Charting New Paths in Cancer Research: Insights from the Frontiers in Cancer Science Conference 2024.

The 16th annual Frontiers in Cancer Science conference convened leading experts to discuss the latest developments in cancer research. Key research themes included mechanisms of treatment resistance and innovative strategies to target resistant cancer cells, metabolic plasticity and its therapeutic vulnerabilities, modulation of the tumor microenvironment to enhance therapeutic efficacy, recent advances in immunotherapies and engineered immune cells, and strategies to overcome tumor immune evasion. The conference also highlighted the development of advanced spatial transcriptomic technologies as a powerful tool to decipher tumor heterogeneity and identify novel therapeutic targets.

Pembrolizumab monotherapy for previously treated metastatic HER2-negative breast cancer with germline deletion: results of the phase II AUROR study.

Background: A common germline deletion polymorphism in the gene increases the rate of somatic hypermutation in breast cancer, which in turn is associated with greater neoantigen burden and immune activation. This phase II study evaluated the impact of the deletion polymorphism on the response to pembrolizumab monotherapy in metastatic HER2-negative breast cancer patients.

Methods: Eligible patients had a confirmed diagnosis of metastatic HER2-negative breast cancer, 1-3 prior lines of therapy, and documented homozygous or heterozygous germline deletion of .

Part II: consensus statements and expert recommendations for BRCA-associated breast cancer in the Asia-Pacific region: clinical management.

Introduction: Existing guidelines have practical gaps in decision and treatment sequencing for BRCA germline pathogenic variant breast cancers. This paper aims to develop clinical-practice consensus guidelines to address these gaps in the clinical management of BRCA germline pathogenic variants-associated breast cancer in the Asia-Pacific region.

Methods: An expert panel of 16 medical oncologists, geneticists, and breast cancer surgeons from the Asia-Pacific region arrived at 25 statements.

Part I: consensus statements and expert recommendations for -negative early breast cancer in the Asia-Pacific region: diagnosis and risk assessment.

Introduction: In the Asia-Pacific region, there is increasing contention on the practical challenges involved in managing human epidermal growth factor receptor 2 (HER2)-negative early breast cancer (eBC). This modified Delphi consensus explores gaps in genetic counselling (GC) and genetic testing (GT), and clinical risk assessment for -negative eBC.

Methods: An expert panel of 16 Asia-Pacific medical oncologists, geneticists, and breast cancer surgeons arrived at 33 statements.

NEXUS: a phase I dose escalation study of selinexor plus nivolumab and ipilimumab in Asian patients with advanced/metastatic solid malignancies.

Background: Selinexor (SEL) is an oral inhibitor of nuclear export protein Exportin 1 (XPO1) previously shown to upregulate programmed cell death protein 1 (PD-L1) and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) expression.

Objective: To investigate the safety and antitumor activity of SEL, nivolumab (NIVO), and ipilimumab (IPI) in Asian patients with treatment-refractory solid organ cancers.

Design: Phase I study of escalating doses of SEL in combination with NIVO + IPI.

Cancer type and gene signatures associated with breakthrough infections following COVID-19 mRNA vaccination.

We used epidemiological data from 21195 patients with cancer and 180407 matched controls, including in-depth analyses in 216 cancer patients, to discover clinical and molecular determinants that predispose cancer patients to breakthrough infections. Patients with B cell malignancies, with differential expression of CD24, CDK14 and PLEKHG1, were most susceptible to breakthrough infections, suggesting that these patients may require more booster immunisations to ameliorate cellular responses and immune protection against COVID-19.

Safety and feasibility of concomitant scalp cooling and limb cryocompression to prevent paclitaxel-induced alopecia and neuropathy.

Introduction: Scalp cooling is standard-of-care for prevention of chemotherapy-induced alopecia (CIA), with proven safety and efficacy. Limb cryotherapy has shown promise in preventing chemotherapy-induced peripheral neuropathy (CIPN). The safe application of concomitant scalp and limb cryotherapies during chemotherapy is crucial due to concerns about potential interactions, including central hypothermia, yet limited data exist on their safe delivery in this context.

Adjuvant Atezolizumab for Early Triple-Negative Breast Cancer: The ALEXANDRA/IMpassion030 Randomized Clinical Trial.

Importance: Triple-negative breast cancer is an aggressive subtype with a high incidence in young patients, a high incidence in non-Hispanic Black women, and a high risk of progression to metastatic cancer, a devastating sequela with a 12- to 18-month life expectancy. Until recently, one strategy for treating early-stage triple-negative breast cancer was chemotherapy after surgery. However, it was not known whether the addition of immune therapy to postsurgery chemotherapy would be beneficial.

Scalp cooling therapy for chemotherapy-induced hair loss in patients with breast or gynecological cancers-an Asian tertiary institution experience.

Purpose: Scalp cooling therapy (SCT) improves chemotherapy-induced alopecia (CIA), but there are few published data about its efficacy in an Asian-predominant population. We report our tertiary institution experience of SCT in patients with breast or gynaecological cancers undergoing chemotherapy.

Methods: The Paxman scalp cooling system was employed for eligible women with breast or gynaecological cancers receiving anthracycline or taxane-based chemotherapy.

Molecular profiling of metastatic breast cancer and target-based therapeutic matching in an Asian tertiary phase I oncology unit.

Introduction: Molecular profiling of metastatic breast cancer (MBC) through the widespread use of next-generation sequencing (NGS) has highlighted actionable mutations and driven trials of targeted therapy matched to tumour molecular profiles, with improved outcomes reported using such an approach. Here, we review NGS results and treatment outcomes for a cohort of Asian MBC patients in the phase I unit of a tertiary centre.

Methods: Patients with MBC referred to a phase I unit underwent NGS via Ion AmpliSeq Cancer Hotspot v2 (ACH v2, 2014-2017) prior to institutional change to FoundationOne CDx (FM1; 2017-2022).

Machine learning unveils an immune-related DNA methylation profile in germline DNA from breast cancer patients.

Background: There is an unmet need for precise biomarkers for early non-invasive breast cancer detection. Here, we aimed to identify blood-based DNA methylation biomarkers that are associated with breast cancer.

Methods: DNA methylation profiling was performed for 524 Asian Chinese individuals, comprising 256 breast cancer patients and 268 age-matched healthy controls, using the Infinium MethylationEPIC array.

Fine-mapping analysis including over 254,000 East Asian and European descendants identifies 136 putative colorectal cancer susceptibility genes.

Genome-wide association studies (GWAS) have identified more than 200 common genetic variants independently associated with colorectal cancer (CRC) risk, but the causal variants and target genes are mostly unknown. We sought to fine-map all known CRC risk loci using GWAS data from 100,204 cases and 154,587 controls of East Asian and European ancestry. Our stepwise conditional analyses revealed 238 independent association signals of CRC risk, each with a set of credible causal variants (CCVs), of which 28 signals had a single CCV.

A glycolytic metabolite bypasses "two-hit" tumor suppression by BRCA2.

Knudson's "two-hit" paradigm posits that carcinogenesis requires inactivation of both copies of an autosomal tumor suppressor gene. Here, we report that the glycolytic metabolite methylglyoxal (MGO) transiently bypasses Knudson's paradigm by inactivating the breast cancer suppressor protein BRCA2 to elicit a cancer-associated, mutational single-base substitution (SBS) signature in nonmalignant mammary cells or patient-derived organoids. Germline monoallelic BRCA2 mutations predispose to these changes.

Alleviating misclassified germline variants in underrepresented populations: A strategy using popmax.

Purpose: Germline variant interpretation often depends on population-matched control cohorts. This is not feasible for population groups that are underrepresented in current population reference databases.

Methods: We classify germline variants with population-matched controls for 2 ancestrally diverse cohorts of patients: 132 early-onset or familial colorectal carcinoma patients from Singapore and 100 early-onset colorectal carcinoma patients from the United States.

Cost-effectiveness analysis of add-on pertuzumab to trastuzumab biosimilar and chemotherapy as neoadjuvant treatment for human epidermal growth receptor 2-positive early breast cancer patients in Singapore.

Objectives: The Asian PEONY trial showed that add-on pertuzumab to trastuzumab and chemotherapy significantly improved pathological complete response in the neoadjuvant treatment of patients with human epidermal growth factor receptor 2-positive (HER2+) early breast cancer (EBC). This study evaluated the cost-effectiveness of pertuzumab as an add-on therapy to trastuzumab and chemotherapy for neoadjuvant treatment of patients with HER2+ EBC in Singapore.

Methods: A six-state Markov model was developed from the Singapore healthcare system perspective, with a lifetime time horizon.

Radium-223 in women with hormone receptor-positive bone-metastatic breast cancer receiving endocrine therapy: pooled analysis of two international, phase 2, randomized, double-blind, placebo-controlled trials.

Background: Most women with advanced breast cancer have skeletal metastases. Radium-223 is an alpha-emitting radionuclide that selectively targets areas of bone metastases.

Methods: Two double-blind, placebo-controlled studies of radium-223 were conducted in women with hormone receptor-positive (HR+), bone-predominant metastatic breast cancer.

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

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.

Impact of BMI in Patients With Early Hormone Receptor-Positive Breast Cancer Receiving Endocrine Therapy With or Without Palbociclib in the PALLAS Trial.

Purpose: BMI affects breast cancer risk and prognosis. In contrast to cytotoxic chemotherapy, CDK4/6 inhibitors are given at a fixed dose, irrespective of BMI or weight. This preplanned analysis of the global randomized PALLAS trial investigates the impact of BMI on the side-effect profile, treatment adherence, and efficacy of palbociclib.

Clinical Guidance on the Monitoring and Management of Trastuzumab Deruxtecan (T-DXd)-Related Adverse Events: Insights from an Asia-Pacific Multidisciplinary Panel.

Trastuzumab deruxtecan (T-DXd)-an antibody-drug conjugate targeting the human epidermal growth factor receptor 2 (HER2)-improved outcomes of patients with HER2-positive and HER2-low metastatic breast cancer. Guidance on monitoring and managing T-DXd-related adverse events (AEs) is an emerging unmet need as translating clinical trial experience into real-world practice may be difficult due to practical and cultural considerations and differences in health care infrastructure. Thus, 13 experts including oncologists, pulmonologists and a radiologist from the Asia-Pacific region gathered to provide recommendations for T-DXd-related AE monitoring and management by using the latest evidence from the DESTINY-Breast trials, our own clinical trial experience and loco-regional health care considerations.

Macrophage IL-1β contributes to tumorigenesis through paracrine AIM2 inflammasome activation in the tumor microenvironment.

Intracellular recognition of self and non-self -nucleic acids can result in the initiation of effective pro-inflammatory and anti-tumorigenic responses. We hypothesized that macrophages can be activated by tumor-derived nucleic acids to induce inflammasome activation in the tumor microenvironment. We show that tumor conditioned media (CM) can induce IL-1β production, indicative of inflammasome activation in primed macrophages.