Comprehensive molecular profiling identifies actionable biomarkers for patients from Thailand and the United Arab Emirates with advanced malignancies.

Background: Comprehensive molecular profiling of tissue samples that can help guide therapy management is not widely available across the globe. Methods: Comprehensive molecular profiling through Caris Molecular Intelligence involves the analysis of DNA through next-generation sequencing, chromogenic or fluorescent in situ hybridization, pyrosequencing, and copy number alterations; RNA through whole-transcriptome sequencing and multiplex PCR of RNA; and protein through immunohistochemistry. Results: Here we describe the experience of molecular profiling of tumor tissue samples from patients diagnosed with advanced solid tumors and treated in two countries, the United Arab Emirates and Thailand. Tumor cancer cases submitted to Caris Life Sciences (Phoenix, Arizona, USA) for molecular profiling from the UAE and Thailand were retrospectively analyzed (data accessed between 2019 and 2020) for their molecular alterations and clinical biomarkers, without regard to ethnicity. A total of 451 samples from 35 distinct types of advanced cancers were examined for mutations, amplifications, overexpression, exon copy number alterations, microsatellite instability, deficient mismatch repair, tumor mutational burden, and fusions. Interrogating each step of the biological pathway, from DNA to RNA to distinct protein, identified an alteration with an associated therapy for 75% of these tumor samples. The most common alterations identified included elevated PDL-1 that can be targeted with an immune checkpoint inhibitors and amplification of HER2 for which a variety of anti HER2 therapies are available. Conclusion: Comprehensive molecular profiling in patients with advanced malignancies can help optimize therapeutic management allowing for improved prognostic outcome.

Discordance in Recommendation Between Next-Generation Sequencing Test Reports and Molecular Tumor Boards in India.

PURPOSE: Accurate understanding of the genomic and transcriptomic data provided by next-generation sequencing (NGS) is essential for the effective utilization of precision oncology. Molecular tumor boards (MTBs) aim to translate the complex data in NGS reports into effective clinical interventions. Often, MTB treatment recommendations differ from those in the NGS reports. In this study, we analyze the discordance between these recommendations and the rationales behind the discordances, in a non-high-income setting, with international input to evaluate the necessity of MTB in clinical practice. METHODS: We collated data from MTB that were virtually hosted in Chennai, India. We included patients with malignancies who had NGS reports on solid tissue or liquid biopsies, and excluded those with incomplete data. MTB forms and NGS reports of each clinical case were analyzed and evaluated for recommendation concordance. Concordance was defined as an agreement between the first recommendation in the MTB forms and the therapeutic recommendations suggested in the NGS report. Discordance was the absence of the said agreement. The rationales for discordance were identified and documented. RESULTS: Seventy MTB reports were analyzed with 49 cases meeting the inclusion criteria. The recommendation discordance was 49% (24 of 49). Discordant recommendations were mainly due to low level of evidence for the drug (75% of cases). CONCLUSION: The discordance between MTB and NGS vendor recommendations highlights the clinical utility of MTB. The educational experiences provided by this initiative are an example of how virtual academic collaborations can enhance patient care and provider education across geographic borders.

Entrectinib for NTRK Fusion-Positive Metastatic Melanoma Progressing on Combined PD-1 and CTLA-4 Inhibition: A Case Report.

Introduction: The burden of melanoma is increasing globally. Despite the use of immunotherapy and targeted therapy, the prognosis of metastatic melanoma remains relatively poor. The integration of comprehensive molecular profiling can lead to the detection of actionable biomarkers and the expansion of treatment options, thereby prolonging cancer patient survival. Case Presentation: We herein present the case of a female 54-year-old patient diagnosed with melanoma of the right knee, for which she underwent surgery. Patient showed progression of disease after 10 cycles of adjuvant nivolumab. Ipilimumab (1 mg/kg every 3 weeks) was added to the treatment regimen but no clinical improvement was observed. Molecular profiling was conducted based on patient tissue, and an ANXA2-NTRK3 fusion was detected in the tumor. This specific fusion has not been previously reported; however, it is in-frame and similar to other known oncogenic NTRK fusions. At the time of entrectinib initiation, the patient had clear disease progression on the right leg on standard of care immunotherapy. She was commenced on entrectinib 200 mg once daily for 2 weeks. Dose escalation was attempted, and treatment intensity was managed based on drug tolerability. Good treatment response was observed on laboratory and radiologic parameters. As of September 2023, i.e., 2.5 years after treatment initiation, patient disease continues to be controlled with entrectinib. Conclusion: Profiling of advanced tumors is important to determine the presence of agnostic markers that can be targeted and ultimately improve the prognostic outcome of patients after the failure of standard of care.

Indirect Treatment Comparison of First-Line CDK4/6-Inhibitors in Post-Menopausal Patients with HR+/HER2- Metastatic Breast Cancer.

Background: CDK4/6-inhibitors have demonstrated similar efficacy and are considered an effective first-line endocrine treatment of patients with hormone-receptor positive (HR+)/human-epidermal-growth-factor-receptor-2 negative (HER2-) metastatic breast cancer (MBC) in the endpoint of progression-free survival (PFS). Amongst these, palbociclib was first to achieve regulatory approval, followed subsequently by ribociclib and abemaciclib. However, recent updates of overall survival (OS) showed inconsistencies in the OS benefit for palbociclib compared with the other two CDK4/6-inhibitors. With the lack of head-to-head comparison studies, our study sought to compare indirect survival outcomes between CDK4/6-inhibitors in this setting using a novel reconstructive algorithm. Methods: Phase III randomized trials comparing first-line aromatase inhibitor with/without a CDK4/6-inhibitor in post-menopausal patients with HR+/HER2- MBC were identified through systemic review and literature search of online archives of published manuscripts and conference proceedings. A graphical reconstructive algorithm was utilized to retrieve time-to-event data from reported Kaplan-Meier OS and PFS plots to allow for comparison of survival outcomes. Survival analyses were conducted with Cox proportional-hazards model with a shared-frailty term. Results: Three randomized phase III trials-PALOMA-2, MONALEESA-2 and MONARCH-3-comprising 1827 patients were included. Indirect pairwise comparisons of all CDK4/6-inhibitors showed no significant PFS differences (all p > 0.05). Likewise, indirect treatment comparison between ribociclib vs. palbociclib (one-stage: HR = 0.903, 95%-CI: 0.746-1.094, p = 0.297), abemaciclib vs. palbociclib (one-stage: HR = 0.843, 95%-CI: 0.690-1.030, p = 0.094) and abemaciclib vs. ribociclib (one-stage: HR = 0.933, 95%-CI: 0.753-1.157, p = 0.528) failed to demonstrate a significant OS difference. Conclusions: Findings from this indirect treatment comparison suggest no significant PFS or OS differences between CDK4/6-inhibitors in post-menopausal patients with HR+/HER2- MBC.

Practical notes on the current ESMO consensus guidelines for the management of patients with metastatic colorectal cancer in resource-constrained environments of low- to middle-income countries.

Letter (no abstract).

Spotlight on International Quality: COVID-19 and Its Impact on Quality Improvement in Cancer Care.

This report from ASCO's International Quality Steering Group summarizes early learnings on how the COVID-19 pandemic and its stresses have disproportionately affected cancer care delivery and its delivery systems across the world. This article shares perspectives from eight different countries, including Austria, Brazil, Ghana, Honduras, Ireland, the Philippines, South Africa, and the United Arab Emirates, which provide insight to their unique issues, challenges, and barriers to quality improvement in cancer care during the pandemic. These perspectives shed light on some key recommendations applicable on a global scale and focus on access to care, importance of expanding and developing new treatments for both COVID-19 and cancer, access to telemedicine, collecting and using COVID-19 and cancer registry data, establishing measures and guidelines to further enhance quality of care, and expanding communication among governments, health care systems, and health care providers. The impact of the COVID-19 pandemic on cancer care and quality improvement has been and will continue to be felt across the globe, but this report aims to share these experiences and learnings and to assist ASCO's international members and our global fight against the pandemic and cancer.

Reporting quality of practice guidelines on colorectal cancer: evaluation using the RIGHT reporting checklist.

BACKGROUND: Clinical practice guidelines are an essential tool for translating evidence into practice. Reporting Items for Practice Guidelines in Healthcare (RIGHT) checklist assists to guide the reporting in guidelines. We used RIGHT to assess the reporting completeness and quality of guidelines on colorectal cancer (CRC). METHODS: We searched the electronic databases Medline (via PubMed), Chinese National Knowledge Infrastructure (CNKI), Wanfang and Chinese Biomedical Literature (CBM) from January 1st, 2018 to December 1st, 2020 for guidelines on CRC. Websites of guideline development organizations were also searched. Two investigators assessed the reporting quality of the included guidelines, and calculated the numbers of guidelines that were compliant with each RIGHT checklist item and the mean proportions of reported items for each of the seven RIGHT checklist domains. RESULTS: Twenty-seven colorectal guidelines were included. The proportions of reported items in each RIGHT domain were 71.0% for Basic information, 66.2% for Background, 45.9% for Evidence, 68.8% for Recommendations, 24.1% for Review and quality assurance, 33.3% for Funding and declaration and management of interests, and 40.7% for Other information. CONCLUSIONS: The reporting quality of colorectal guidelines was moderate. A systematic use of the RIGHT checklist during the development process could improve the reporting quality of guidelines in the future.

Optimizing treatment selection, and sequencing decisions for Management of HR-Positive, HER2-Negative advanced breast cancer - Proceedings from breast cancer expert group meeting.

PURPOSE: The therapeutic landscape of hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-) metastatic breast cancer (mBC) has evolved considerably with the introduction of newer targeted agents and their combinations with endocrine therapies. In this scenario, optimizing treatment selection and sequencing is daunting for clinicians. The purpose of this review is to provide evidence-based answers to key clinical questions on treatment selection and sequencing for the management of HR + HER2 - mBC. DESIGN: A panel of nine key opinion leaders from Argentina, Brazil, Colombia, Mexico, Moscow, Singapore, South Korea, Taiwan, and UAE convened in October 2018. They reviewed the literature and formulated answers to clinical questions on optimizing the management of HR + HER2 - mBC. RESULTS: Evidence-based answers were formulated for: (1) optimal initial treatment choice; (2) ovarian function suppression, optimal endocrine partner, and role of cyclin-dependent kinase 4/6 (CDK4/6) inhibitors (in premenopausal women); (3) better first-line standard of care than aromatase inhibitors; (4) preferred second-line treatment; (5) treatment of oligometastatic disease; (6) factors influencing first-line single-agent endocrine therapy choice; (7) influence of endocrine resistance on treatment selection; (8) optimal maintenance regimen in visceral crisis; and (9) need for a breast cancer registry for patients with HR + HER2 - mBC. The panel also proposed a treatment-sequencing algorithm for the management of HR + HER2 - mBC. CONCLUSION: The current article will serve as a comprehensive guide for optimizing the management of HR + HER2 - mBC. The proposed breast cancer registry will help identify unmet needs and develop strategic regional policies to help improve access to optimized care for HR + HER2 - mBC.

Impact of geography on prognostic outcomes of 21,509 patients with metastatic colorectal cancer enrolled in clinical trials: an ARCAD database analysis.

BACKGROUND: Benchmarking international cancer survival differences is necessary to evaluate and improve healthcare systems. Our aim was to assess the potential regional differences in outcomes among patients with metastatic colorectal cancer (mCRC) participating in international randomized clinical trials (RCTs). DESIGN: Countries were grouped into 11 regions according to the World Health Organization and the EUROCARE model. Meta-analyses based on individual patient data were used to synthesize data across studies and regions and to conduct comparisons for outcomes in a two-stage random-effects model after adjusting for age, sex, performance status, and time period. We used mCRC patients enrolled in the first-line RCTs from the ARCAD database, which provided enrolling country information. There were 21,509 patients in 27 RCTs included across the 11 regions. RESULTS: Main outcomes were overall survival (OS) and progression-free survival (PFS). Compared with other regions, patients from the United Kingdom (UK) and Ireland were proportionaly over-represented, older, with higher performance status, more frequently male, and more commonly not treated with biological therapies. Cohorts from central Europe and the United States (USA) had significantly longer OS compared with those from UK and Ireland (p = 0.0034 and p < 0.001, respectively), with median difference of 3-4 months. The survival deficits in the UK and Ireland cohorts were, at most, 15% at 1 year. No evidence of a regional disparity was observed for PFS. Among those treated without biological therapies, patients from the UK and Ireland had shorter OS than central Europe patients (p < 0.001). CONCLUSIONS: Significant international disparities in the OS of cohorts of mCRC patients enrolled in RCTs were found. Survival of mCRC patients included in RCTs was consistently lower in the UK and Ireland regions than in central Europe, southern Europe, and the USA, potentially attributed to greater overall population representation, delayed diagnosis, and reduced availability of therapies.

Optimizing the management of HER2-negative metastatic breast cancer in the era of PARP inhibitors-proceedings from breast cancer expert group meeting.

The therapeutic landscape of human epidermal growth factor receptor 2-negative (HER2-) metastatic breast cancer (mBC) has evolved considerably with the introduction of newer targeted agents such as poly-ADP ribose polymerase inhibitors (PARPi), novel chemotherapeutic agents, immunotherapy, and endocrine therapies. In this scenario, optimizing the appropriate treatment sequence is a daunting task for clinicians. To develop evidence-based answers to key clinical questions on treatment selection and appropriate treatment sequence for the management of patients with HER2- mBC in the era of PARPi, a breast cancer expert group meeting was convened. The expert panel comprised of eight key opinion leaders from Argentina, Brazil, Colombia, Egypt, Mexico, Moscow, South Korea, and the United Arab Emirates, who convened and reviewed the literature, discussed the clinical practices across the participating regions, and formulated answers to key clinical questions for optimizing the management of HER2- mBC. In this review, evidence-based answers have been provided pertaining to (I) the specific mBC population to be considered for BRCA testing, optimal time point of BRCA testing, and genetic counselling in mBC patients; (II) the role of PARPi versus platinum therapy in HER2- mBC patients in the metastatic setting; (III) sequencing treatment in metastatic triple-negative breast cancer (TNBC) and hormone receptor-positive HER2- mBC patients, and defining the place of PARPi in the sequencing algorithms; and (IV) the need for a breast cancer registry for patients with HER2- mBC. This expert review will serve as a comprehensive guide to clinicians for optimizing BRCA testing and managing patients with BRCA mutation (BRCAm) and HER2- mBC. The data collected from the proposed HER2- mBC registry will help understand the treatment practices, identify unmet needs, and develop strategic policies regionally to help improve access to optimized care of HER2- mBC.

Palbociclib and beyond for the treatment of HR + HER2- metastatic breast cancer: an Asian-Pacific perspective and practical management guide on the use of CDK4/6 inhibitors.

Breast cancer is the most frequent cancer amongst women worldwide including in Asia where the incidence rate is rapidly increasing. Even with treatment, around 30% of patients with early breast cancer progress to metastatic disease, with hormone receptor positive (HR+) and human epidermal growth factor receptor 2 negative (HER2-) breast cancer the most common phenotype. First-line endocrine therapy targeting the estrogen receptor signaling pathway provides a median progression-free survival or time to progression of 6-15 months in HR + HER2- metastatic breast cancer. Recently, cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitors, combined with endocrine therapy, have achieved more than two years median progression-free survival in HR + HER2- metastatic breast cancer. However, the characteristics of the Asian breast cancer population differ from those of Western populations and need to be considered when selecting a suitable treatment. Breast cancer is diagnosed at a younger age in Asian populations and late stage at presentation is generally more common in low-/middle-income countries than high-income countries. Consequently, the proportion of premenopausal women with metastatic breast cancer is higher in Asian compared with Western populations. While CDK4/6 inhibitors have been approved in the USA (FDA) since 2015, experience with them in Asia is more limited. We review the experience with the CDK4/6 inhibitor palbociclib in Asian patients with HR + HER2- metastatic breast cancer and provide guidance on the use of palbociclib in these patients.

Understanding the benefits and challenges of first-line cyclin-dependent kinases 4 and 6 inhibitors in advanced breast cancer among postmenopausal women.

Endocrine therapy (ET) has been regarded for many years as the standard treatment for patients with hormone receptor-positive (ER+), HER2-negative (HER2-) advanced breast cancer (ABC) without visceral crisis. However, the efficacy of single-agent ET is constrained by the development of resistance, attributed to alterations in several intracellular signaling pathways, including those related to cell cycle dysregulation. The cyclin-dependent kinases 4 and 6 (CDK4/6) are principal regulators of cell cycle progression from the G1-phase into the DNA synthesis (S)-phase. In vitro inhibition of CDK4/6 activity has potent antiproliferative properties against luminal breast cancer cell lines, which are enhanced when combined with traditional ET. This has led to a substantial interest in targeting this pathway to overcome endocrine resistance in the clinic. Three selective CDK4/6 inhibitors (palbociclib, ribociclib, and abemaciclib) have been approved as first-line therapy in combination with an aromatase inhibitor, or fulvestrant in the case of ribociclib in patients with ER+/HER2- ABC. To date, there is no clue as to which subgroup of patients might benefit most from these combinations. Here, we outline some of the established approaches to overcome endocrine resistance, with special emphasis on the unique mechanism of action of CDK4/6 inhibitors.

The evolving role of immune oncology in colorectal cancer.

Metastatic colorectal cancer still remains an essentially non curable disease. However, with advances in chemotherapeutic and personalizing therapeutic approaches with the incorporation of targeted therapy such as anti-EGFR and anti-VEGF agents survival associated with metastatic colorectal cancer has certainly improved over the last two decades. Patients who are not amenable to surgery median survival remain approximately 2 to 3 years. In an attempt to improve prognostic outcome over the last decade research has focused on therapeutic options geared towards harnessing the immune system with success observed with the use of immune checkpoint inhibitors in the realm of a number of solid tumors including lung and renal cancer. The use of immunomodulatory therapeutic approaches for the management of unselected advanced colorectal cancer has not seen the same success with low response rates reported. The turning point was our recent understanding that efficacy of immunotherapy was limited to a subset of patients with hyper mutated microsatellite instability-high (MSI-H) tumors. This review will focus on summarizing available knowledge on the immunological and molecular landscape of colorectal cancer that can help determine subsets of immunogenic CRC, determine potential predictive markers to help select patients for immunotherapeutic approaches as well looking at the existing evidence of incorporating immune checkpoint inhibitors to the therapeutic management of patients with mCRC.

Targeting the host immune system: PD-1 and PD-L1 antibodies and breast cancer.

PURPOSE OF REVIEW: This article describes the role of the PD-1 axis and reviews current data and future directions inhibiting PD-1 and PD-L1 in breast cancer. RECENT FINDINGS: Four phase I monotherapy expansion trials in patients with metastatic breast cancer have demonstrated low but durable single agent responses to PD-1 and PD-L1 inhibitors, ranging from 4.8 to 19%. Higher response rates are seen in triple negative breast cancer, compared with hormone receptor positive disease. Variability in requirements for tumor PD-L1 expression, and variations in testing complicate cross trial comparisons. A fifth phase Ib trial reported a 38% response rate in metastatic triple negative breast cancer treated with the combination of a PD-L1 inhibitor and nab-paclitaxel chemotherapy. Treatment is generally well tolerated, with low rates of immune toxicity including hypothyroidism, pneumonitis, hepatitis, colitis, and hypophysitis, occurring even months after the end of therapy. SUMMARY: Immune checkpoint inhibitor therapy has recently been shown to have clinical efficacy in the treatment of breast cancer. The most compelling data are in the triple negative subtype, with responses documented in hormone receptor positive disease as well. Numerous trials are evaluating various combination strategies and biomarkers in early and late stage disease to enhance immunogenicity and response.

Ten-year survival in women with primary stage IV breast cancer.

PURPOSE: To evaluate breast cancer-specific survival at 10 years in patients who present with primary stage IV breast cancer, and to determine whether survival varies with age of diagnosis. METHODS: We retrieved the records of 25,323 women diagnosed with primary stage IV breast cancer in the surveillance, epidemiology, and end results 18 registries database from 1990 to 2012. For each case, we extracted information on age at diagnosis, tumour size, nodal status, oestrogen receptor status, progesterone receptor status, ethnicity, cause of death and date of death. The Cox proportional hazards model was used to estimate the unadjusted and adjusted hazard ratio (HR) of death due to stage IV breast cancer, according to age group. RESULTS: Among 25,323 women with stage IV breast cancer, 2542 (10.0 %) were diagnosed at age 40 or below, 5562 (22.0 %) were diagnosed between ages 41 and 50 and 17,219 (68.0 %) were diagnosed between ages 51 and 70. After a mean follow-up of 2.2 years, 16,387 (64.7 %) women died of breast cancer (median survival 2.3 years). The ten-year actuarial breast cancer-specific survival rate was 15.7 % for women ages 40 and below, 14.9 % for women ages 41-50 and 11.7 % for women ages 51 to 70 (p < 0.0001). In an adjusted analysis, the risk of death from breast cancer at 10 years was significantly lower for women ages 40 and below (HR 0.78; 95 % CI 0.74-0.82; p < 0.0001) and for women ages 41-50 (HR 0.82; 95 % CI 0.79-0.85; p < 0.0001), compared to women ages 51-70. CONCLUSIONS: Approximately 13 % of women with primary stage IV breast cancer survive 10 years after diagnosis. Women diagnosed with stage IV breast cancer before age 50 have better survival at 10 years compared to older women.

Oxaliplatin-related neuropathy in Indian patients - no difference between generic and original molecules.

BACKGROUND: Oxaliplatin-induced neuropathy is a dose-limiting toxicity that significantly affects patients' quality of life. The aim of this study was to compare its occurrence between a generic versus the original molecule in Indian patients. MATERIALS AND METHODS: Between August 2012 and July 2013, 163 patients receiving oxaliplatin were prospectively enrolled. A data recording form was used in the clinic to record detailed information. RESULTS: The median age of patients was 55 years (range, 19-79). Chemotherapy regimens used included: capecitabine, oxaliplatin (59), epirubicin, oxaliplatin, and capecitabine (20), docetaxel, oxaliplatin, and capecitabine (11), 5-FU, leucovorin, oxaliplatin (9), and gemcitabine-oxaliplatin (64). The median cumulative dose of oxaliplatin was 780 mg/m2. Eighty patients received the original version and 83 the generic one. Overall, 63 patients (38%) developed neuropathy. There was no significant difference in the incidence of neuropathy between the two forms of oxaliplatin used (P = 0.50). Forty-nine percent of female patients had neuropathy as compared to 30% of male patients (P = 0.014). Older patients had a trend toward a higher incidence of neuropathy: 44% of patients above age fifty developed neuropathy compared to 30% of patients younger than 50 (P = 0.06). CONCLUSION: This is the first study to specifically show that neuropathy rates do not vary with the use of generic versus original oxaliplatin.