Ataxia-telangiectasia mutated (ATM), ataxia-telangiectasia mutated and rad3 related (ATR) and DNA-dependent protein kinase catalytic sub-unit (DNA-PKcs) play critical roles in DNA damage response ...(DDR) by linking DNA damage sensing to DDR effectors that regulate cell cycle progression and DNA repair. Our objective was to evaluate if ATM, ATR and DNA-PKcs expressions could predict response to therapy and clinical outcome in epithelial ovarian cancers.
We investigated ATM, ATR, and DNA-PKcs expressions in ovarian epithelial cancers protein expression (n=194 patients), mRNA expression (n=156 patients) and correlated to clinicopathological outcomes as well as expression of X-ray repair cross-complementing protein 1 (XRCC1), cell division cycle-45 (CDC45), cyclin-dependent kinase 1(CDK1) and Ki-67 in tumours.
High ATM protein expression was associated with serous cystadenocarcinomas (p=0.021) and platinum resistance (p=0.017). High DNA-PKcs protein expression was associated with serous cystadenocarcinomas (p=0.006) and advanced stage tumours (p=0.018). High ATM protein (p=0.001), high ATM mRNA (p=0.018), high DNA-PKcs protein (p=0.002), high DNA-PKcs mRNA (p=0.044) and high ATR protein (p=0.001) expressions are correlated with poor ovarian cancer specific survival (OCSS). In multivariate Cox model, high DNA-PKcs (p=0.006) and high ATR (p=0.043) protein expressions remain independently associated with poor OCSS.
ATM, ATR and DNA-PKcs expressions may have prognostic and predictive significances in epithelial ovarian cancer.
The data presented here provides evidence that ATM, ATR and DNA-PKcs involved in DDR are not only promising biomarkers but are also rational targets for personalized therapy in ovarian cancer.
•ATM, ATR and DNA-PKcs are key factors involved in DNA damage response (DDR).•We investigated ATM, ATR and DNA-PKcs in ovarian cancer.•High levels of ATM, ATR and DNA-PKcs have prognostic significance.•High level of ATM predicts resistance to cisplatin therapy.
•The RILA assay is the leading candidate biomarker for radiotherapy toxicity.•We describe work to standardise its use across multiple centres.•Patient factors including smoking and arthritis were ...found to affect RILA score.•RILA predicts acute breast pain but not other acute end-points.•This work establishes the basis for implementing the assay clinically.
Predicting which patients will develop adverse reactions to radiotherapy is important for personalised treatment. Prediction will require an algorithm or nomogram combining clinical and biological data. The radiation-induced lymphocyte apoptosis (RILA) assay is the leading candidate as a biological predictor of radiotherapy toxicity. In this study we tested the potential of the assay for standardisation and use in multiple testing laboratories.
The assay was standardised and reproducibility determined using samples from healthy volunteers assayed concurrently in three laboratories in Leicester (UK), Mannheim (Germany) and Montpellier (France). RILA assays were performed on samples taken prior to radiotherapy from 1319 cancer patients enrolled in the REQUITE project at multiple centres. The patients were being treated for breast (n = 753), prostate (n = 506) or lung (n = 60) cancer.
Inter-laboratory comparisons identified several factors affecting results: storage time, incubation periods and type of foetal calf serum. Following standardisation, there was no significant difference in results between the centres. Significant differences were seen in RILA scores between cancer types (prostate > breast > lung), by smoking status (non-smokers > smokers) and co-morbidity with rheumatoid arthritis (arthritics > non-arthritics).
An analysis of acute radiotherapy toxicity showed as expected that RILA assay does not predict most end-points, but unexpectedly did predict acute breast pain. This result may elucidate the mechanism by which the RILA assay predicts late radiotherapy toxicity.
The work shows clinical trials involving multiple laboratory measurement of the RILA assay are feasible and the need to account for tumour type and other variables when applying to predictive models.
Studies have shown that rectal distension has a significant impact on treatment failure in patients receiving radical radiotherapy for prostate cancer. A distended rectum contributes to excessive ...organ movement during treatment, resulting in significant underdosing of the target volume and higher treatment failure rates. The increasing use of highly conformal, precise radiotherapy techniques places greater importance on reducing this risk. We tested whether imaging during radiotherapy helps minimise the negative impact that rectal distension has on long-term tumour control.
The rectal diameter (anterior/posterior and lateral) was prospectively measured at radiotherapy planning in 172 consecutive patients undergoing radical radiotherapy with three-dimensional conformal radiotherapy. Daily, and then weekly, imaging during radiotherapy ensured that prostate movement remained within predefined tolerances. Patients were followed up for a median of 72 months with regular prostate-specific antigen (PSA) measurements to ascertain biochemical PSA relapse and survival information.
In this cohort of predominately high-risk localised prostate cancer, rectal distension had no significant impact on PSA relapse. We suggest that regular imaging during radiotherapy negates the risk caused by rectal distension on local treatment failure.
•One of the largest prostate cancer cohort studies on symptom agreement.•Agreement was better for observable than subjective treatment-related symptoms.•Fatigue had a negative impact on the ...agreement.•Patients usually graded their symptoms more severely than healthcare professionals.•PROs should complement symptom assessment by healthcare professionals.
Previous studies showed that healthcare professionals and patients had only moderate to low agreement on their assessment of treatment-related symptoms. We aimed to determine the levels of agreement in a large cohort of prostate cancer patients.
Analyses were made of data from 1,756 prostate cancer patients treated with external beam radiotherapy (RT) and/or brachytherapy in Europe and the USA and recruited into the prospective multicentre observational REQUITE study. Eleven pelvic symptoms at the end of RT were compared after translating patient-reported outcomes (PROs) into CTCAE-based healthcare professional ratings. Gwet's AC2 agreement coefficient and 95% confidence intervals were calculated for each symptom. To compare severity of grading between patients and healthcare professionals, percent agreement and deviations for each symptom were graphically depicted. Stratified and sensitivity analyses were conducted to identify potential influencing factors and to assess heterogeneity and robustness of results.
The agreement for the 11 pelvic symptoms varied from very good (AC2 > 0.8: haematuria, rectal bleeding, management of sphincter control) to poor agreement (AC2 ≤ 0.2: proctitis and urinary urgency). Fatigue had a negative impact on the agreement. Patients tended to grade symptoms more severely than healthcare professionals. Information on sexual dysfunction was missing more frequently in healthcare professional assessment than PROs.
Agreement was better for observable than subjective symptoms, with patients usually grading symptoms more severely than healthcare professionals. Our findings emphasize that PROs should complement symptom assessment by healthcare professionals and be taken into consideration for clinical decision-making to incorporate the patient perspective.
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