). Chemotherapy use was compared between cohorts by age and RS. Budgetary impacts of RS testing on chemotherapy costs were evaluated pre- and post-TAILORx. RESULTS: Among the 2066 patients included, chemotherapy use declined by 19% after RS funding was introduced and by an additional 23% after TAILORx publication (P = .001). Reduction in chemotherapy use was significant for RS 11-20 tumors (C3 vs C2, P = .004). There was no significant change in chemotherapy use in patients >50 years old (C2:12% vs C3:10%, P = .22). RS testing was associated with higher cost savings post-TAILORx, except in patients 70 to 80 years old, where testing led to excess costs when adjusting for the low rate of RS-concordant chemotherapy prescribed. CONCLUSIONS: TAILORx has had population-based impacts on chemotherapy prescribing in intermediate RS tumors and patients ≤50 years old. The lower clinical use of RS and increased spending in patients 70-80 years old highlights the importance of careful selection of older candidates for high-cost genomic testing. LAY SUMMARY: The 21-gene recurrence score (RS) test helps predict whether patients with hormone-positive, HER2-negative, lymph node-negative breast cancer are likely to benefit from chemotherapy. The recent trial assigning individualized options for treatment (Rx) (TAILORx) found that patients with intermediate RS tumors did not benefit from chemotherapy. The authors assessed whether TAILORx results translated to real-world changes in chemotherapy prescribing patterns. In this study, chemotherapy use decreased by 23% after TAILORx, with the greatest reductions seen among intermediate RS tumors and younger patients. In contrast, RS testing had lower clinical value and increased treatment costs in elderly patients, which requires further study to ensure optimal care for this age group.

Impact of new cancer therapies on outpatient treatment delivery for colorectal cancer: A population-based study.

We investigated the impact of new systemic therapies approved in Canada for colorectal cancer on the frequency, intensity and duration of oncology clinic and infusion visits over five treatment phases from diagnosis (P1, P3) to treatment (P2, P4) of primary and metastatic disease, respectively, and during the last 6 months of life (P5). In total, 15,157 adult patients with newly diagnosed colorectal cancer and referred between 2000 and 2012 to any cancer clinic in British Columbia, Canada, were included. Frequency, intensity and duration of medical oncology clinic visits (CVs), oncology infusions (OIs) and oncology prescriptions (OPs) were measured by treatment phase. Mean, total and adjusted total duration for CVs increased for P1-5. CVs increased in P1-5, and in P1-4 when adjusted by treatment length. Adjusted and unadjusted OIs decreased in P1 coinciding with the introduction of an oral treatment option, but increased in P2-5. Mean OI duration increased in P1-5, while total and adjusted total decreased in P1 and increased in P2-5. OPs increased in P2-4, but were unchanged in P1 and P5. Multi-fold increases in resources and time required per patient were also observed, which have significant implications for demand projections in cancer care planning and delivery. In conclusion, patients required more visits in almost all treatment phases, visits on average took longer and patients were in treatment for longer periods of time.

The impact of new systemic therapies on survival and time on hormonal treatment in hormone receptor-positive, human epidermal growth factor receptor 2-negative metastatic breast cancer: A population-based study in British Columbia from 2003 to 2013.

BACKGROUND: The purpose of this study was to determine whether new systemic therapy regimens have resulted in improved survival and increased time on first- and second-line hormonal treatment for patients with hormone receptor (HR)-positive metastatic breast cancer (MBC) over time. METHODS: Patients diagnosed with HR-positive, human epidermal growth factor receptor 2 (HER2)-negative MBC were identified across 3 time cohorts (2003-2005, 2007-2009, and 2011-2013). Data were prospectively collected. Cases with previous, synchronous, or subsequent contralateral breast cancer were excluded. The types of first- and second-line therapies, the times on first- and second-line hormonal treatment, and the median survival times were compared across the cohorts. RESULTS: Within the time period analyzed, 9 new adjuvant systemic therapies (with or without neoadjuvant therapy) and 2 metastatic systemic therapies were approved at BC Cancer for the treatment of HR-positive, HER2-negative MBC. In the 3 time cohorts, 3953 patients diagnosed with MBC were identified. Among the 2432 patients (62%) who had HR-positive/HER2-negative disease, 2197 (90%) received at least 1 line of systemic therapy after the diagnosis of MBC, and 80% of these patients (1752 of 2197) received first- and/or second-line hormonal treatment. The median duration on hormonal treatment was 9.0 months for the first line and 6.1 months for the second line. The durations were similar across the time cohorts (range for the first line, 8.9-9.0 months; range for the second line, 6.0-6.1 months). The median survival for the entire study population was 2.0 years (95% confidence interval, 1.8-2.1 years), and there was no significant difference between the cohorts (range, 1.9-2.0 years). CONCLUSIONS: Even though more adjuvant and metastatic systemic therapies have been approved since 2003, population-level gains in survival and the time on hormonal treatment for patients with HR-positive, HER2-negative MBC have not been made over the course of a decade.

Outcomes of Surgical and Chemotherapeutic Treatments of Goblet Cell Carcinoid Tumors of the Appendix.

BACKGROUND: Goblet cell carcinoids (GCCs) of the appendix are rare mucinous neoplasms, for which optimal therapy is poorly described. We examined prognostic clinical and treatment factors in a population-based cohort. METHODS: Patients diagnosed with GCC from 1984 to 2014 were identified from the British Columbia Cancer Agency and the Vancouver Lower Mainland Pathology Archive. RESULTS: Of 88 cases with confirmed appendiceal GCCs, clinical data were available in 86 cases (annual population incidence: 0.66/1,000,000). Median age was 54 years (range 25-91) and 42 patients (49%) were male. Metastasis at presentation was the strongest predictor of overall survival (OS), with median OS not reached for stage I-III patients, and measuring 16.2 months [95% confidence interval (CI) 9.1-29] for stage IV patients. In 67 stage I-III patients, 51 (76%) underwent completion hemicolectomy and 9 (17%) received adjuvant 5-fluorouracil-based chemotherapy. No appendicitis at initial presentation and Tang B histology were the only prognostic factors, with inferior 5-year recurrence-free survival (53 vs. 83% with appendicitis, p = 0.02; 45% Tang B vs. 89% Tang A, p < 0.01). Of 19 stage IV patients, 10 (62.5%) received 5-fluorouracil-based chemotherapy and 11 (61%) underwent multiorgan resection (MOR) ± hyperthermic intraperitoneal chemotherapy (HIPEC). Low mitotic rate and MOR ± HIPEC were associated with improved 2-year OS, but only MOR ± HIPEC remained significant on multivariate analysis (hazard ratio 5.4, 95% CI 1.4-20.9; p = 0.015). CONCLUSIONS: In this population-based cohort, we demonstrate excellent survival outcomes in stage I-III appendiceal GCCs and clinical appendicitis. Hemicolectomy remains the standard treatment. In metastatic disease, outcomes remain poor, although MOR ± HIPEC may improve survival.

Prognostic Factors for Locoregional Recurrence in Neuroendocrine Tumors of the Rectum.

BACKGROUND: Optimal management of rectal neuroendocrine tumors is not yet well defined. Various pathologic factors, particularly tumor size, have been proposed as prognostic markers. OBJECTIVE: We characterized sequential patients diagnosed with rectal neuroendocrine tumors in a population-based setting to determine whether tumor size and other pathologic markers could be useful in guiding locoregional management. DESIGN: This study is a retrospective analysis of data from the British Columbia provincial cancer registry. SETTINGS: The study was conducted at a tertiary care center. PATIENTS: Sequential patients diagnosed with rectal neuroendocrine tumors between 1999 and 2011 were identified. Neuroendocrine tumors were classified as G1 and G2 tumors with a Ki-67 ≤20% and/or mitotic count ≤20 per high-power field. MAIN OUTCOME MEASURES: Baseline clinicopathologic data including TNM staging, depth of invasion, tumor size, treatment modalities, and outcomes including survival data were measured. RESULTS: Of 91 rectal neuroendocrine tumors, the median patient age was 58 years, and 35 were men. Median tumor size was 6 mm. Median length of follow-up was 58.1 months, with 3 patients presenting with stage IV disease. Treatment included local ablation (n = 5), local excision (n = 79), surgical resection (n = 4), and pelvic radiation (n = 1; T3N1 tumor). Final margin status was positive in 17 cases. Local relapse occurred in 8 cases and 1 relapse to bone 13 months after T3N1 tumor resection. Univariate analysis demonstrated an association between local relapse and Ki-67, mitotic count, grade, and lymphovascular invasion (p < 0.01). Larger tumor size was associated with decreased disease-free survival. LIMITATIONS: Sample size was 91 patients in the whole provincial population over a 13-year time period because of the low incidence of rectal neuroendocrine tumors. CONCLUSIONS: In this population-based cohort, rectal neuroendocrine tumors generally presented with small, early tumors and were treated with local excision or surgical resection without pelvic radiation. Pathologic markers play a role in risk stratification and prognostication. See Video Abstract at http://links.lww.com/DCR/A514.

The utility of abbreviated patient-reported outcomes for predicting survival in early stage colorectal cancer.

BACKGROUND: Patient-reported outcomes (PROs) are increasingly used in clinical settings. Prior research suggests that PROs collected at baseline may be associated with cancer survival, but most of those studies were conducted in patients with breast or lung cancer. The objective of this study was to determine the correlation between prospectively collected PROs and cancer-specific outcomes in patients with early stage colorectal cancer. METHODS: Patients who had newly diagnosed stage II or III colorectal cancer from 2009 to 2010 and had a consultation at the British Columbia Cancer Agency completed the brief Psychosocial Screen for Cancer (PSSCAN) questionnaire, which collects data on patients' perceived social supports, quality of life (QOL), anxiety and depression, and general health. PROs from the PSSCAN were linked with the Gastrointestinal Cancers Outcomes Database, which contains information on patient and tumor characteristics, treatment details, and cancer outcomes. Cox regression models were constructed for overall survival (OS), and Fine and Gray regression models were developed for disease-specific survival (DSS). RESULTS: In total, 692 patients were included. The median patient age was 67 years (range, 26-95 years), and the majority had colon cancer (61%), were diagnosed with stage III disease (54%), and received chemotherapy (58%). In general, patients felt well supported and reported good overall health and QOL. On multivariate analysis, increased fatigue was associated with worse OS (hazard ratio [HR], 1.99; P = .00007) and DSS (HR, 1.63; P = .03), as was lack of emotional support (OS: HR, 4.36; P = .0003; DSS: HR, 1.92; P = .02). CONCLUSIONS: Although most patients described good overall health and QOL and indicated that they were generally well supported, patients who experienced more pronounced fatigue or lacked emotional support had a higher likelihood of worse OS and DSS. These findings suggest that abbreviated PROs can inform and assist clinicians to identify patients who have a worse prognosis and may need more vigilant follow-up. Cancer 2017;123:1839-1847. © 2017 American Cancer Society.

Survival with metastatic breast cancer based on initial presentation, de novo versus relapsed.

PURPOSE: We hypothesized different Overall Survival (OS) in metastatic breast cancer (MBC) after relapse vs de novo presentation. METHODS: We identified women in British Columbia with MBC diagnosed between 01/2001 and 12/2009. OS from MBC was calculated for relapsed vs de novo cohorts in 3 subgroups, based on hormone receptors (HR) and HER2 status. Age at MBC, disease-free interval (DFI), de novo vs relapsed, year of MBC diagnosis, and systemic treatment were entered into univariable and multivariable analyses. RESULTS: We identified 3645 pts with known HR of which 2796 had known HER2. Median follow-up was 91 months. Median OS was longer for de novo vs relapsed MBC: HR+/HER2- 34 versus 23 months (mos) (p < 0.0001), HR-/HER2- (TN) 11 versus 8 mos (p = 0.02), HER2+ 29 versus 15 mos (p < 0.0001). For TN disease, no variable independently discriminated a group with increased risk of death. For both the HR +/HER2- and the HER2 + groups, relapsed vs de novo status (HzR 1.4 [95% CI 1.2-1.5; p < 0.0001], and HzR 1.6 [95% CI 1.4-1.9; p < 0.0001], respectively) and age >50 (HzR 1.2 [95% CI 1.1-1.4; p = 0.001] and HzR 1.3 [95% CI 1.1-1.5; p = 0.01], respectively) were associated with increased risk of death on multivariable analysis. CONCLUSION: These data provide information that may guide discussions about prognosis between physicians and patients with MBC. In addition, it highlights the importance of stratifying for initial stage at diagnosis in future MBC therapeutic trials.

Adjuvant chemotherapy use and outcomes of patients with high-risk versus low-risk stage II colon cancer.

BACKGROUND: Adjuvant chemotherapy (AC) is frequently considered in patients with stage II colon cancer who are considered to be at high risk. However, to the authors' knowledge, the survival benefits associated with AC in these patients remain largely unproven. In the current study, the authors sought to examine the use of AC in patients with AJCC stage II colon cancer and to compare the impact of AC on outcomes in patients with high-risk versus low-risk disease in a population-based setting. METHODS: Patients with stage II colon cancer who were evaluated at 1 of 5 regional cancer centers in British Columbia from 1999 to 2008 were analyzed. Kaplan-Meier and Cox regression methods were used to correlate high-risk versus low-risk status and receipt of AC with recurrence-free survival (RFS), disease-specific survival (DSS), and overall survival (OS). RESULTS: A total of 1697 patients were identified: 1286 (76%) with high-risk and 411 (24%) with low-risk disease, among whom 373 (29%) and 51 (12%),respectively, received AC. Individuals with high-risk disease treated with AC were younger (median age, 62 years vs 72 years; P<.001) and had better Eastern Cooperative Oncology Group performance status (0/1: 47% vs 33%; P = .001). For high-risk patients, AC was associated with improved OS (hazard ratio [HR], 0.65; 95% confidence interval [95% CI], 0.50-0.83 [P = .001]). However, no significant benefits with regard to RFS or DSS were observed. Subgroup analyses revealed that AC in patients with T4 disease was associated with significantly improved RFS (HR, 0.63; 95% CI, 0.42-0.95 [P = .03]), DSS (HR, 0.59; 95% CI, 0.37-0.93 [P = .02]), and OS (HR, 0.50; 95% CI, 0.33-0.77 [P = .002]). For patients with low-risk disease, AC was associated with inferior RFS (HR, 2.18; 95% CI, 1.00-4.79 [P = .05]) and DSS (HR, 3.01; 95% CI, 1.10-8.23 [P = .03]). CONCLUSIONS: In this population-based analysis, AC was associated with an OS advantage in high-risk patients, most likely due to patient selection. RFS, DSS, and OS benefits were mainly observed in patients with T4 disease, suggesting a limited role for AC in patients deemed to be high risk by non-T4 features.

Effect of M1a and M1b category in metastatic colorectal cancer.

BACKGROUND: In 2009, the American Joint Committee on Cancer version 7 staging system introduced the M1 subclassifications M1a (single metastatic site) and M1b (peritoneal or multiple metastatic sites). The study objectives were to evaluate the prognostic effect of site of metastasis and M1a/b category among patients with newly diagnosed colorectal cancer and synchronous metastasis. PATIENTS AND METHODS: Patients with newly diagnosed pathologic or clinical category M1 colorectal cancer referred to the British Columbia Cancer Agency between 1999 and 2007 were included. Demographic, tumor, treatment, and outcome data were prospectively collected, and prognostic factors were identified. Univariate Cox models were used to assess the prognostic impact of individual sites of metastasis and to determine the effect of M1a/b category on overall survival (OS). RESULTS: Among 2,049 eligible patients, 70% had M1a and 30% M1b category disease. The most common sites of common single sites of metastasis included liver (56%), lung (5.3%), and peritoneum (3.6%). Metastasis to a single organ or site, including peritoneum, was associated with improved OS compared with multiple sites of metastasis. In multivariate analysis, M1b category conferred inferior survival and hazard ratio (HR) 1.38 (95% confidence interval [CI]: 1.22, 1.55), along with age >70 and Eastern Cooperative Oncology Group performance status of 3-4. Resection of primary tumor was associated with improved survival, HR 0.46 (95% CI: 0.41, 0.52). Results were similar in subgroup analysis of patients undergoing resection of their primary tumor when histology, tumor, and node category were included. CONCLUSION: The results lend support to the introduction of M1a/b colorectal cancer categories. Consideration may be given to classifying patients with solitary peritoneal metastasis only as M1a rather than M1b category. Further refinement of category M1a to reflect resectability of metastasis at initial diagnosis may improve prognostication.

Does age affect outcome with breast cancer?

Prior data about the influence of age at diagnosis of breast cancer on patient outcomes and survival has been conflicting. Using the Breast Cancer Outcomes Unit database at BC Cancer, this retrospective population-based study identified a cohort of 24,469 patients diagnosed with invasive breast cancer between 2005 and 2014. Median follow-up was 11.5 years. We analyzed clinical and pathological features at diagnosis and treatment specific variables compared across the following age cohorts: <35, 35-39, 40-49, 50-59, 60-69, 70-79, and 80 years of age and older. We assessed the impact of age on breast cancer specific survival (BCSS) and overall survival (OS) by age and subtype. There were distinct clinical-pathological and treatment pattern differences at both extremes of age at diagnosis. Patients <35 and 35-39 years old were more likely to present with higher risk features, HER2 positive or triple-negative biomarkers, and more advanced TNM stage at diagnosis. They were more likely to undergo treatment with mastectomy, axillary lymph node dissection, radiotherapy and chemotherapy. Conversely, patients ≥80 years old were generally more likely to have hormone-sensitive HER2-negative disease, and lower TNM stage at diagnosis. They were less likely to undergo surgery or be treated with radiotherapy and chemotherapy. Both younger and elderly age at breast cancer diagnosis were independent risk factors for poorer prognosis after controlling for subtype, LVI, stage, and treatment factors. This work will help clinicians to more accurately estimate patient outcomes, patterns of relapse, and provide evidence-based treatment recommendations.

Treatment Patterns and Outcomes of Preoperative Neoadjuvant Radiotherapy in Patients with Early-onset Rectal Cancer.

Preoperative radiotherapy for early-stage rectal cancer has risks and benefits that may impact treatment choice in young patients. We reviewed radiotherapy use and outcomes for rectal cancer by age. Patients with early-stage rectal cancer in the Canadian province of British Columbia from 2002 to 2016 were identified (n = 6,232). Baseline characteristics, treatment response, overall survival (OS), disease-free survival (DFS), disease-specific survival (DSS), and locoregional recurrence rate (LRR) were compared between patients <50 (early-onset; n = 532) and ≥50 years old (average-onset; n = 5,700). Early-onset patients were more likely to receive preoperative chemoradiotherapy than short-course radiotherapy [OR, 2.20; 95% confidence interval (CI), 1.67-2.89; P < 0.0001], but also had higher nodal (P = 0.00096) and overall clinical staging (P = 0.033). Cancer downstaging and pathologic complete response rates were similar in those receiving neoadjuvant chemoradiotherapy by age. Early-onset and average-onset patients had similar DSS (P = 0.91) and DFS (P = 0.27) in multivariate analysis unless non-colorectal deaths, which were higher in older patients, were censored in the DFS model (HR, 1.30; 95% CI, 1.01-1.68; P = 0.042). LRR also did not differ between age groups (P = 0.88). Outcomes did not differ based on radiotherapy type. Young patients with rectal cancer are more likely to present with higher staging and receive long-course chemoradiotherapy. DSS did not differ by age group; however, young patients had worse DFS when we censored competing risks of death in older patients. Significance: This population-based study suggests younger patients are more likely to receive chemoradiotherapy, potentially due to higher stage at diagnosis, and response is comparable by age.

Molecular alterations between the primary breast cancer and the subsequent locoregional/metastatic tumor.

BACKGROUND: Metastatic breast cancers have historically been presumed to have the same predictive biomarkers as the initial primary tumor. We compared the expression of these biomarkers in a large paired tissue microarray (TMA) series of primary and subsequent relapsed tumors. METHODS: Using the British Columbia Cancer Agency Breast Cancer Outcomes Unit database, patients with biopsy-proven relapses were identified and linked to a large TMA series of primary breast cancers from 1986-1992. Charts were reviewed, and tissue blocks of the metastatic cancer were collected to create a separate TMA. Immunohistochemical assessment with the same antibodies and conditions was performed for estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor (HER)-2 on both the primary and relapsed tumors. RESULTS: One hundred sixty cases were received that had tumor adequate for analyses. Of these, 71.9% had no changes in either the ER or PR status or HER-2 status. Of the 45 (28.1%; 95% confidence interval [CI], 21.2%-35.1%) tumors that did have changes in receptor status, 7.5% were in-breast recurrences or new breast primaries, 4.4% had changes in PR status only and were therefore deemed clinically irrelevant, and 19.4% (95% CI, 13.3%-25.5%) had changes in either the ER or HER-2 status from regional or distant relapses. Five percent of tumors had a receptor status change going from ER(+) or PR(+) to ER(-) or PR(-); 9.4% went from ER(-) or PR(-) to ER(+) or PR(+). With regard to HER-2 status, 3.8% of tumors went from positive to negative and 1.3% went from negative to positive. For all discordant cases, biopsies of the relapsed lesion were obtained prior to initiation of first-line treatment for metastatic disease. In the primary tumors that were ER(+), time to relapse was significantly shorter in the discordant relapsed cases than in the concordant ones (p = .0002). Changes in loss or gain of either biomarker were seen across the discordant cases. CONCLUSIONS: A significant proportion of relapsed tumors had changes in either ER or HER-2 status, which would dramatically alter treatment recommendations and clinical behavior. This study suggests that biopsies of relapsed and metastatic breast cancers should be performed routinely in clinical practice.

Assessing the real-world cost-effectiveness of adjuvant trastuzumab in HER-2/neu positive breast cancer.

BACKGROUND: Among women with surgically removed, high-risk HER-2/neu-positive breast cancer, trastuzumab has demonstrated significant improvements in disease-free and overall survival. The objective of this study is to evaluate the cost-effectiveness of the currently recommended 12-month adjuvant protocol of trastuzumab using a Markov modeling approach and real-world cost data. METHODS: A 10-health-state Markov model tracked patients' quarterly transitions between health states in the local and advanced states of breast cancer. Clinical data were obtained from the joint analysis of the National Surgical Adjuvant Breast and Bowel Project and North Central Cancer Treatment Group, as well as from the metastatic study conducted by Norum et al. Clinical outcomes were adjusted for quality of life using utility estimates published in a systematic review. Real cost data were obtained from the British Columbia Cancer Agency and were evaluated from a payer perspective. Costs and utilities were discounted at 5% per year, respectively, for a 28-year time horizon. RESULTS: In the base case analysis, treatment with a 12-month adjuvant trastuzumab regimen resulted in a gain of 1.38 quality-adjusted life years or 1.17 life years gained at a cost of $18,133 per patient. Thus, the cost per QALY gained for the base case is $13,095. Cost per LYG is $15,492. CONCLUSIONS: Over the long term, treatment of HER-2/neu mutation positive breast cancer with a 12-month protocol of trastuzumab in the adjuvant setting is predicted to be cost-effective in a Canadian context.

Effect of community population size on breast cancer screening, stage distribution, treatment use and outcomes.

OBJECTIVE: Residents of rural communities have decreased access to cancer screening and treatments compared to urban residents, though use of resources and patient outcomes have not been assessed with a comprehensive population-based analysis. The objectives of this study were to investigate whether breast cancer screening and treatments were utilized less frequently in rural BC and whether this translated into differences in outcomes. METHODS: All patients diagnosed with breast cancer in British Columbia (BC) during 2002 were identified from the Cancer Registry and linked to the Screening Mammography database. Patient demographics, pathology, stage, treatments, mammography use and death data were abstracted. Patients were categorized as residing in large, small and rural local health authorities (LHAs) using Canadian census information. Use of resources and outcomes were compared across these LHA size categories. We hypothesized that mastectomy rates (instead of breast-conserving surgery) would be higher in rural areas, since breast conservation is standardly accompanied by adjuvant radiotherapy, which has limited availability in rural BC. In contrast we hypothesized that cancer screening and systemic therapy use would be similar, as they are more widely dispersed across BC. Exploratory analyses were performed to assess whether disparities in screening and treatment utilization translated into differences in survival. RESULTS: 2,869 breast cancer patients were included in our study. Patients from rural communities presented with more advanced disease (p=0.01). On multivariable analysis, patients from rural, compared to urban, LHAs were less likely to be screening mammography attendees (OR=0.62; p<0.001). Women from rural communities were less likely to undergo breast-conserving surgery (multivariable OR=0.47; p<0.001). There was no significant difference in use of chemotherapy (p=0.54) or hormonal therapy (p=0.36). The 5-year breast cancer-specific survival for large, small and rural LHAs was 90%, 88% and 86%, respectively (p=0.08), while overall survival was 84%, 81% and 77%, respectively (p=0.01). On multivariable analysis with 7.4 years of median follow-up, neither breast cancer-specific survival (HR=1.16; 0.76-1.76; p=0.49) nor overall survival (HR=1.25; 0.92-1.70; p=0.16) was significantly worse for patients from rural compared to large LHAs. CONCLUSION: There was a significant difference in screening mammography use, stage distribution and loco-regional treatments use by population size of LHA. After controlling for differences in patient and tumour factors by LHA, survival was not significantly different.

Locoregional Recurrence and Survival Outcomes in Breast Cancer Treated With Modern Neoadjuvant Chemotherapy: A Contemporary Population-based Analysis.

BACKGROUND: Data guiding radiotherapy (RT) decisions after neoadjuvant chemotherapy (NAC) is largely retrospective, based on older treatment approaches without molecular subtype information. This study evaluated outcomes in breast cancer patients treated with modern NAC by molecular subtype and locoregional treatment. MATERIALS AND METHODS: There were 949 patients diagnosed between 2005 and 2016 treated with NAC followed by surgery ± locoregional radiotherapy (LRRT). Outcomes were 7-year locoregional relapse-free survival (LRRFS), breast cancer-specific survival (BCSS), and overall survival (OS). RESULTS: Median follow-up was 6.5 years, 92% had cT2-4 and 72% cN1-3 disease. Subtypes were: 21% Luminal A, 18% Luminal B, 35% Her2+, and 21% triple-negative breast cancer (TNBC). Combined taxane and anthracycline-based NAC was used in 91.7% of cases. All patients with Her2+ disease received anti-Her2 therapy. After NAC, the majority (84.9%) underwent mastectomy, and received LRRT (86.1%). Only 11% had mastectomy without RT. Pathologic complete response (pCR) rates were 2.5% for Luminal A, 14.4% Luminal B, 27% TNBC, and 35.1% Her2+. Overall, adjuvant LRRT was associated with improved outcomes but was most significant for improved LRRFS in TNBC (92.5% vs. 68.5%, P < .001; Her2+ 95.4% vs. 93.6%, P = .81; Luminal A 97.4% vs. 100%, P = .49; Luminal B 89.7% vs. 100%, P = .17). On multivariable analysis, factors associated with reduced LRRFS were grade 3 histology (HR 4.96, P = .009) and no pCR (HR 7.0, P = .0008). Predictors of lower BCSS and OS were age >50, grade 3, cT3-4, lack of pCR, LRRT omission, and TNBC and Her2+ subtypes. CONCLUSION: In this analysis of patients treated with modern NAC, pCR rates varied by molecular subtype. Patients who did not receive LRRT, particularly those with TNBC, had lower survival compared to those treated with LRRT. These findings support the need for prospective studies to evaluate the safety of de-escalating RT after NAC.

pN0(i+) and pN1mi Breast Cancer: Treatment and Outcomes in Comparison With pN0 and pN1a in the Modern Era.

PURPOSE: Locoregional recurrence risk and the role of locoregional radiation therapy (LRRT) in pN0(i+) and pN1mi breast cancer are unclear. This study compares locoregional relapse-free survival (LRRFS) in patients with pN0(i+) and pN1mi relative to pN0 and pN1a disease and evaluates LRRFS according to locoregional treatment. METHODS AND MATERIALS: We studied 10,271 patients referred between 2006 and 2011 with newly diagnosed pT1-T2, pN0, pN0(i+), pN1mi, or pN1a, M0 breast cancer. Outcomes were 10-year Kaplan-Meier LRRFS, relapse-free survival (RFS), distant relapse-free survival, and breast cancer-specific survival. Multivariable analysis of LRRFS and RFS was performed in pN0(i+) and pN1mi cohorts. RESULTS: Median follow-up was 9.3 years. In patients with pN0 (n = 7492), pN0(i+) (n = 305), pN1mi (n = 619), and pN1a (n = 1855) disease, LRRT was used in 1.1%, 24.3%, 45.7%, and 71.1%, respectively. Ten-year outcomes were LRRFS 96%, 92%, 97%, and 96% (P < .001), distant RFS 94%, 91%, 90%, and 84% (P < .001), and breast cancer-specific survival 95%, 90%, 93%, and 87% (P < .001), respectively. Ten-year LRRFS for patients treated with breast-conserving surgery alone, with breast RT, and with LRRT were 81%, 93%, and 91% for patients with pN0(i+) (P = .16) and 94%, 96%, and 100% for patients with pN1mi (P = .02), respectively. Among patients treated with mastectomy, 10-year LRRFS with surgery alone and with LRRT were 93% and 100% for patients with pN0(i+) (P = .12) and 95% and 99% for patients with pN1mi (P = .09). On multivariable analysis of patients with pN0(i+) and pN1mi, systemic therapy was associated with improved LRRFS in patients with pN0(i+) (hazard ratio [HR], 0.2; [0.06-0.6]; P = .005) and patients with pN1mi (HR, 0.1; [0.03-0.5]; P = .006). In patients with pN1mi, LRRT was associated with a trend toward increased LRRFS (HR, 0.2; [0.03-1.1]; P = .07). LRRT was not significantly associated with improved RFS in pN0(i+) or pN1mi disease. CONCLUSIONS: In the era of sentinel node staging and modern systemic therapy, patients with pN0(i+) and PN1mi treated with LRRT experienced 10-year LRR risks ≤10% after breast-conserving surgery or mastectomy and RT. LRRT was associated with a trend toward increased LRRFS in pN1mi but not pN0(i+) disease.

Association Between Regional Nodal Irradiation and Breast Cancer Recurrence-Free Interval for Patients With Low-Risk, Node-Positive Breast Cancer.

PURPOSE: Randomized clinical trials have shown that regional nodal irradiation (RNI) in patients with unselected N1 breast cancer improves breast cancer-specific survival. However, the benefit of RNI in women with biologically low-risk N1 breast cancer is uncertain. We conducted a population-based study to determine whether RNI is associated with improved breast cancer recurrence-free interval (BCRFI) in this population. METHODS AND MATERIALS: Patients aged 40 to 79 years with pT1-2 pN1 (node-positive) breast cancer diagnosed between 2005 and 2014 were identified. The inclusion criteria were modeled off of the TAILOR RT study, which is a randomized noninferiority clinical trial designed to assess the value of RNI in patients with low-risk N1 disease. Eligible patients had breast-conserving surgery or mastectomy and axillary lymph node dissection with 1 to 3 positive nodes, breast-conserving surgery and sentinel lymph node biopsy with 1 to 2 positive nodes, or mastectomy and sentinel lymph node biopsy with 1 positive node. Additionally, patients had luminal A breast cancers, as approximated by estrogen receptor positive (Allred 6-8/8), progesterone receptor (PR) positive (Allred 6-8/8), human epidermal growth factor receptor 2-negative, and grade 1 to 2 immunohistochemical testing. All patients were prescribed hormonal treatment. The primary endpoint of BCRFI, the time to any breast cancer recurrence or breast cancer-related death, was analyzed using a multivariate competing risks analysis. RESULTS: The cohort included 1169 women with a median follow-up of 9.2 years. Radiation treatments were not performed in 151 women treated with mastectomy alone, were delivered to the breast only in 133 women, and were delivered locoregionally in 885 women. Patients undergoing RNI were younger (median age: 58 vs 62 years), more likely to have 2 to 3 macroscopic lymph nodes involved, and more often received chemotherapy (all P < .05). The 10-year estimate of BCRFI was 90% without RNI versus 90% with RNI (P = .5). On multivariable analysis, RNI was not a significant predictor of BCRFI (hazard ratio: 1.0; P = .9). CONCLUSIONS: In this retrospective analysis, RNI was not associated with improved BCRFI for women with biologically low-risk N1 breast cancer. We advocate accrual to the ongoing TAILOR RT study.

Breast Tangent Beam Energy, Surgical Bed-to-Skin Distance and Local Recurrence After Breast-Conserving Treatment.

PURPOSE: Higher energy (>6 MV) photons reduce dose inhomogeneity with breast tangent beams, thereby reducing late breast toxicity, but skin and superficial tissue sparing by higher energy beams raises concerns about local recurrence (LR) risk. This study aimed to determine whether beam energy and surgical bed-to-skin distance affect LR. METHODS AND MATERIALS: This population-based study included newly diagnosed invasive breast cancers without skin involvement (pT1-4a, any-N, M0) treated with breast-conserving surgery and adjuvant whole breast radiation therapy without bolus or beam spoilers. The primary endpoint was the cumulative incidence of LR (CILR). Multivariable analysis (MVA) included mean beam energy, age, T-stage, nodal status, overall stage, lymphovascular invasion (LVI), grade, margin status, extensive intraductal component (EIC), breast cancer subtype, hormone therapy, and chemotherapy. In a subgroup with contoured surgical beds, another MVA included surgical bed-to-skin distance. RESULTS: The cohort consisted of 10,083 women treated from 2002 to 2011: 327 with 4 MV, 6006 with 6 MV, 2083 with >6 to 10 MV, and 1667 with >10 MV tangents. The median follow-up time was 11.1 years. The 10-year CILR was 3.1% (95% confidence interval [CI], 1.6-5.4) with 4 MV, 2.8% (2.4-3.3) with 6 MV, 4.2% (3.4-5.3) with >6 to 10 MV, and 2.6% (1.9-3.5) with >10 MV. On MVA of the entire cohort, LR risk was increased with positive margins, LVI, EIC, and lack of hormone therapy, but was not associated with beam energy (hazard ratio [HR], 1.01; 95% CI, 0.96-1.05; P = .8). On MVA of 3359 patients with contoured surgical beds, LR risk was not associated with surgical bed-to-skin distance (HR, 1.00; 95% CI, 0.99-1.02; P = .8). CONCLUSIONS: Use of higher breast tangent beam energies is not associated with increased risk of LR, including in cases with surgical beds that are close to the skin.

Characterizing the KRAS G12C mutation in metastatic colorectal cancer: a population-based cohort and assessment of expression differences in The Cancer Genome Atlas.

Introduction: In metastatic colorectal cancer (mCRC), RAS mutations impart inferior survival and resistance to anti-epidermal growth factor receptor (EGFR) antibodies. KRAS G12C inhibitors have been developed and we evaluated how KRAS G12C differs from other RAS mutations. Patients and Methods: This retrospective review evaluated patients in British Columbia, Canada with mCRC and RAS testing performed between 1 January 2016 and 31 December 2018. Sequencing information from The Cancer Genome Analysis (TCGA) was also obtained and analysed. Results: Age at diagnosis, sex, anatomic location and stage at diagnosis did not differ by RAS mutation type. Progression free survival on first chemotherapy for patients with metastatic KRAS G12C tumours was 11 months. Median overall survival did not differ by RAS mutation type but was worse for both KRAS G12C (27 months) and non-G12C alterations (29 months) than wildtype (43 months) (p = 0.01). Within the TCGA, there was no differential gene expression between KRAS G12C and other RAS mutations. However, eight genes with copy number differences between the G12C and non-G12C RAS mutant groups were identified after adjusting for multiple comparisons (FITM2, PDRG1, POFUT1, ERGIC3, EDEM2, PIGU, MANBAL and PXMP4). We also noted that other RAS mutant mCRCs had a higher tumour mutation burden than those with KRAS G12C mutations (median 3.05 vs 2.06 muts/Mb, p = 4.2e-3) and that KRAS G12C/other RAS had differing consensus molecular subtype distribution from wildtype colorectal cancer (CRC) (p < 0.0001) but not each other (p = 0.14). Conclusion: KRAS G12C tumours have similar clinical presentation to other RAS mutant tumours, however, are associated with differential copy number alterations.