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Development of Training Materials for Pathologists to Provide Machine Learning Validation Data of Tumor-Infiltrating Lymphocytes in Breast Cancer
The High Throughput Truthing project aims to develop a dataset for validating artificial intelligence and machine learning models (AI/ML) fit for regulatory purposes. The context of this AI/ML validation dataset is the reporting of stromal tumor-infiltrating lymphocytes (sTILs) density evaluations in hematoxylin and eosin-stained invasive breast cancer biopsy specimens. After completing the pilot study, we found notable variability in the sTILs estimates as well as inconsistencies and gaps in the provided training to pathologists. Using the pilot study data and an expert panel, we created custom training materials to improve pathologist annotation quality for the pivotal study. We categorized regions of interest (ROIs) based on their mean sTILs density and selected ROIs with the highest and lowest sTILs variability. In a series of eight one-hour sessions, the expert panel reviewed each ROI and provided verbal density estimates and comments on features that confounded the sTILs evaluation. We aggregated and shaped the comments to identify pitfalls and instructions to improve our training materials. From these selected ROIs, we created a training set and proficiency test set to improve pathologist training with the goal to improve data collection for the pivotal study. We are not exploring AI/ML performance in this paper. Instead, we are creating materials that will train crowd-sourced pathologists to be the reference standard in a pivotal study to create an AI/ML model validation dataset. The issues discussed here are also important for clinicians to understand about the evaluation of sTILs in clinical practice and can provide insight to developers of AI/ML models.
Journal Article
Pancreatitis After Treatment With Encorafenib, Binimetinib, and Cetuximab for BRAF V600E Mutation-Positive Colorectal Cancer
BRAF V600E mutation-positive advanced recurrent colorectal cancer has a poor prognosis. Encorafenib, binimetinib, and cetuximab were approved for use to treat this cancer in 2020 in Japan. Here, we present the case of a patient with BRAF V600E mutation-positive colorectal cancer, who was treated with encorafenib, binimetinib, and cetuximab, and developed grade 3 pancreatitis at our hospital. After pancreatitis treatment, the drug doses were reduced from 300 mg to 225 mg of encorafenib and from 90 mg to 60 mg of binimetinib, and the treatment was resumed. Since then, no grade 3 or higher adverse events were observed. Although pancreatitis has been reported to occur after the use of encorafenib and binimetinib, it is rare. With appropriate dose reduction and attention to side effects, this regimen is considered feasible for the long-term treatment of BRAF V600E mutation-positive advanced recurrent colorectal cancer in patients aged >70 years.
Journal Article
Analyzing Neoadjuvant Chemotherapy Effects in HER2-Low Breast Cancer: Real World Data
Neoadjuvant chemotherapy (NAC) can be used as upfront therapy in aggressive breast cancer (BC). human epidermal growth factor receptor 2 (HER2)-low BC, defined as tumors scoring +1 or +2 on immunohistochemistry without HER2 gene amplification by in situ hybridization, lacks information on real-world data (RWD) outcomes, especially in the NAC setting. This subgroup, which does not reach the HER2 positive criteria due to its lower receptor expression, represents a distinct clinical category potentially requiring tailored therapeutic approaches.
The objective of this study is to characterize patients with BC with HER2-low status who received NAC in a Brazilian public reference center for female tumors and key outcomes such as pathological complete response (pCR), overall survival (OS), and metastasis-free survival (MFS).
A retrospective cohort study based on a large BC database from a reference cancer center in Brazil. Patients with BC that received NAC, diagnosed between 2011 and 2020, were included if they presented HER2-low status (defined as tumors scoring +1 or +2 on immunohistochemistry without HER2 gene amplification by in situ hybridization) and had complete data on outcomes. Clinical and demographic data were collected, such as age, menopausal status, Ki-67, hormone receptor expression and others. Key outcomes from the study comprised pCR (defined as ypT0/TIs/ypN0), overall survival, and metastasis-free survival (MFS). Survival analyses were conducted through the semiparametric Kaplan-Meier method to assess OS and MFS by pCR status, considering BC diagnosis as the index date.
Overall, 297 patients were eligible and 141 were included in the study after matching the HER2-low definition. The pCR was seen in 18 out of 141 patients (12.7%). The median overall survival was 8.2 years, and the median MFS was 2.7 years. The OS of pCR was 83.4% and non-pCR was 58.1%; the DFS of pCR was 55.5% and non-pCR 40.6%.
This study gives updated insights on pCR, OS, and MFS in women with HER2-low BC exposed to NAC.
Journal Article
Cancer stem cells : philosophy and therapies
\"An innovative theory proposes a new therapeutic strategy to break the stalemate in the war on cancer. It is called cancer stem cell (CSC) theory, and Lucie Laplane offers a comprehensive analysis, based on an original interdisciplinary approach that combines biology, biomedical history, and philosophy. Rather than treat cancer by aggressively trying to eliminate all cancerous cells--with harmful side-effects for patients--CSC theory suggests the possibility of targeting the CSCs, a small fraction of cells that lie at the root of cancers. CSCs are cancer cells that also have the defining properties of stem cells--the abilities to self-renew and to differentiate. According to this theory, only CSCs and no other cancer cells can induce tumor formation. To date, researchers have not agreed on the defining feature of CSCs--their stemness. Drawing from a philosophical perspective, Laplane shows that there are four possible ways to understand this property: stemness can be categorical (an intrinsic property of stem cells), dispositional (an intrinsic property whose expression depends on external stimuli), relational (an extrinsic property determined by a cell's relationship with the microenvironment), or systemic (an extrinsic property controlled at the system level). Our ability to cure cancers may well depend upon determining how these definitions apply to different types of cancers.\"-- Provided by publisher.
Book
Pembrolizumab-Induced Pancreatitis: Take It With a Grain of Salt
Keytruda (pembrolizumab) is an immunomodulator that prevents the interaction between programmed cell death protein (PD-1) and programmed death ligand (PD-L1/2) on immune cells and tumour cells, thereby preventing T cell dysfunction. At times, mounting a strong immune response against tumour cells may not spare normal cells, leading to a variety of multisystemic adverse effects. With this, we present a case of a 64-year-old male who developed acute pancreatitis after completing eight cycles of Keytruda for castrate-resistant metastatic prostate cancer for six months, after all other causes of pancreatitis were excluded.
Journal Article