The delay in diagnosis and treatment of breast cancer remains a serious problem. Several psychological and behavioural patient attributes strongly determine both patient-related delay time and system-related delay time, but their strength is different in particular countries.
Olaparib (AZD2281) is an oral poly(ADP-ribose) polymerase (PARP) inhibitor with antitumour activity in cancer patients with BRCA1/2 germline mutations and in patients with homologous recombination deficiency. In this dose-finding study, patients were randomized to olaparib 10, 30, 100, 200 or 400 mg (capsule formulation) twice daily for the 4-5 days preceding breast cancer surgery. The primary objective was to identify an effective biological dose of olaparib for future trials. Secondary endpoints included evaluation of PARP-1 inhibition dose/exposure-response, and safety. Olaparib plasma pharmacokinetics (PK) and the pharmacodynamics (PD) in tumour and peripheral blood mononuclear cells (PBMCs) were evaluated. Population PK/PD modelling was performed on pooled data from this study and a previously reported study. Sixty patients were randomized (n = 12, each dose). Dose-dependent increases in exposure to olaparib were observed, but at ~50 % lower plasma exposure levels than seen in advanced disease studies. The mean maximal extent of PARP inhibition in PBMCs and tumour tissue was 50.6 % and 70.0 %, respectively, and was similar to inhibitory levels reported previously. No PARP inhibition-dose relationship was observed. Due to the unexpectedly low olaparib exposure, we were unable to determine an effective biological dose. Common adverse events included procedural pain (n = 31 patients), nausea, asthenia, malaise and increased blood creatinine (n = 6, each); these were of mild-to-moderate intensity, and all were manageable. Despite low olaparib exposure, PARP inhibition was consistent with previous reports. Reasons for the inter-study differences in exposure are unclear. The tolerability profile of olaparib was consistent with previous studies.
Aneuploid cells should have a reduced proliferation rate due to difficulty in proceeding through mitosis. However, contrary to this, high aneuploidy is associated with aggressive tumour growth and poor survival prognosis, in particular in triploid breast cancer. A further paradox revolves around the observation that, while cell senescence should inhibit proliferation, the senescence marker p16INK4a correlates with poor treatment outcome in patients with a very aggressive triple-negative breast carcinoma (TNBC). In this study, we aim to pour light on the possible relationship of these conundrums with polyploidy of tumour cells. We performed detailed analysis of DNA histogram profiles in diagnostic core biopsies of 30 cases of operable breast cancer and found that near triploidy in TNBC and other forms correlated with weak or no response to neoadjuvant chemotherapy (NAC) as scored by Miller-Payne index. Polyploid cells in operation samples from tumours that were non-responsive to NAC treatment were Ki67 and CD44 positive. In addition, polyploid cells were positive for markers of embryonic stemness (OCT4, SOX2, NANOG) and senescence (p16INK4a). The relationship patterns between p16INK4a and NANOG were heterogeneous, with predominantly mutually exclusive expression but also synergistic and intermediate variants in the same samples. We conclude that the aneuploidy and senescence paradoxes can be explained by the mutual platform of polyploidy, conferring genomic and epigenetic instability as a survival advantage. Such cells are able to bypass aneuploidy restrictions of conventional mitosis and overcome the barrier of senescence by a shift to self-renewal, resulting in progression of cancer.
Summary. Cancer rehabilitation programs mainly involve endurance training while little attention has been paid to strength training. Breast cancer (BC) patients lose muscle strength while undergoing adjuvant treatment, thus affecting daily activities and quality of life. Maximal strength training, with an emphasis on velocity in the concentric phase, improves maximal strength and muscle force development characteristics. However, the effect of maximal strength training on quality of life for BC patients undergoing treatment remains elusive. Consequently, the aim of this study was to evaluate the effectiveness of maximal strength training in Health related quality of life in women with newly diagnosed BC. Materials and Methods: 55 BC patients with disease stage I–III were randomized into a training group and control group. The training group performed maximal strength training twice a week for 3 months, whereas the control group followed prescribed treatment without strength training. Overall quality of life was measured by The European Organization for Research and Treatment of Cancer Core Quality of life Questionnaire-C30 and additional BC module BR23 before and after the intervention. Results: The results obtained from pre-tests and those obtained after 3 months of intervention revealed that patients in the training group significantly increased one repetition maximum, by 20.4 kg (20%) (p = 0.001, d = 0.9). Simultaneously, statistically significant alterations were observed in this variable for the control group, one repetition maximum decreased by 8.9 kg (9%) (p = 0.001, d = 0.5). The overall quality of life improved significantly by 13% for the training group with large effect (p = 0.002, d = 0.6), but no relevant changes were observed in the control group (p = 0.44, d = 0.2). Results revealed remarkable changes in overall quality of life after 3-month post-test period between the two groups with large effect (p = 0.002, d = 0.9). The training sessions had helped in diminishing the sense of fatigue by 24% (p = 0.03, d = 0.6), while it had got worse by 25% (p = 0.02, d = 0.4) for the control group. Again, the data on large effect were noticed to differ between the groups (p = 0.01, d = 0.6). Conclusion: Maximal strength training for BC patients was well tolerated, safe and feasible and showed strength improvements that led to improved muscle strength and improved overall quality of life. These data certainly support the therapeutic role for maximal strength training in the treatment of BC.
Inhibition of CAIX reduces the self-renewal capacity of breast cancer cells, and the combination of doxorubicin and CAIX inhibition is an attractive therapeutic strategy in basal-like and triple-negative breast cancer, which warrants further investigations.
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