Triple-Negative Breast Cancer: A Review of Current Curative Intent Therapies.

Breast cancer is the most commonly diagnosed malignancy in women, with triple-negative breast cancer (TNBC) accounting for 10-20% of cases. Historically, fewer treatment options have existed for this subtype of breast cancer, with cytotoxic chemotherapy playing a predominant role. This article aims to review the current treatment paradigm for curative-intent TNBC, while also reviewing potential future developments in this landscape. In addition to chemotherapy, recent advances in the understanding of the molecular biology of TNBC have led to promising new studies of targeted and immune checkpoint inhibitor therapies in the curative-intent setting. The appropriate selection of TNBC patient subgroups with a higher likelihood of benefit from treatment is critical to identify the best treatment approach.

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.

A multi-centre study comparing granulocyte-colony stimulating factors to antibiotics for primary prophylaxis of docetaxel-cyclophosphamide induced febrile neutropenia.

BACKGROUND: Primary febrile neutropenia (FN) prophylaxis with ciprofloxacin or granulocyte-colony stimulating factors (G-CSF) is recommended with docetaxel-cyclophosphamide (TC) chemotherapy for early-stage breast cancer (EBC). A pragmatic randomised trial compared the superiority of G-CSF to ciprofloxacin and a cost-utility analysis were conducted. METHODS: EBC patients receiving TC chemotherapy were randomised to ciprofloxacin or G-CSF. The primary outcome was a composite of FN and non-FN treatment-related hospitalisation. Secondary outcomes included; rates of FN, non-FN treatment-related hospitalisation, chemotherapy dose reductions/delays/discontinuations. Primary analysis was performed with the intention to treat population. Cost-utility analyses were conducted from the Canadian public payer perspective. RESULTS: 458 eligible patients were randomised: 228 to ciprofloxacin and 230 to G-CSF. For the primary endpoint there was non-statistically significant difference (Risk difference = -6.7%, 95%CI = -13.5%-0.1%, p = 0.061) between ciprofloxacin patients (46,20.2%) and G-CSF (31,13.5%). Patients receiving ciprofloxacin were more likely to experience FN (36/228, 15.8% vs 13/230, 5.7%) than patients receiving G-CSF (p < 0.001). Non-FN treatment-related hospitalisation occurred in 40/228 (17.5%) of ciprofloxacin patients vs 28/230 (12.2%) of G-CSF patients (p = 0.12). There were no differences in other secondary outcomes. G-CSF was associated with an incremental cost-effectiveness ratio of C$1,760,796 per one quality-adjusted life year gained. CONCLUSION: The primary endpoint of superiority of G-CSF over ciprofloxacin was not demonstrated. While there were reduced FN rates with G-CSF, there were no differences in chemotherapy dose delays/reductions or discontinuations. With the commonly used willingness to pay value of C$50,000/QALY, G-CSF use was not cost-effective compared to ciprofloxacin and deserves scrutiny from the payer perspective.

Paraneoplastic acquired haemophilia A in extensive-stage small cell lung cancer (ES-SCLC) in the era of immunotherapy.

Small cell lung cancer (SCLC) is a deadly and rapidly progressive disease that can present with various paraneoplastic syndromes on initial workup. Acquired factor VIII (FVIII) deficiency, also known as acquired haemophilia A (AHA), has been identified as a rare paraneoplastic syndrome in SCLC. Here, we present a 61-year-old woman with a massive gastrointestinal bleed and prolonged activated partial thromboplastin time (PTT) in the emergency department. She was diagnosed with rare paraneoplastic AHA secondary to extensive-stage SCLC (ES-SCLC). She was treated with high-dose steroids and factor bypassing agents, which led to the resolution of bleeding and undetectable FVIII inhibitor levels. She was subsequently treated for ES-SCLC with carboplatin, etoposide and atezolizumab. This case report highlights a rare clinical presentation of paraneoplastic AHA that necessitates prompt recognition in patients with SCLC with ongoing bleeding and elevated PTT.

Research priorities in metastatic breast cancer: A James Lind Alliance Priority Setting Partnership.

Breast cancer remains the most common cancer among women, and the second most common cause of cancer death. With advances in treatment, women are living longer, in some cases many years, with metastatic breast cancer (MBC). These advances are a direct result of research, however, many studies are primarily researcher or industry led, with minimal input from patients and caregivers. The James Lind Alliance (JLA) brings patients, caregivers, and clinicians together in priority setting partnerships (PSPs) to determine key priorities in research. In this study, we utilized the JLA approach to identify unanswered questions on MBC from patient and clinical perspectives and prioritized to reach a top 10. Following the established JLA approach, MBC patients, caregivers, and health care professionals (HCPs) were surveyed to elicit their questions regarding MBC. Research questions were generated from survey responses, and following literature review to ensure the questions were currently not completely answered, an interim prioritization survey was conducted to identify a shortlist of questions taken to a final consensus meeting. One thousand, one-hundred and ninety-four responses were collected from 668 individuals, which were refined into 62 unique unanswered questions. The interim prioritization survey was completed by 174 individuals, and the top 27 questions were taken to a final meeting to determine by consensus the top 10. The top 10 questions cover a wide range of research questions, identified by valuable stakeholders as being priorities. This list can be used to inform prioritization and funding of future MBC research.

Economic analysis of osimertinib in previously untreated EGFR-mutant advanced non-small cell lung cancer in Canada.

INTRODUCTION: Osimertinib improves progression-free survival in previously untreated EGFR-positive advanced non-small cell lung cancer (NSCLC) patients, with marked intracranial response rates. However, its cost-effectiveness in a publically funded health care system has not been established. We assessed the cost-effectiveness of first-line osimertinib from the public payer perspective in the Canadian health care system. METHODS: A Markov model was developed to project the outcomes and direct medical costs of initial treatment with osimertinib or current standard-of-care (SoC) EGFR TKIs, gefinitib or afatinib, in patients with previously untreated EGFR-mutant advanced NSCLC. Clinical and cost input estimates were informed from the available literature. Model outcomes included costs (in 2018 Canadian dollars), life years (LYs), quality-adjusted life-years (QALYs), and the cost utility of osimertinib compared to SoC EGFR TKI, or incremental cost per QALY gained. RESULTS: Initial treatment with osimertinib was associated with a gain of 0.79 QALY [95% confidence interval (CI), 0.74 to 0.83] at an incremental cost of $176,394 CAD (95% CI, 176,383 to 176,405) vs. SoC EGFR TKI (incremental cost-effectiveness ratio [ICER]: $223,133/QALY gained; 95%CI, 198,144 to 252,805). Osimertinib had a 0% probability of being cost-effective at a willingness-to-pay threshold of $100,000 per QALY. Deterministic sensitivity analysis showed that the cost of osimertinib had the largest impact on ICER results. CONCLUSION: At the current marketed price, first-line osimertinib therapy in patients with advanced EGFR-mutant lung adenocarcinoma is not cost-effective in Canada. Reduction of osimertinib cost, for example by 25%, can significantly improve the cost-effectiveness profile.

Drug development for breast, colorectal, and non-small cell lung cancers from 1979 to 2014.

BACKGROUND: Understanding the drug development pathway is critical for streamlining the development of effective cancer treatments. The objective of the current study was to delineate the drug development timeline and attrition rate of different drug classes for common cancer disease sites. METHODS: Drugs entering clinical trials for breast, colorectal, and non-small cell lung cancer were identified using a pharmaceutical business intelligence database. Data regarding drug characteristics, clinical trials, and approval dates were obtained from the database, clinical trial registries, PubMed, and regulatory Web sites. RESULTS: A total of 411 drugs met the inclusion criteria for breast cancer, 246 drugs met the inclusion criteria for colorectal cancer, and 315 drugs met the inclusion criteria for non-small cell lung cancer. Attrition rates were 83.9% for breast cancer, 87.0% for colorectal cancer, and 92.0% for non-small cell lung cancer drugs. In the case of non-small cell lung cancer, there was a trend toward higher attrition rates for targeted monoclonal antibodies compared with other agents. No tumor site-specific differences were noted with regard to cytotoxic chemotherapy, immunomodulatory, or small molecule kinase inhibitor drugs. Drugs classified as "others" in breast cancer had lower attrition rates, primarily due to the higher success of hormonal medications. Mean drug development times were 8.9 years for breast cancer, 6.7 years for colorectal cancer, and 6.6 years for non-small cell lung cancer. CONCLUSIONS: Overall oncologic drug attrition rates remain high, and drugs are more likely to fail in later-stage clinical trials. The refinement of early-phase trial design may permit the selection of drugs that are more likely to succeed in the phase 3 setting. Cancer 2017;123:4672-4679. © 2017 American Cancer Society.

Tumour thrombus of the inferior vena cava extending into the right atrium in the setting of colon cancer.

Tumour thrombus is seen in renal cell and hepatocellular carcinoma, but is rarely reported in colorectal cancer. A woman aged 46 years, with metastatic colonic adenocarcinoma, was found to have a large mass in the inferior vena cava (IVC) extending into the right atrium. Although this lesion was initially thought to be bland thrombus, imaging with contrast-enhanced CT scan and contrast-enhanced ultrasound supported the diagnosis of tumour thrombus. Despite the large size of the lesion, the patient was asymptomatic. Her lack of symptoms, and poor overall prognosis from her cancer led to the decision to avoid aggressive surgical or radiological interventions. Several months later, the patient passed away. At autopsy, there was no evidence of fatal embolisation from the pre-existing thrombus. Diagnosis of tumour thrombus in the IVC is difficult and management can be challenging due to the significant risks associated with treatment options.