Improving survival in metastatic colorectal cancer through optimized patient selection.

The systemic treatment options for patients with metastatic colorectal cancer have recently expanded with the US Food and Drug Administration approval of fruquintinib being added to previously approved trifluridine/tipiracil with or without bevacizumab and regorafenib. These therapies are recommended for use based on the initial clinical trials that focused on their safety and efficacy in extending overall survival of patients with refractory metastatic disease, as well as later studies, including the ReDOS study that confirmed the dose-escalation strategy of regorafenib to be key in optimizing duration of therapy and preventing side effects. Although more research is needed on how to sequence third-line therapies, data from real-world studies showed that switching from regorafenib to trifluridine/tipiracil with or without bevacizumab allowed patients to have a chemotherapy-free break and led to improved survival, suggesting that there may be a benefit for using regorafenib first. Current treatment guidelines state that each therapy can be given before or after the others. Generally, sequencing considerations in the refractory setting include multiple variables such as tumor characteristics, toxicities, factors that are important to the patient, response to prior lines of therapy, and extent of disease.

Characterization of Incidental Pathogenic Germline Findings Detected via ctDNA among Patients with Non-Small Cell Lung Cancer in a Predominantly Hispanic/Latinx Population.

Pathogenic germline variants (PGVs) may be under-detected as causative etiologies in patients with non-small cell lung cancer (NSCLC). The prevalence of PGVs has been reported between 1 and 15% of patients, depending on the patient population. The rate within Hispanic/Latinx populations remains unknown. We retrospectively analyzed the genomic results (Guardant360, Redwood City, CA, USA) of 878 patients with advanced or metastatic NSCLC at five centers in South Florida, USA, from 2019 to 2022 to analyze the rate of incidental PGVs (iPGVs) identified via circulating cell-free tumor DNA (ctDNA). We then stratified the results by tumor histology, age, gender, race, ethnicity, genetic pathway, and co-mutations. Twenty-one iPGVs were identified (21/878 = 2.4%). Among the 21 iPGVs identified, 14 patients were female (66.7%) and 7 were male (33.3%), with a median age of 67 years and tobacco history of 2.5 pack-years. In total, 52.4% of patients identified as Hispanic/Latinx (n = 11) of any race; 19.0% as Ashkenazi Jewish (n = 4), 9.5% as non-Hispanic/Latinx black (n = 2), and 19.0% as non-Hispanic/Latinx white (n = 4). iPGVs in the homologous recombination repair pathway were solely expressed in this cohort (10 ATM, 8 BRCA2, and 3 BRCA1). In total, 76% (16/21) of patients with iPGVs co-expressed somatic alterations, with 56% (9/16) demonstrating alterations in targetable genes. Overall, our real-world findings offer a point prevalence of iPGVs in patients with NSCLC of diverse populations, such as patients who report Hispanic/Latinx ethnicity.

Splenic Rupture Secondary to Amyloidosis: A Case Report and Review of the Literature.

Amyloidosis is a term describing the extracellular deposit of fibrils composed of subunits of several different normal serum proteins in various tissues. Amyloid light chain (AL) amyloidosis contains fibrils that are composed of fragments of monoclonal light chains. Many different disorders and conditions can lead to spontaneous splenic rupture, including AL amyloidosis. We present a case of a 64-year-old woman with spontaneous splenic rupture and hemorrhage. A final diagnosis of systemic amyloidosis secondary to plasma cell myeloma was made with infiltrative cardiomyopathy and possible diastolic congestive heart failure exacerbation. We also provide a narrative review of all documented cases of splenic rupture associated with amyloidosis from the year 2000 until January 2023, along with the main clinical findings and management strategies.

Novel ATM Gene c.5644 C > T (p.Arg1882*) Variant Detected in a Patient with Pancreatic Adenocarcinoma and Two Primary Non-Small Cell Lung Adenocarcinomas: A Case Report

Ataxia-telangiectasia is an autosomal recessive disorder that usually manifests in childhood due to mutations in the Ataxia-Telangiectasia Mutated (ATM) gene. It is believed that there is an association between this gene mutation/polymorphism and cancer risk, including breast, lung, and pancreatic cancers. We report a rare case of a 69-year-old woman who developed three different primary cancers, including non-small cell lung cancer (NSCLC) in both lungs and pancreatic adenocarcinoma, and was later found to have a rarely reported variant mutation in the ATM gene, namely Exon 39, c.5644 C > T. We hypothesize that the ATM gene, c.5644 C > T mutation could be a plausible contributor in the pathogenesis of these three cancers. This hypothesis has yet to be validated by larger studies that focus on a mechanistic approach involving DNA repair genes such as the ATM. More importantly, this paves the way to developing new patient-specific targeted therapies and inaugurating precision medicine as a cornerstone in cancer therapeutics.

ROS1 altered breast cancers - a distinctive molecular subtype of PR- metastatic breast cancers: Expanding the scope of targeted therapeutics.

BACKGROUND: Breast cancer, one of the leading causes of cancer-related mortality in women worldwide, exhibits wide-ranging histo-morphologic, clinical and molecular diversity. OBJECTIVE: This study compares the genetic alterations of breast tumors with the histo-morphological, hormone receptor status and metastatic "organotropism". MATERIALS AND METHODS: Twenty-two cases of primary invasive breast carcinoma with local/distant metastasis were retrieved from the pathology archives. The status of estrogen and progesterone receptors by immunohistochemistry was recorded along with other pertinent case data. Next generation sequencing was performed on formalin-fixed paraffin embedded blocks of tumor. RESULTS: The mean age of the study subjects was 57.9 ± 13.3 years. TP53 mutation was the most common gene alteration in this study and was seen in 40.9% cases. ROS1 gene was mutated in 44.4% PR negative breast cancers while being wild type in the twelve PR positive tumors. (p = 0.021).STRING interaction network constructed with ROS1 and PR revealed a significantly higher number of interactions in this network than expected (p-value 0.000973). CONCLUSION: This study highlights the significantly higher incidence of ROS1 gene alterations in metastatic PR- breast cancers, with STRING network analysis revealing higher nodal interaction in the nodal network comprised of PR and ROS1 exclusive of ER.

The mutational landscape of upper gastrointestinal adenocarcinomas- A study of similarities and differences.

PURPOSE: The gastrointestinal tract is home to a wide variety of neoplasms. Gastrointestinal adenocarcinomas display distinct prognostic patterns. With the advent of next generation sequencing, attempts are being made to delineate distinct molecular characteristics of these adenocarcinomas from adjoining anatomical sites. METHODS: Thirty-seven cases of upper gastrointestinal adenocarcinomas including those of the esophagus, gastroesophageal junction, stomach, small intestine and gallbladder were retrieved. Next generation sequencing data consisting of base substitutions, copy number variations, indels and rearrangements, in 324 genes, were analyzed for recurrent genetic abnormalities. Statistical analysis was performed using IBM SPSS25 and SAS software. RESULTS: Genetic alterations were found in 181 genes. APC mutations were found in 50% of the esophageal adenocarcinomas, 5% of the gastric adenocarcinomas and 33.3% of the small intestinal adenocarcinomas (p = 0.04). PIK3 gene family mutations were found in 10% of the gastric adenocarcinomas, 66% of the gall bladder adenocarcinomas and 66% of the small intestinal adenocarcinomas (p = 0.002). The mutations were found exclusively in the PIK3 class 1 family. TP53 mutations were more common in tumors with intact DNA mismatch repair protein expression as assessed by immunohistochemistry (p = 0.042). CONCLUSION: In this study, APC gene mutations were found to be more frequent in esophageal and small intestinal adenocarcinomas than previously reported. PIK3 class 1 gene family mutations were found to be more frequent in gallbladder and small intestinal adenocarcinomas. An inverse relationship was found between TP53 mutations and loss of DNA mismatch repair protein expression.

Efficacy and safety of lifileucel, a one-time autologous tumor-infiltrating lymphocyte (TIL) cell therapy, in patients with advanced melanoma after progression on immune checkpoint inhibitors and targeted therapies: pooled analysis of consecutive cohorts of the C-144-01 study.

BACKGROUND: Patients with advanced melanoma have limited treatment options after progression on immune checkpoint inhibitors (ICI). Lifileucel, a one-time autologous tumor-infiltrating lymphocyte (TIL) cell therapy, demonstrated an investigator-assessed objective response rate (ORR) of 36% in 66 patients who progressed after ICI and targeted therapy. Herein, we report independent review committee (IRC)-assessed outcomes of 153 patients treated with lifileucel in a large multicenter Phase 2 cell therapy trial in melanoma. METHODS: Eligible patients had advanced melanoma that progressed after ICI and targeted therapy, where appropriate. Melanoma lesions were resected (resected tumor diameter ≥1.5 cm) and shipped to a central good manufacturing practice facility for 22-day lifileucel manufacturing. Patients received a non-myeloablative lymphodepletion regimen, a single lifileucel infusion, and up to six doses of high-dose interleukin-2. The primary endpoint was IRC-assessed ORR (Response Evaluation Criteria in Solid Tumors V.1.1). RESULTS: The Full Analysis Set consisted of 153 patients treated with lifileucel, including longer-term follow-up on the 66 patients previously reported. Patients had received a median of 3.0 lines of prior therapy (81.7% received both anti-programmed cell death protein 1 and anti-cytotoxic lymphocyte-associated protein 4) and had high disease burden at baseline (median target lesion sum of diameters (SOD): 97.8 mm; lactate dehydrogenase (LDH) >upper limit of normal: 54.2%). ORR was 31.4% (95% CI: 24.1% to 39.4%), with 8 complete responses and 40 partial responses. Median duration of response was not reached at a median study follow-up of 27.6 months, with 41.7% of the responses maintained for ≥18 months. Median overall survival and progression-free survival were 13.9 and 4.1 months, respectively. Multivariable analyses adjusted for Eastern Cooperative Oncology Group performance status demonstrated that elevated LDH and target lesion SOD >median were independently correlated with ORR (p=0.008); patients with normal LDH and SOD

Analysis of Genetic Alterations in Cutaneous Malignant Melanomas Unveils Unique Loco-Regional Variations and Novel Predictors of Metastatic Potential.

ABSTRACT: Cutaneous malignant melanoma is an aggressive cancer that contributes significantly to cancer-related mortality. Over the years, a deeper scrutiny of melanoma biology has led to identification of diverse evolutionary patterns involving various genetic pathways. This study attempts to further understand the genetic landscape of cutaneous malignant melanoma in terms of loco-regional variations and malignant potential. Thirty-five cases of cutaneous malignant melanoma were retrieved from the archives and were classified based on location of the primary tumor and presence or absence of metastatic disease. Next-generation sequencing data consisting of base substitutions, copy number variations, indels, and rearrangements in a total of 324 genes were analyzed for recurrent genetic alterations. Statistical analysis was performed using IBM SPSS26 software. Mutations in KDM gene family were found in 62.5% of the melanomas in the head and neck as compared with 10% in melanomas of the extremity and trunk (P = 0.03). Mutations in the RAS gene family were found in 70% of melanomas in the extremities as compared to 12.5% in melanomas of the head and neck (P = 0.003). BTK gene mutations were found exclusively in melanomas of the head and neck (P = 0.032). CREBBP mutations were seen in 50% of the nonmetastatic melanomas as compared with 3.57% of metastatic melanomas (P = 0.005). This study highlights the loco-regional variations in cutaneous malignant melanoma for genetic alterations involving the KDM, RAS, and BTK gene family. In addition, the CREBBP mutational status is identified as a potential prognostic marker for predicting metastatic potential in cutaneous malignant melanomas.

Title- Genomic landscape of squamous cell carcinoma- Different genetic pathways culminating in a common phenotype.

INTRODUCTION: Squamous cell carcinomas (SqCCs) are the most common solid tumors in humans and are found across multiple organ systems. Although, integrated analysis of genetic alterations divulge similarities between SqCCs from various body sites, certain genes appear to be more frequently mutated in a given SqCC. These subtle differences may hold the key to determining the differentiation characteristics and predicting aggressiveness of tumors. MATERIALS AND METHOD: Fifty-four cases of SqCCs, in which the primary location of the tumor could be ascertained by clinical and radiological findings, were included in this study. Next generation sequencing data was analyzed for recurrent genetic abnormalities. RESULTS: Genetic alterations were found in 219 genes in the 54 cases studied. TP53 mutations were found to be more frequent in pulmonary SqCCs (86.5%) as compared to non-pulmonary SqCCs (58.8%) (p<0.05). NOTCH gene family mutations and CREBBP mutations were limited to non-pulmonary SqCC (p<0.005) and were mutated in 41.2% and 17.6% cases. CONCLUSION: A detailed comparative analysis of the genetic alterations identified by sequencing identified higher frequency of TP53 mutations in lung SqCCs as compared to non-pulmonary SqCCs. NOTCH and CREBPP mutations were found to be absent in lung and head and neck SqCCs and more frequent in SqCCs from other locations.

Retinoblastoma co-repressor 1 (RB) and cyclin-dependent kinase inhibitor (CDKN) as a multi-gene panel for differentiating pulmonary from non-pulmonary origin in metastatic neuroendocrine carcinomas.

BACKGROUND: Neuroendocrine carcinomas (NECs) arise from neuroendocrine cells present throughout the body, and often present with metastases even with small and undetectable primary tumors. Additionally, neuroendocrine differentiation can be seen in carcinomas of non-neuroendocrine origin further complicating the landscape of metastatic NECs. Organ specific immunohistochemical markers such as TTF1, CDX2 and PAX8 are often lost in high grade tumors and may be non-contributory in localizing the primary site. Though NECs share a common cellular origin, they exhibit great variability in biologic behavior, prognosis and treatment based on the primary organ of origin. DESIGN: Twenty one cases of metastatic NECs were retrieved from our archives and were classified based on location of the primary tumor derived from clinical and radiological findings. Next generation sequencing data was retrieved and analyzed for recurrent genetic abnormalities in these cases. Statistical analysis was performed using IBM SPSS25 software. RESULTS: RB1 mutations were exclusive to NECs metastasizing from lung primary and were detected in 5 of 12 (41.6 %) cases (p = 0.04). CDKN gene family (CDKN1B and 2 A) mutations were limited to metatstatic NECs of non-pulmonary origin and were detected in 4 of 9 (44.4 %) cases (p = 0.02). CONCLUSION: The location of the primary tumor in metastatic NECs appears to have significant prognostic and therapeutic implications. But due to the morphological homogeneity, higher grade of tumor, variable sensitivity of immunohistochemical markers, and small, often undetectable primary tumors, the localization of the primary tumor in cases of metastatic NECs is a challenge. In this study, RB1 and CDKN gene family mutations are identified as possible markers for differentiating pulmonary and non-pulmonary origin in metatstatic NECs.

Validation of Microsatellite Instability Detection Using a Comprehensive Plasma-Based Genotyping Panel.

PURPOSE: To analytically and clinically validate microsatellite instability (MSI) detection using cell-free DNA (cfDNA) sequencing. EXPERIMENTAL DESIGN: Pan-cancer MSI detection using Guardant360 was analytically validated according to established guidelines and clinically validated using 1,145 cfDNA samples for which tissue MSI status based on standard-of-care tissue testing was available. The landscape of cfDNA-based MSI across solid tumor types was investigated in a cohort of 28,459 clinical plasma samples. Clinical outcomes for 16 patients with cfDNA MSI-H gastric cancer treated with immunotherapy were evaluated. RESULTS: cfDNA MSI evaluation was shown to have high specificity, precision, and sensitivity, with a limit of detection of 0.1% tumor content. In evaluable patients, cfDNA testing accurately detected 87% (71/82) of tissue MSI-H and 99.5% of tissue microsatellite stable (863/867) for an overall accuracy of 98.4% (934/949) and a positive predictive value of 95% (71/75). Concordance of cfDNA MSI with tissue PCR and next-generation sequencing was significantly higher than IHC. Prevalence of cfDNA MSI for major cancer types was consistent with those reported for tissue. Finally, robust clinical activity of immunotherapy treatment was seen in patients with advanced gastric cancer positive for MSI by cfDNA, with 63% (10/16) of patients achieving complete or partial remission with sustained clinical benefit. CONCLUSIONS: cfDNA-based MSI detection using Guardant360 is highly concordant with tissue-based testing, enabling highly accurate detection of MSI status concurrent with comprehensive genomic profiling and expanding access to immunotherapy for patients with advanced cancer for whom current testing practices are inadequate.See related commentary by Wang and Ajani, p. 6887.

The effects of physical activity on cancer prevention, treatment and prognosis: A review of the literature.

INTRODUCTION: The World Health Organization has reported that approximately 35% of cancer-related deaths are attributed to modifiable risk factors. Among the most important risk factors amenable to modification are obesity and lack of physical activity. The purpose of this article is to review the current evidence of the benefits of physical activity in various types of cancer. METHODS: A PubMed search for the key words "physical activity and cancer" as well as "exercise and cancer" was used to identify all indexed publications on this topic for potential utilization in this review. One MET was defined as the amount of oxygen consumed while a person is sitting quietly and is about 3.5 mL O2/kg body weight/min. MET represents the ratio of the working metabolic rate to the resting metabolic rate. RESULTS: Routine physical activity was found to be associated with a reduced incidence of several of the most common malignancies, including colon, breast, lung, and endometrial cancer as well as many others. Physical activity also appears to reduce all-cause mortality and cancer-related mortality among patients with breast and colon cancer, and may improve the functional status and quality of life for these patients during cancer therapy. CONCLUSIONS: The benefits of physical activity in the prevention and progression of cancer patients are multiple. However, the strength of the available evidence is limited by the observational nature of most studies. Given the probable improvement in prevention, mortality, and quality of life with structured physical activity in different malignancies, it is important that healthcare providers discuss physical activity programs with their cancer patients. Larger randomized trials are recommended.

An Occult Malignancy Behind a Demyelinating Disease: POEMS Syndrome.

We report a case of a 38-year-old man presenting with bilateral lower extremity weakness and paresthesias that progressed during a 4-month period to severe polyneuropathy forcing the patient to be bed bound. Throughout his multiple hospitalizations, he was treated erroneously for chronic inflammatory demyelinating polyneuropathy, without significant improvement in his symptoms. In addition, he developed hepatosplenomegaly (organomegaly); endocrinopathies such as diabetes mellitus, central hypogonadism, and hypothyroidism; monoclonal spike evidenced in the serum electrophoresis; and hyperpigmentation of skin, altogether consistent with POEMS syndrome. During his last hospitalization he developed excruciating pain on his left hip, and imaging revealed the presence of a 9 × 6 cm osteolytic mass with sclerotic rim in the left acetabulum. Biopsy of the mass confirmed an isolated IgG lambda plasmacytoma. The patient received radiation to his left acetabular lesion followed by left hip replacement. Subsequently, the patient underwent autologous bone marrow transplant. Eighteen months after his initial presentation, he had satisfactory clinical response and is functional without significant limitations. POEMS syndrome is a rare paraneoplastic syndrome secondary to an underlying plasma cell disorder, which can oftentimes be overlooked and misdiagnosed. The median age of presentation is 51 years, and only 31% of the cases occur in fairly young patients under the age of 45 as evidenced in this case. As clinicians, we should be aware of the constellation of features associated with POEMS syndrome and be able to recognize them promptly.

Gastric small-cell carcinoma found on esophagogastroduodenoscopy: a case report and literature review.

Introduction. Characterized as an undifferentiated, neuroendocrine tumor arising from totipotent stem cells, small-cell carcinoma (SCC) most commonly arises from the lung. Extrapulmonary small-cell carcinomas (ESCC) are rare and account for only four percent of SCC. Gastric ESCC, more commonly seen in Japanese male patients in their seventh decade of life, accounts for approximately 0.1 percent of ESCC. Case Presentation. A 75-year-old Hispanic male presented with a several week history of worsening epigastric pain with nausea and vomiting. Computer tomography (CT) of the abdomen and pelvis showed a large heterogeneous mass involving the posterior gastric wall with diffuse extension into the gastric cardia. Esophagogastroduodenoscopy (EGD) revealed a large fungating mass in the lesser curvature of the stomach. Biopsy of the mass revealed small-cell carcinoma of the stomach. The patient was diagnosed with extensive/stage 4 disease and started on chemoradiation. Discussion. Our case, of a very rare condition highlights, the importance of recognizing atypical pathologic diagnoses. More research will need to be conducted with GSCC patients in order to better characterize disease pathogenesis, genetic mutations, and optimal disease management. The hope is to identify biomarkers that will identify patients earlier in their disease course when cure is possible.

A De Novo Germline APC Mutation (3927del5) in a Patient with Familial Adenomatous Polyposis: Case Report and Literature Review.

INTRODUCTION: Characterized by the development of hundreds to thousands of colonic adenomas, classic familial adenomatous polyposis (FAP) is one of the most common hereditary syndromes associated with an increased risk of colorectal cancer. Several studies have attempted to correlate specific APC mutations with clinical phenotype.6 However, there is considerable variability in the expression of specific phenotypes within families and among individuals with identical mutations.7 CASE PRESENTATION: A 30 year-old Hispanic female presented to the emergency department with a 2-week history of persistent, worsening, left lower quadrant abdominal pain. She had no family history of malignancy. Sigmoidoscopy revealed innumerable polyps in the rectum and sigmoid colon and a large mass in the sigmoid colon. Biopsy of the mass revealed a moderately differentiated adenocarcinoma invading the subserosa. Endoscopy revealed innumerable polyps. Genetic testing of the patient via southern blot revealed a germline APC mutation 3927del5, resulting in a premature truncation of the APC protein at amino acid position 1312. CONCLUSION: Genetic information has only recently started being incorporated into clinical care. More research and randomized clinical trials need to be conducted to definitively characterize random mutations. Once these mutations are further understood, FAP patients may be able to be risk stratified and this may ultimately improve the screening, diagnosis, and treatment of this rare condition.

Inter-tumor heterogeneity.

Advances in the molecular study of cancer have focused on biomarkers in the setting of tumor-driving mutations within the great heterogeneity of the tumor genomic landscape. It is clearly recognized now that even two tumors originating from the same organ even if histological they appear similar their behavior and response to therapy can be different. These findings have increased interest and research to find truly prognostic and predictive biomarkers to serve as tools in better assessing the natural course of disease and response to treatments in the hope of truly individualizing cancer therapy in the future.