Cost-effectiveness analysis of multigene expression profiling assays to guide adjuvant therapy decisions in women with invasive early-stage breast cancer.

Gene expression profiling (GEP) testing using 12-gene recurrence score (RS) assay (EndoPredict®), 58-gene RS assay (Prosigna®), and 21-gene RS assay (Oncotype DX®) is available to aid in chemotherapy decision-making when traditional clinicopathological predictors are insufficient to accurately determine recurrence risk in women with axillary lymph node-negative, hormone receptor-positive, and human epidermal growth factor-receptor 2-negative early-stage breast cancer. We examined the cost-effectiveness of incorporating these assays into standard practice. A decision model was built to project lifetime clinical and economic consequences of different adjuvant treatment-guiding strategies. The model was parameterized using follow-up data from a secondary analysis of the Anastrozole or Tamoxifen Alone or Combined randomized trial, cost data (2017 Canadian dollars) from the London Regional Cancer Program (Canada) and secondary Canadian sources. The 12-gene, 58-gene, and 21-gene RS assays were associated with cost-effectiveness ratios of $36,274, $48,525, and $74,911/quality-adjusted life year (QALY) gained and resulted in total gains of 379, 284.3, and 189.5 QALYs/year and total budgets of $12.9, $14.2, and $16.6 million/year, respectively. The total expected-value of perfect information about GEP assays' utility was $10.4 million/year. GEP testing using any of these assays is likely clinically and economically attractive. The 12-gene and 58-gene RS assays may improve the cost-effectiveness of GEP testing and offer higher value for money, although prospective evidence is still needed. Comparative field evaluations of GEP assays in real-world practice are associated with a large societal benefit and warranted to determine the optimal and most cost-effective assay for routine use.

Identification and survival outcomes of a cohort of patients with cancer of unknown primary in Ontario, Canada.

BACKGROUND: Cancer of unknown primary origin (CUP) is defined by the presence of pathologically identified metastatic disease without clinical or radiological evidence of a primary tumour. Our objective was to identify incident cases of CUP in Ontario, Canada, and determine the influence of histology and sites of metastases on overall survival (OS). MATERIAL AND METHODS: We used the Ontario Cancer Registry (OCR) and the Same-Day Surgery and Discharge Abstract Database (SDS/DAD) to identify patients diagnosed with CUP in Ontario between 1 January 2000, and 31 December 2005. Patient diagnostic information, including histology and survival data, was obtained from the OCR. We cross-validated CUP diagnosis and obtained additional information about metastasis through data linkage with the SDS/DAD database. OS was assessed using Cox regression models adjusting for histology and sites of metastases. RESULTS: We identified 3564 patients diagnosed with CUP. Patients without histologically confirmed disease (n = 1821) had a one-year OS of 10.9%, whereas patients with confirmed histology (n = 1743) had a one-year OS of 15.6%. The most common metastatic sites were in the respiratory or digestive systems (n = 1603), and the most common histology was adenocarcinoma (n = 939). Three-year survival rates were 3.5%, 5.3%, 41.6% and 3.6% among adenocarcinoma, unspecified carcinoma, squamous cell carcinoma and undifferentiated histology, respectively. Three-year survival rates were 40%, 2.4%, 8.0% and 4.6% among patients with metastases localised to lymph nodes, the respiratory or digestive systems, other specified sites, and unspecified sites, respectively. CONCLUSION: CUP patients in Ontario have a poor prognosis. Some subgroups may have better survival rates, such as patients with metastases localised to lymph nodes and patients with squamous cell histology.

Appraisal of Systemic Treatment Strategies in Early HER2-Positive Breast Cancer-A Literature Review.

BACKGROUND: The overexpression of the human epidermal growth factor receptor 2 (HER2+) accounts for 15-20% of all breast cancer phenotypes. Even after the completion of the standard combination of chemotherapy and trastuzumab, relapse events occur in approximately 15% of cases. The neoadjuvant approach has multiple benefits that include the potential to downgrade staging and convert previously unresectable tumors to operable tumors. In addition, achieving a pathologic complete response (pCR) following preoperative systemic treatment is prognostic of enhanced survival outcomes. Thus, optimal evaluation among the suitable strategies is crucial in deciding which patients should be selected for the neoadjuvant approach. METHODS: A literature search was conducted in the Embase, Medline, and Cochrane electronic libraries. CONCLUSION: The evaluation of tumor and LN staging and, hence, stratifying BC recurrence risk are decisive factors in guiding clinicians to optimize treatment decisions between the neoadjuvant versus adjuvant approaches. For each individual case, it is important to consider the most likely postsurgical outcome, since, if the patient does not obtain pCR following neoadjuvant treatment, they are eligible for adjuvant T-DM1 in the case of residual disease. This review of HER2-positive female BC outlines suitable neoadjuvant and adjuvant systemic treatment strategies for guiding clinical decision making around the selection of an appropriate therapy.

Cost-effectiveness of a 21-gene recurrence score assay versus Canadian clinical practice in women with early-stage estrogen- or progesterone-receptor-positive, axillary lymph-node negative breast cancer.

BACKGROUND: A 21-gene recurrence score (RS) assay may inform adjuvant systematic treatment decisions in women with early stage breast cancer. We sought to investigate the cost effectiveness of using the RS-assay versus current clinical practice (CCP) in women with early-stage estrogen- or progesterone-receptor-positive, axilliary lymph-node negative breast cancer (ER+/ PR + LN- ESBC) from the perspective of the Canadian public healthcare system. METHODS: We developed a Markov model to project the lifetime clinical and economic consequences of ESBC. We evaluated adjuvant therapy separately in post- and pre-menopausal women with ER+/ PR + LN- ESBC. We assumed that the RS-assay would reclassify pre- and post-menopausal women among risk levels (low, intermediate and high) and guide adjuvant systematic treatment decisions. The model was parameterized using 7 year follow up data from the Manitoba Cancer Registry, cost data from Manitoba administrative databases, and secondary sources. Costs are presented in 2010 CAD. Future costs and benefits were discounted at 5%. RESULTS: The RS-assay compared to CCP generated cost-savings in pre-menopausal women and had an ICER of $60,000 per QALY gained in post-menopausal women. The cost effectiveness was most sensitive to the proportion of women classified as intermediate risk by the RS-assay who receive adjuvant chemotherapy and the risk of relapse in the RS-assay model. CONCLUSIONS: The RS-assay is likely to be cost effective in the Canadian healthcare system and should be considered for adoption in women with ER+/ PR + LN- ESBC. However, ongoing assessment and validation of the assay in real-world clinical practice is warranted.

A Population-Based Study to Evaluate the Associations of Nodal Stage, Lymph Node Ratio and Log Odds of Positive Lymph Nodes with Survival in Patients with Small Bowel Adenocarcinoma.

PURPOSE: This study aimed to determine the real-world prognostic significance of lymph node ratio (LNR) and log odds of positive lymph nodes (LOPLN) in patients with non-metastatic small bowel adenocarcinoma. METHODS: Patients diagnosed with early-stage small bowel adenocarcinoma between January 2007 and December 2018 from a large Canadian province were identified. We calculated the LNR by dividing positive over total lymph nodes examined and the LOPLN as log ([positive lymph nodes + 0.5]/[negative lymph nodes + 0.5]). The LNR and LOPLN were categorized at cut-offs of 0.4 and -1.1, respectively. Multivariable Cox proportional hazards models were constructed for each nodal stage, LNR and LOPLN, adjusting for measured confounding factors. Harrell's C-index and Akaike's Information Criterion (AIC) were used to calculate the prognostic discriminatory abilities of the different models. RESULTS: We identified 141 patients. The median age was 67 years and 54.6% were men. The 5-year overall survival rates for patients with stage I, II and III small bowel adenocarcinoma were 50.0%, 56.6% and 47.5%, respectively. The discriminatory ability was generally comparable for LOPLN, LNR and nodal stage in the prognostication of all patients. However, LOPLN had higher discriminatory ability among patients with at least one lymph node involvement (Harrell's C-index, 0.75, 0.77 and 0.82, and AIC, 122.91, 119.68 and 110.69 for nodal stage, LNR and LOPLN, respectively). CONCLUSION: The LOPLN may provide better prognostic information when compared to LNR and nodal stage in specific patients.

Real-world Safety and Efficacy of Raltitrexed in Patients With Metastatic Colorectal Cancer.

BACKGROUND: Use of fluoropyrimidine-based therapy in patients with metastatic colorectal cancer is associated with significant toxicities. This study aimed to assess the safety and efficacy of raltitrexed use in patients with metastatic colorectal cancer who developed significant toxicities after fluoropyrimidine-based treatment. PATIENTS AND METHODS: We identified patients with metastatic colorectal cancer who were treated with raltitrexed-based systemic therapy after developing serious adverse events with fluoropyrimidine-based treatment in a large Canadian province from 2004 to 2018. Demographic, tumor, and treatment characteristics were retrieved from the electronic medical records. Progression-free and overall survival were assessed from the start of raltitrexed-based therapy. RESULTS: A total of 86 patients were identified for the study. The median age was 66.5 years, and 58.1% of patients were men. The primary cancer site was right, left, and transverse colon in 38.4%, 27.9%, and 9.3%, respectively. The remaining 24.4% had rectal cancer. Among all patients, 43.0% had received more than 2 prior systemic therapies, and 37.6% had developed previous cardiotoxicity to fluoropyrimidine-based treatment. The median progression-free and overall survival were 8.5 and 10.2 months, respectively. On multivariable Cox regression model, patients with left-sided colon cancer (hazard ratio [HR], 0.33; 95% confidence interval [CI], 0.12-0.97; P = .044) and the Eastern Cooperative Oncology Group performance status of 0/1 (HR, 0.10; 95% CI, 0.01-0.82; P = .032) had a longer progression-free survival, whereas left-sidedness of colon cancer was the only factor that predicted overall survival (HR, 0.30; 95% CI, 0.10-0.88; P = .029). Raltitrexed was well-tolerated with common adverse events that included anemia in 41.7% of patients and chemotherapy-induced nausea and vomiting in 27.4%. Most toxicities were grade 1/2, but 16.7% of patients experienced grade 3. There were no cardiac events and treatment-related deaths. CONCLUSIONS: Raltitrexed in patients with colorectal cancer who were previously treated with fluoropyrimidine-based systemic therapy is effective and well-tolerated.

Developing a clinical-pathologic model to predict genomic risk of recurrence in patients with hormone receptor positive, human epidermal growth factor receptor-2 negative, node negative breast cancer.

INTRODUCTION: Patients with hormone receptor (HR)-positive, human epidermal growth factor receptor-2 (HER2)-negative, node negative (NN) breast cancer may be offered a gene expression profiling (GEP) test to determine recurrence risk and benefit of adjuvant chemotherapy. We developed a clinical-pathologic (CP) model to predict genomic recurrence risk and examined its performance characteristics. METHODS: Patients diagnosed with HR-positive, HER2-negative, NN breast cancer with a tumour size < 30 mm and who underwent a GEP test [OncotypeDX or Prosigna] in Alberta from October 2017 through March 2019 were identified. Patients were classified as low or high genomic risk. Multivariable logistic regression analysis was performed to examine the associations of CP factors with genomic risk. A CP model was developed using coefficients of regression and sensitivity analyses were performed. RESULTS: A total of 366 patients were eligible (135 were tested using OncotypeDX and 231 with Prosigna). Of these, 64 (17.5%) patients were classified as high genomic risk. On multivariable logistic regression, tumour size > 20 mm (odds ratio [OR], 3.58; 95% confidence interval [CI], 1.84-6.98; P<0.001), low expression of progesterone receptor (OR, 3.46; 95% CI, 1.76-6.82; P<0.001), and histological grade III (OR, 7.24; 95% CI, 3.82-13.70; P<0.001) predicted high genomic risk. A CP model using these variables was developed to provide a score of 0-4. A CP cut-point of 0, identified 56% of genomic low risk patients with a specificity of 98.4%. CONCLUSIONS: A CP model could be used to narrow the population of breast cancer patients undergoing GEP testing.

Four cycles of docetaxel and cyclophosphamide as adjuvant chemotherapy in node negative breast cancer: A real-world study.

INTRODUCTION: The optimal number of cycles of adjuvant docetaxel and cyclophosphamide (DC) in patients with node negative breast cancer is not known. We aimed to analyse the survival outcomes of patients with node negative and human epidermal growth factor receptor (HER2)-negative breast cancer treated with four cycles of DC. METHODS: Patients with node negative and HER2-negative breast cancer treated with four cycles of DC after surgery in a large Canadian province from 2008 to 2012 were identified. We analysed the 4-year and 9-year invasive disease free survival (iDFS) and overall survival (OS). Cox regression models were constructed to examine the associations of clinical characteristics with survival outcomes. RESULTS: A total of 657 patients were eligible for the current analysis. The median age was 53 years and 71.2% of patients had hormone receptor-positive breast cancer. Approximately three-fourths of patients had grade III tumours. At a median follow-up of nine years, the 4-year iDFS and OS were 91.0% and 95.5% and the corresponding 9-year rates were 80.5% and 88.0%, respectively. On multivariable Cox regression analysis, grade III tumour predicted worse iDFS (hazard ratio [HR], 2.15; 95% confidence interval [CI], 1.09-4.21; P = 0.026) and OS (HR, 3.15; 95% CI, 1.18-8.45; P = 0.022). CONCLUSIONS: Adjuvant chemotherapy with four cycles of DC in a select population of node negative breast cancer was associated with encouraging long-term survival. In the absence of a randomized comparison between four and six cycles of DC, this study presents real-world evidence to consider four cycles of DC as a reasonable option.

The Clinical Significance of Occult Gastrointestinal Primary Tumours in Metastatic Cancer: A Population Retrospective Cohort Study.

PURPOSE: The purpose of this study was to estimate the incidence of occult gastrointestinal (GI) primary tumours in patients with metastatic cancer of uncertain primary origin and evaluate their influence on treatments and overall survival (OS). MATERIALS AND METHODS: We used population heath data from Manitoba, Canada to identify all patients initially diagnosed with metastatic cancer between 2002 and 2011. We defined patients to have "occult" primary tumour if the primary was found at least 6 months after initial diagnosis. Otherwise, we considered primary tumours as "obvious." We used propensity-score methods to match each patient with occult GI tumour to four patients with obvious GI tumour on all known clinicopathologic features. We compared treatments and 2-year survival data between the two patient groups and assessed treatment effect on OS using Cox regression adjustment. RESULTS: Eighty-three patients had occult GI primary tumours, accounting for 17.6% of men and 14% of women with metastatic cancer of uncertain primary. A 1:4 matching created a matched group of 332 patients with obvious GI primary tumour. Occult cases compared to the matched group were less likely to receive surgical interventions and targeted biological therapy, and more likely to receive cytotoxic empiric chemotherapeutic agents. Having an occult GI tumour was associated with reduced OS and appeared to be a nonsignificant independent predictor of OS when adjusting for treatment differences. CONCLUSION: GI tumours are the most common occult primary tumours in men and the second most common in women. Patients with occult GI primary tumours are potentially being undertreated with available GI site-specific and targeted therapies.

The Potential Clinical and Economic Value of Primary Tumour Identification in Metastatic Cancer of Unknown Primary Tumour: A Population-Based Retrospective Matched Cohort Study.

PURPOSE: Several genomic tests have recently been developed to identify the primary tumour in cancer of unknown primary tumour (CUP). However, the value of identifying the primary tumour in clinical practice for CUP patients remains questionable and difficult to prove in randomized trials. OBJECTIVE: We aimed to assess the clinical and economic value of primary tumour identification in CUP using a retrospective matched cohort study. METHODS: We used the Manitoba Cancer Registry to identify all patients initially diagnosed with metastatic cancer between 2002 and 2011. We defined patients as having CUP if their primary tumour was found 6 months or more after initial diagnosis or never found during the course of disease. Otherwise, we considered patients to have metastatic cancer from a known primary tumour (CKP). We linked all patients with Manitoba Health databases to estimate their direct healthcare costs using a phase-of-care approach. We used the propensity score matching technique to match each CUP patient with a CKP patient on clinicopathologic characteristics. We compared treatment patterns, overall survival (OS) and phase-specific healthcare costs between the two patient groups and assessed association with OS using Cox regression adjustment. RESULTS: Of 5839 patients diagnosed with metastatic cancer, 395 had CUP (6.8%); 1:1 matching created a matched group of 395 CKP patients. CUP patients were less likely to receive surgery, radiation, hormonal and targeted therapy and more likely to receive cytotoxic empiric chemotherapeutic agents. Having CUP was associated with reduced OS (hazard ratio [HR] 1.31; 95% confidence interval 1.1-1.58), but this lost statistical significance with adjustment for treatment differences. CUP patients had a significant increase in the mean net cost of initial diagnostic workup before diagnosis and a significant reduction in the mean net cost of continuing cancer care. CONCLUSION: Identifying the primary tumour in CUP patients might enable the use of more effective therapies, improve OS and allow more efficient allocation of healthcare resources.

Cost effectiveness of a 21-gene recurrence score assay versus Canadian clinical practice in post-menopausal women with early-stage estrogen or progesterone-receptor-positive, axillary lymph-node positive breast cancer.

BACKGROUND: A 21-gene recurrence score (RS) assay provides a method of guiding treatment decisions in women with early-stage breast cancer (ESBC). We investigated the cost effectiveness of using the RS assay versus current clinical practice (CCP) in post-menopausal women with estrogen- or progesterone-receptor-positive, one to three positive axillary lymph-node ESBC from the perspective of the Canadian public healthcare system. METHODS: We developed a decision analytic model to project the lifetime clinical and economic consequences of ESBC. We assumed that the RS assay would classify patients among risk levels (low, intermediate and high) and corresponding adjuvant treatment regimens. The model was parameterized using 7-year follow-up data from the Manitoba Cancer Registry, cost data from Manitoba Health administrative databases and secondary sources. Costs are presented in 2012 Canadian dollars, and future costs and benefits were discounted at 5 %. RESULTS: In the base case analysis, the RS assay compared with CCP led to an increase of 0.08 quality-adjusted life-year (QALY) and an increase in cost of Can$36.2 per person, resulting in an incremental cost-effectiveness ratio (ICER) of Can$464/QALY gained. The ICER was most sensitive to the proportion of women classified to intermediate risk by the RS assay who received adjuvant chemotherapy, and absolute risk of relapse among patients receiving the RS assay. CONCLUSIONS: The RS assay is likely to be cost effective in the Canadian healthcare system. Field evaluations of the assay in this patient population will help reduce uncertainty in clinical guidelines for intermediate-range RS-assay values and specific disease outcomes by the RS assay, which are important drivers of ICER.

Cost-effectiveness of adding cetuximab to platinum-based chemotherapy for first-line treatment of recurrent or metastatic head and neck cancer.

PURPOSE: To assess the cost effectiveness of adding cetuximab to platinum-based chemotherapy in first-line treatment of patients with recurrent or metastatic head and neck squamous cell carcinoma (HNSCC) from the perspective of the Canadian public healthcare system. METHODS: We developed a Markov state transition model to project the lifetime clinical and economic consequences of recurrent or metastatic HNSCC. Transition probabilities were derived from a phase III trial of cetuximab in patients with recurrent or metastatic HNSCC. Cost estimates were obtained from London Health Sciences Centre and the Ontario Case Costing Initiative, and expressed in 2011 CAD. A three year time horizon was used. Future costs and health benefits were discounted at 5%. RESULTS: In the base case, cetuximab plus platinum-based chemotherapy compared to platinum-based chemotherapy alone led to an increase of 0.093 QALY and an increase in cost of $36,000 per person, resulting in an incremental cost effectiveness ratio (ICER) of $386,000 per QALY gained. The cost effectiveness ratio was most sensitive to the cost per mg of cetuximab and the absolute risk of progression among patients receiving cetuximab. CONCLUSION: The addition of cetuximab to standard platinum-based chemotherapy in first-line treatment of patients with recurrent or metastatic HNSCC has an ICER that exceeds $100,000 per QALY gained. Cetuximab can only be economically attractive in this patient population if the cost of cetuximab is substantially reduced or if future research can identify predictive markers to select patients most likely to benefit from the addition of cetuximab to chemotherapy.