Does dose reduction of afatinib affect treatment outcomes of patients with EGFR-mutant metastatic non-small cell lung cancer in real-world clinical practice?

Background: Afatinib can be started at a dose lower than the recommended starting dose of 40 mg/day for the treatment of epidermal growth factor receptor (EGFR)-mutant non-small cell lung cancer (NSCLC), however treatment outcomes in real-world clinical practice remains unclear. Methods: This retrospective study of patients with NSCLC from 18 major hospitals (public, private or university teaching hospitals) enrolled in Malaysia's National Cardiovascular and Thoracic Surgical Database (NCTSD) assessed the efficacy of lower doses of afatinib on treatment outcomes in a real-world clinical practice. Data on clinical characteristics, afatinib dosing, and treatment outcomes for patients included in NCTSD from 1st January 2015 to 31st December 2020 were analyzed. Results: Of the 133 patients studied, 94.7% had adenocarcinoma. Majority of the patients (60.9%) had EGFR exon 19 deletion and 23.3% had EGFR exon 21 L858R point mutation. The mean age of patients was 64.1 years and majority (83.5%) had Eastern Cooperative Oncology Group performance status of 2-4 at diagnosis. The most common afatinib starting doses were 40 mg (37.6%), 30 mg (29.3%), and 20 mg (26.3%) once daily (OD), respectively. A quarter of patients had dose reduction (23.3%) due to side effects or cost constraints. Majority of the patients had partial response to afatinib (63.2%) whilst 2.3% had complete response. Interestingly, the objective response rate was significantly higher (72.3%) with afatinib OD doses of less than 40 mg compared to 40 mg (54.0%) (P=0.032). Patients on lower doses of afatinib were two times more likely to achieve an objective response [odds ratio =2.64; 95% confidence interval (CI): 1.20-5.83; P=0.016]. These patients had a numerically but not statistically longer median time to treatment failure (TTF). Median TTF (95% CI) for the overall cohort was 12.4 (10.02-14.78) months. Median overall survival (95% CI) was 21.30 (15.86-26.75) months. Conclusions: Lower afatinib doses (<40 mg OD) could be equally effective as standard dose in patients with EGFR-mutant advanced NSCLC and may be more suited to Asian patients, minimizing side effects that may occur at higher dosages of afatinib leading to dose interruptions and affecting treatment outcomes.

The Elusive Primary: Metastatic Adenocarcinoma of the Breast Presenting Solely as a Hard Sternal Mass.

BACKGROUND Carcinoma of unknown primary (CUP) is a diverse category of malignancies diagnosed in patients who have metastatic disease but without an identifiable primary tumor at initial presentation. CASE REPORT We report a case of CUP which was later diagnosed to be metastatic adenocarcinoma of the breast in a 62-year-old woman. The patient initially presented to a primary care clinic with an incidental finding of a small hard mass in the middle of the sternum, with no other clinical findings in the breast or axillary lymph nodes. Chest X-ray, ultrasound, and CT scan of the sternum suggested a benign sternal lesion, and a mammogram was normal. Due to the persistence of the mass, a biopsy was performed. The histopathological findings revealed a metastatic adenocarcinoma, most likely from breast origin, with positive estrogen receptor (ER) and mammaglobin on immunohistochemistry studies. The patient subsequently underwent PET scan, repeat mammogram, and MRI of the breast. Following high uptake in the rectum on PET, a colonoscopy was performed, revealing a suspicious rectal mass. The mass was surgically excised, and the final histopathological examination concluded the mass was a second primary adenocarcinoma of the rectum. Genetic analyses for BRCA1 and BRCA2 were negative. CONCLUSIONS This is a rare case of an isolated bone-like lesion on the sternum due to metastatic adenocarcinoma of the breast in a patient with no prior history of breast cancer and lacking any clinical or radiological evidence of breast or axillary lymph node lesions on presentation. The patient was also subsequently diagnosed with 2 primary carcinomas. Thorough clinical examination, extensive radiological investigations, laboratory investigations, histopathological examination, and a multidisciplinary approach are essential in managing CUP.

Acquired radioresistance in EMT6 mouse mammary carcinoma cell line is mediated by CTLA-4 and PD-1 through JAK/STAT/PI3K pathway.

Cancer recurrence is often associated with the acquisition of radioresistance by cancer tissues due to failure in radiotherapy. The underlying mechanism leading to the development of acquired radioresistance in the EMT6 mouse mammary carcinoma cell line and the potential pathway involved was investigated by comparing differential gene expressions between parental and acquired radioresistance cells. EMT6 cell line was exposed to 2 Gy/per cycle of gamma-ray and the survival fraction between EMT6-treated and parental cells was compared. EMT6RR_MJI (acquired radioresistance) cells was developed after 8 cycles of fractionated irradiation. The development of EMT6RR_MJI cells was confirmed with further irradiation at different doses of gamma-ray, and both the survival fraction and migration rates were measured. Higher survival fraction and migration rates were obtained in EMT6RR_MJI cells after exposure to 4 Gy and 8 Gy gamma-ray irradiations compared to their parental cells. Gene expression between EMT6RR_MJI and parental cells was compared, and 16 genes identified to possess more than tenfold changes were selected and validated using RT-PCR. Out of these genes, 5 were significantly up-regulated i.e., IL-6, PDL-1, AXL, GAS6 and APCDD1. Based on pathway analysis software, the development of acquired radioresistance in EMT6RR_MJI was hypothesized through JAK/STAT/PI3K pathway. Presently, CTLA-4 and PD-1 were determined to be associated with JAK/STAT/PI3K pathway, where both their expressions were significantly increased in EMT6RR_MJI compared to parental cells in the 1st, 4th and 8th cycle of radiation. As a conclusion, the current findings provided a mechanistic platform for the development of acquired radioresistance in EMT6RR_MJI through overexpression of CTLA-4 and PD-1, and novel knowledge on therapeutic targets for recurrent radioresistant cancers.

Metastatic Prostate Cancer Synchronous with Male Breast Papillary Ductal Carcinoma in situ: Management Dilemma and Literature Review.

Prostate cancer is common in men, but tumour of the male breast is rare. For these two tumours to be presented synchronously in a male patient is even rarer. The focus of this paper is the case of a 72-year-old man diagnosed with papillary ductal carcinoma in situ after he presented with a unilateral breast mass associated with nipple discharge. Imaging staging for his breast tumour and subsequent prostate biopsy found an incidental synchronous asymptomatic prostate adenocarcinoma as well as bone metastases. He denies risk factors for malignancies and refuses genetic testing. The first part of our discussion will highlight the uncommon occurrence of male breast ductal carcinoma in situ and its management controversies. The subsequent part of our discussion will focus on the association between male breast cancer and prostate cancer, and implication of this on the future treatment of these patients. More importantly, our case will illustrate the challenges in managing dual primaries that present concurrently.

A novel and non-invasive approach utilising nasal washings for the detection of nasopharyngeal carcinoma.

Nasopharyngeal carcinoma (NPC) is an epithelial cancer of the nasopharynx which is highly associated with Epstein-Barr virus (EBV). Worldwide, most of the top 20 countries with the highest incidence and mortality rates of NPC are low- and middle-income countries. Many studies had demonstrated that EBV could be detected in the tissue, serum and plasma of NPC patients. In this study, we explored the potential of assays based on non-invasive nasal washings (NW) as a diagnostic and prognostic tool for NPC. A total of 128 patients were evaluated for NW EBV DNA loads and a subset of these samples were also tested for 27 EBV and human miRNAs shortlisted from literature. EBV DNA and seven miRNAs showed area under the receiver operating characteristic curve (AUC) values of more than 0.7, suggestive of their potential utility to detect NPC. Logistic regression analyses suggested that combination of two NW assays that test for EBNA-1 and hsa-miR-21 had the best performance in detecting NPC. The trend of NW EBV DNA load matched with clinical outcome of 71.4% (10 out of 14) NPC patients being followed-up. In summary, the non-invasive NW testing panel may be particularly useful for NPC screening in remote areas where healthcare facilities and otolaryngologists are lacking, and may encourage frequent testing of individuals in the high risk groups who are reluctant to have their blood tested. However, further validation in an independent cohort is required to strengthen the utility of this testing panel as a non-invasive detection tool for NPC.

Prolonged survival of metastatic hepatocellular carcinoma: a case report.

Management of hepatocellular carcinoma (HCC) generally follows EASL-EORTC clinical practise guideline. We report a case of a 50-year-old man who had multinodular HCC with lung metastases, whose management had deviated from the standard guideline but still survive 5 years after initial diagnosis.