Harnessing gene fusion-derived neoantigens for 'cold' breast and prostate tumor immunotherapy.

Breast and prostate cancers are generally considered immunologically 'cold' tumors due to multiple mechanisms rendering them unresponsive to immune checkpoint blockade therapies. With little success in garnering positive outcomes in modern immunotherapeutic clinical trials, it is prudent to re-examine the role of immunogenic neoantigens in these cold tumors. Gene fusions are driver mutations in hormone-driven cancers that can result in alternative mutation-specific neoantigens to promote immunotherapy sensitivity. This review focuses on 1) gene fusion formation mechanisms in neoantigen generation; 2) gene fusion neoantigens in cancer immunotherapeutic strategies and associated clinical trials; and 3) challenges and opportunities in computational and liquid biopsy technologies. This review is anticipated to initiate further research into gene fusion neoantigens of cold tumors for further experimental validation.

Molecular vulnerabilities and therapeutic resistance in hormone receptor positive and HER2 dependent breast cancer tumours.

Over the past two decades, high sensitivity to HER2-amplified primary breast cancers has been achieved with HER2-targeted therapies. CDK4/6 inhibitors have long been identified as a potential treatment option for advanced breast cancer patients. However, acquired HER2 heterogeneity leading to resistance during the treatment has been identified as a bottleneck. This review focuses on the recent resistance mechanisms identified and potential therapeutic targets for conventional and combination endocrine therapies with CDK4/6 inhibitors by various breast cancer clinical trials and research groups in HER amplified and/or mutated breast cancer tumour. Activating HER2 alterations, JNK pathway, hyperactivated TORC1, co-mutations in HER2 and HER3, phenotypic changes of HER2, and few other advanced findings are identified as potential therapeutic targets in treating current HER2 endocrine therapy-resistant tumour. Along with the HER2-focused resistance mechanisms, we also describe how the microbiome may play a role in breast cancer therapy and its potential for new therapeutic strategies to overcome drug resistance in breast cancers.

Immune microenvironment, homologous recombination deficiency, and therapeutic response to neoadjuvant chemotherapy in triple-negative breast cancer: Japan Breast Cancer Research Group (JBCRG)22 TR.

BACKGROUND: Triple-negative breast cancer (TNBC) is a biologically diverse disease, with characteristics such as homologous recombination deficiency (HRD), gene mutation, and immune reactions. Japan Breast Cancer Research Group 22 is a multicenter trial examining TNBC's response to neoadjuvant chemotherapy (NAC) according to the HRD status. This translational research investigated the clinical significance of the immune microenvironment of TNBC in association with HRD, tumor BRCA1/2 (tBRCA1/2) mutation, and response to NAC. METHODS: Patients aged below 65 years with high HRD or germline BRCA1/2 (gBRCA1/2) mutation randomly received paclitaxel + carboplatin (group A1) or eribulin + carboplatin (A2), followed by anthracycline. Patients aged below 65 years with low HRD or those aged 65 years or older without gBRCA1/2 mutation randomly received eribulin + cyclophosphamide (B1) or eribulin + capecitabine (B2); nonresponders to the first four cycles of the therapy received anthracycline. A pathological complete response (pCR) was defined as the absence of residual cancer cells in the tissues. Pretreatment biopsy specimens were stained by multiplexed fluorescent immunohistochemistry using antibodies against CD3, CD4, CD8, Foxp3, CD204, and pan-cytokeratin. Immune cells with specific phenotypes were counted per mm2 in cancer cell nests (intratumor) and stromal regions. The immune cell densities were compared with clinicopathological and genetic factors including tumor response. RESULTS: This study analyzed 66 samples. T1 tumors had a significantly higher density of intratumoral CD8+ T cells than T2 or larger tumors. The tBRCA1/2 mutation or HRD status was not associated with the density of any immune cell. The density of intratumoral and stromal CD4+ T cells was higher in patients showing pCR than in those without pCR. In a multivariate analysis, intratumoral and stromal CD4+ T cell density significantly predicted pCR independent of age, chemotherapy dose, HRD status, and treatment groups (P = 0.009 and 0.0057, respectively). In a subgroup analysis, the predictive value of intratumoral and stromal CD4+ T cell density persisted in the platinum-containing chemotherapy group (A1+A2) but not in the non-platinum-containing group (B1+B2). CONCLUSIONS: Intratumoral and stromal CD4+ T cell density was an independent predictor of pCR in patients with TNBC. A larger study is warranted to confirm the results. TRIAL REGISTRATION: UMIN000023162.

Oncobiology and treatment of breast cancer in young women.

Female breast cancer emerged as the leading cancer type in terms of incidence globally in 2020. Although mortality due to breast cancer has improved during the past three decades in many countries, this trend has reversed in women less than 40 years since the past decade. From the biological standpoint, there is consensus among experts regarding the clinically relevant definition of breast cancer in young women (BCYW), with an age cut-off of 40 years. The idea that breast cancer is an aging disease has apparently broken in the case of BCYW due to the young onset and an overall poor outcome of BCYW patients. In general, younger patients exhibit a worse prognosis than older pre- and postmenopausal patients due to the aggressive nature of cancer subtypes, a high percentage of cases with advanced stages at diagnosis, and a high risk of relapse and death in younger patients. Because of clinically and biologically unique features of BCYW, it is suspected to represent a distinct biologic entity. It is unclear why BCYW is more aggressive and has an inferior prognosis with factors that contribute to increased incidence. However, unique developmental features, adiposity and immune components of the mammary gland, hormonal interplay and crosstalk with growth factors, and a host of intrinsic and extrinsic risk factors and cellular regulatory interactions are considered to be the major contributing factors. In the present article, we discuss the status of BCYW oncobiology, therapeutic interventions and considerations, current limitations in fully understanding the basis and underlying cause(s) of BCYW, understudied areas of BCYW research, and postulated advances in the coming years for the field.

Next-Generation Clinical Trials and Research with Successful Collaborations.

While clinical trials have evolved and improved over time, fundamental changes are needed to reflect the outcomes of great relevance to the institutions where they are performed, by integrating scientific rationale and society's movement to increase efficiency, accountability, and transparency by fast integrating the next-generation advances offered by omics technology and artificial intelligence. Several global clinical and exploratory collaborative studies that achieved successful outcomes in terms of patients' survival, drug toxicity, efficacy, safety, biomarkers, and consensus reached to improve good clinical practices are addressed in this article. Going forward, through collaborations, cooperation, and intellectual curiosity many more advances can be made in clinical trial approaches that can bring transparency, accountability, best outcomes, and develop friendship with trust among all the involved.