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In recent years the description of well-defined molecular subtypes of breast cancer, together with the identification of the driving genetic alterations and signaling pathways, has led to the clinical development of a number of successful molecular targeted agents. This is best exemplified in the subset of HER2-amplified breast cancers, in which an increasing number of active agents are changing the natural history of this aggressive disease. Other targets are under exploration, and the clinical development of these agents will require a change from the current large, randomized trials in unselected patient populations to smaller trials in groups with a molecularly defined tumor type. In addition, combinatorial approaches that act on the secondary mutations and/or compensatory pathways in resistant tumors may markedly improve on the effects of targeted agents used alone.

Trastuzumab deruxtecan (T-DXd) intracranial activity has been observed in small or retrospective patient cohorts with human epidermal growth factor receptor 2–positive (HER2 + ) advanced/metastatic breast cancer (mBC) and stable or active (untreated/previously treated and progressing) brain metastases (BMs). The phase 3b/4 DESTINY-Breast12 study investigated T-DXd in patients with HER2 + mBC and is, to our knowledge, the largest prospective study of T-DXd in patients with BMs in this setting. Patients (stable/active BMs ( n  = 263) and no BMs ( n  = 241)) treated with one or more prior anti-HER2–based regimens received T-DXd (5.4 mg per kg). Primary endpoints were progression-free survival (PFS; BMs cohort) and objective response rate (ORR) per Response Evaluation Criteria in Solid Tumors version 1.1 (non-BMs cohort). Additional endpoints included central nervous system (CNS) PFS, ORR, time to second progression, CNS ORR (BMs cohort), incidence of new symptomatic CNS metastases (non-BMs cohort), time to progression, duration of response, overall survival and safety (both cohorts). No formal hypothesis testing was conducted for this single-arm, open-label study. In the BMs cohort, 12-month PFS was 61.6% (95% confidence interval (CI): 54.9–67.6), and 12-month CNS PFS was 58.9% (95% CI: 51.9–65.3). In the non-BMs cohort, ORR was 62.7% (95% CI: 56.5–68.8). Grade 3 or higher adverse events occurred in 51% (BMs cohort) and 49% (non-BMs cohort) of patients. Investigator-reported interstitial lung disease/pneumonitis occurred in 16% (grade ≥3: 3%) of patients with BMs and 13% (grade ≥3: 1%) of patients without BMs. These data show substantial and durable overall and intracranial activity for T-DXd, supporting its use in previously treated patients with HER2 + mBC irrespective of stable/active baseline BMs. ClinicalTrials.gov identifier: NCT04739761 . In the non-randomized phase 3b/4 DESTINY-Breast12 study, trastuzumab deruxtecan (T-DXd) treatment of patients with HER2 + advanced breast cancer and active or stable brain metastases showed consistent intracranial activity and systemic efficacy of T-DXd.

Expression of the NCOA3 gene (nuclear receptor coactivator 3) produced the protein AIB-1, which competed with PAX2 for binding to the ERBB2 cis regulatory element, leading to an increase in ERBB2 transcription and an increase in cell proliferation in the presence of tamoxifen. [...] increased AIB-1 concentrations block PAX2 binding and ERBB2 gene repression, thereby reversing the antiproliferative effects of tamoxifen (4).

The phosphatidylinositol 3-kinase subunit PIK3CA is frequently mutated in human cancers. Here we used gene targeting to \"knock in\" PIK3CA mutations into human breast epithelial cells to identify new therapeutic targets associated with oncogenic PIK3CA. Mutant PIK3CA knockin cells were capable of epidermal growth factor and mTOR-independent cell proliferation that was associated with AKT, ERK, and GSK3β phosphorylation. Paradoxically, the GSK3β inhibitors lithium chloride and SB216763 selectively decreased the proliferation of human breast and colorectal cancer cell lines with oncogenic PIK3CA mutations and led to a decrease in the GSK3β target gene CYCLIN D1. Oral treatment with lithium preferentially inhibited the growth of nude mouse xenografts of HCT-116 colon cancer cells with mutant PIK3CA compared with isogenic HCT-116 knockout cells containing only wild-type PIK3CA. Our findings suggest GSK3β is an important effector of mutant PIK3CA, and that lithium, an FDA-approved therapy for bipolar disorders, has selective antineoplastic properties against cancers that harbor these mutations.

Background: Vasomotor symptoms (VMSs) associated with menopause represent a significant challenge for many patients after cancer treatment, particularly if conventional menopausal hormone therapy (MHT) is contraindicated. Methods: The Menopause after Cancer (MAC) Study (NCT04766229) was a single-arm phase II trial examining the impact of a composite intervention consisting of (1) the use of non-hormonal pharmacotherapy to manage VMS, (2) digital cognitive behavioral therapy for insomnia (dCBT-I) using Sleepio (Big Health), (3) self-management strategies for VMS delivered via the myPatientSpace mobile application and (4) nomination of an additional support person/partner on quality of life (QoL) in women with moderate-to-severe VMS after cancer. The primary outcome was a change in cancer-specific global QoL assessed by the EORTC QLC C-30 v3 at 6 months. Secondary outcomes included the frequency of VMS, the bother/interference of VMS and insomnia symptoms. Results: In total, 204 women (82% previous breast cancer) with a median age of 49 years (range 28–66) were recruited. A total of 120 women completed the protocol. Global QoL scores increased from 62.2 (95%CI 58.6–65.4) to 70.4 (95%CI 67.1–73.8) at 6 months (p < 0.001) in the intention to treatment (ITT) cohort (n = 204) and from 62 (95%CI 58.6–65.4) to 70.4 (95%CI 67.1–73.8) at 6 months (p < 0.001) in the per-protocol (PP) cohort (n = 120). At least 50% reductions were noticed in the frequency of VMS as well as the degree of bother/interference of VMS at six months. The prevalence of insomnia reduced from 93.1% at the baseline to 45.2% at 6 months (p < 0.001). The Sleep Condition Indicator increased from 8.5 (SEM 0.4) to 17.3 (SEM 0.5) (p < 0.0005) in the ITT cohort and 7.9 (SEM 0.4) to 17.3 (SEM 0.5) (p < 0.001) in the PP cohort. Conclusions: A targeted composite intervention improves the quality of life for cancer patients with frequent and bothersome vasomotor symptoms with additional benefits on frequency, the bother/interference of VMS and insomnia symptoms.

The selective estrogen receptor modulator tamoxifen has been used for more than three decades to treat metastatic and early-stage receptor-positive breast cancer and, more recently, to prevent the disease. Biotransformation of tamoxifen to the potent antiestrogen endoxifen is performed by cytochrome P450 (CYP) enzymes, in particular the CYP2D6 isoform. Genetic variants in the CYP2D6 gene may result in CYP2D6 enzymes with reduced or null activity. Strong and intermediate inhibitors of CYP2D6, which may be used to treat hot flashes or psychiatric conditions in breast cancer patients, can also negatively impact enzyme function. Prospective data are lacking, but the balance of current evidence strongly suggests that, compared with women with two wild-type alleles, the presence of two null alleles, and possibly one null allele, predicts reduced tamoxifen metabolism and an inferior outcome in postmenopausal women with early breast cancer who receive adjuvant treatment with the drug. Unfortunately, studies to date have been largely retrospective and the interpretation of their results is limited by examination of archival tissue samples and the inclusion of heterogeneous populations. Although we do not currently recommend routine CYP2D6 testing for women who do not have alternative standard therapies, the use of concomitant strong or intermediate inhibitors of CYP2D6 should be avoided if feasible. This review summarizes the literature to date with a focus on clinically relevant recent studies that examined the association between CYP2D6 polymorphisms and tamoxifen-associated outcomes.

Background Expanded access programs (EAPs) allow cancer patients with unmet clinical need to obtain access to pre-authorisation treatments. There is no standardised process for implementing these programs nationally, and real-world data on their impact is lacking. Aims This study aimed to evaluate the prevalence of such EAPs and their impact in a cancer centre. Methods Data relating to adult cancer patients treated via EAPs from 2011 to 2021 in three Cork university hospitals was collated. Descriptive statistics were employed to get an overview of the impact these programs currently have on cancer care provision. Results We identified 193 patients who accessed EAPs during the study period, availing of 33 separate drugs for a total of 50 different cancer indications. The prevalence of EAP usage was shown to have been trending upwards in recent years with a total of 189 programs being accessed throughout the period. Drugs provided were from a number of different anti-cancer drug classes, particularly targeted therapies ( n  = 18) and immune checkpoint inhibitors ( n  = 17). Cancers from a wide range of both solid and liquid tumour types were treated with EAP drugs, and patients treated were from across a broad spectrum of ages (26–82, SD 11.99). Conclusions EAPs have an increasing role in accessing novel cancer therapies in our community and by extension nationally. Equity of EAP access would be facilitated by a national registry of available agents which we have established. Assessment of their benefits and toxicities would be enhanced by the requirement for a real-world database as a condition of EAP approval.

Background Comprehensive geriatric assessment (CGA) is recommended by international guidelines prior to initiation of systemic anti-cancer treatment (SACT). In practice, CGA is limited by time constraints, lack of resources and expert interpretation. Aims The primary objective of this pilot study was to establish the prevalence of frailty (assessed by G8), cognitive impairment (assessed by Mini-Cog), and risk of chemotherapy toxicity (assessed by CARG Chemo-Toxicity Calculator) among patients (pts) ≥65 years commencing SACT. We selected these three screening tools due to the ease of conducting them in a busy outpatient setting. In addition, they have been validated to predict frailty and risk of toxicity from SACT among older adults with cancer. Methods Eligible participants were identified from medical oncology clinics. Assessments were conducted in an outpatient setting by treating physicians. Pt records were reviewed to gather demographic and cancer details. Statistical analyses were conducted using SPSS statistical software. Results Sixty-three participants were enrolled. The mean age of participants was 73yrs (range=65-88). Thirty-three (52.4%) were female and 30 (47.6%) were male. The majority (n=38, 60.3%) had metastatic cancer. The mean G8 score was 11.9 (range=6-19). Eighty-three percent had a G8 score ≤14. Mini-Cog was positive in 13 pts (21%). The mean CARG score was 7.5 (range=0-16), and 80% had a risk of at least 50% grade ≥3 toxicity. Of these, 48 (76.2%) received chemotherapy and 15 (23.8%) received non-cytotoxic SACT. In multi-variate analyses, age, cancer type, treatment type, and disease stage did not impact G8, Mini-Cog, or CARG scores. Conclusions Our study has several limitations but suggests that the majority of older adults with cancer would qualify for formal CGA assessment. The risk of high-grade toxicity from SACT is substantial in this cohort. Chronological age was not found to negatively impact pts’ frailty, cognition, or risk of toxicity.

2010 has been another prolific year in breast cancer research with a number of original observations bringing us closer to personalized care. Studies with novel targeted agents in defined breast cancer subgroups have revealed exciting developments and highlight the importance of patient selection.

2010 has been another prolific year in breast cancer research with a number of original observations bringing us closer to personalized care. Studies with novel targeted agents in defined breast cancer subgroups have revealed exciting developments and highlight the importance of patient selection.