Recent Submissions


    Smith, Susan; Jones, Steve (HemaSphere, 2022-06)
    Background: Ibrutinib (IBR) is an oral covalent Bruton tyrosine kinase inhibitor (BTKi), licensed for treatment of relapsed or refractory mantle cell lymphoma (MCL). Under NHS interim Covid-19 agreements in England, IBR with or without rituximab (R) was approved for the frontline treatment for MCL patients (pts) as a safer alternative to conventional immunochemotherapy. Although recent phase 2 studies have reported high response rates in low-risk patients for this combination in the frontline setting, randomised phase 3 and real-world data are currently lacking. Aims: To describe the real-world response rates (overall response rate (ORR), complete response (CR) rate) and toxicity profile of IBR +/- R in adult patients with previously untreated MCL. Methods: Following institutional approval, adults commencing IBR +/- R for untreated MCL under interim Covid-19 arrangements were prospectively identified by contributing centres. Hospital records were interrogated for demographic, pathology, response, toxicity and survival data. ORR/CR were assessed per local investigator according to the Lugano criteria using CT and/or PET-CT. Results: Data were available for 66 pts (72.7% male, median age 71 years, range 41-89). Baseline demographic and clinical features are summarised in Table 1. 23/66 pts (34.8%) had high-risk disease (defined as presence of TP53 mutation/deletion, blastoid or pleomorphic variant MCL, or Ki67%/MiB-1 ≥30%). IBR starting dose was 560mg in 56/62 pts (90%) and was given with R in 22/64 pts (34%). At a median follow up of 8.7 months (m) (range 0-18.6), pts had received a median of 7 cycles of IBR. 19/60 pts (32%) required a dose reduction or delay in IBR treatment. New atrial fibrillation and grade ≥3 any-cause toxicity occurred in 3/59 pts (5.8%) and 8/57 (14.0%) respectively.
  • Antibiotic prophylaxis in breast surgery: a meta-analysis to identify the optimal strategy to reduce infection rates in breast surgery.

    Akbari, Amir R
    Intro: Breast surgeries are an increasingly frequent operation, with an exponential rise in breast cancer diagnoses, and women opting for cosmetic surgeries. SSIs are the most common post-operative complication with many negative consequences including sepsis and even death. These are treated with prophylactic antibiotics prior to surgery. Breast surgery is currently defined as 'clean', although literature indicates that the infection rate is higher than should be expected for this classification. The aim of this meta-analysis is to evaluate whether pre-operative antibiotics reduce SSI frequency and which class of antibiotics achieve the best reduction. Methods: A literature search through online libraries was used to find clinical trials investigating pre-breast-surgery antibiotics and SSI frequency. These were grouped all together and separately by class of antibiotics. Additionally studies investigating breast cancer surgeries and non-cancer surgeries were grouped separately. A forest-plot was created for each group to calculate an estimated effect, these were then compared against each other. Results: Use of antibiotics resulted in a reduction in SSI frequency by 3.55% overall, and reduced frequency in all types of surgeries performed. Cephalosporins reduced SSI frequency by 2.23%, Beta-lactamase inhibitors 4.17% and macrolides achieved the greatest effect with a 14.58% reduction. Conclusion: This meta-analysis proves that antibiotics reduce SSI frequency in breast surgery and supports the notion to remove the 'clean' classification. This definition may result in failure to provide prophylaxis, resulting in patients suffering from preventable SSIs and their negative consequences. Macrolides were the most effective followed by beta-lactamase inhibitors and cephalosporins, this may be implemented in structuring new guidelines favouring use of macrolides before conducting breast surgery.
  • eQTL set-based association analysis identifies novel susceptibility loci for Barrett's esophagus and esophageal adenocarcinoma

    Jankowski, Janusz
    Background: Over 20 susceptibility single-nucleotide polymorphisms (SNPs) have been identified for esophageal adenocarcinoma (EAC) and its precursor, Barrett's esophagus (BE), explaining a small portion of heritability. Methods: Using genetic data from 4,323 BE and 4,116 EAC patients aggregated by international consortia including the Barrett's and Esophageal Adenocarcinoma Consortium (BEACON), we conducted a comprehensive transcriptome-wide association study (TWAS) for BE/EAC, leveraging Genotype Tissue Expression (GTEx) gene expression data from six tissue types of plausible relevance to EAC etiology: mucosa and muscularis from the esophagus, gastroesophageal (GE) junction, stomach, whole blood, and visceral adipose. Two analytical approaches were taken: standard TWAS using the predicted gene expression from local expression quantitative trait loci (eQTLs), and set-based SKAT association using selected eQTLs that predict the gene expression. Results: While the standard approach did not identify significant signals, the eQTL set-based approach identified eight novel associations, three of which were validated in independent external data (eQTL SNP sets for EXOC3, ZNF641 and HSP90AA1). Conclusions: This study identified novel genetic susceptibility loci for EAC and BE using an eQTL set based genetic association approach. Impact: This study expanded the pool of genetic susceptibility loci for EAC and BE, suggesting the potential of the eQTL set based genetic association approach as an alternative method for TWAS analysis.
  • Evaluation of a novel paper-based algorithm for breast family history risk assessment.

    Milburn, Nikki; Jahan, Ali; Elamin, Ghassan (EJSO: European Journal of Surgical Oncology, 2022-05)
  • Transforming the 2-week wait (2WW) pathway: management of breast pain in primary care.

    Jahan, Mohamed; Milburn, Nikki (BMJ Open Quality, 2022-03)
    Breast pain has no association with breast cancer yet is a frequent reason for referral from Primary to Secondary Care, often on an urgent (2-week wait) referral. The referral often causes significant patient anxiety, further heightened by screening mammograms and/or ultrasound scans in the absence of an associated red flag symptom or finding by the patient or general practitioner. This paper reports the pilot implementation of a specialist Primary Care Breast Pain Clinic in Mid-Nottinghamshire where patients were seen, examined without any imaging and assessed for their risk of familial breast cancer: numerous studies have reported 15%–>30% of patients with breast pain only have a family history of breast cancer. 177 patients with breast pain only were seen in this clinic between March, 2020 and April, 2021 with a 6-month interim suspension due to COVID-19. The mean age of patients was 48.4 years (range: 16–86). 172/177 (97.2%) patients required no imaging although there were three (1.7%) inappropriate referrals and two additional abnormalities (1.1%—hamartoma, thickening/tethering) that were referred onward. There were no cancers. 21 (12.4%) patients were identified to have an increased familial risk of breast cancer and were referred to the specialist familial cancer service. 170/177 patients completed an anonymous questionnaire on leaving the clinic. 167/169 (99%) were reassured regarding their breast pain, 155/156 (99%) were reassured of the Familial Risk Assessment, 162/168 (96%) were reassured regarding their personal risk assessment while 169/170 (99%) were ‘extremely likely/likely to recommend the service’. This specialist Primary Care Breast Pain Clinic provides service improvement across all levels of care (Primary, Secondary and Tertiary). Patients were successfully managed in the community with high levels of patient satisfaction and together this obviated referral to secondary care. The familial breast cancer risk assessment also helped identify unmet need in the community.
  • Incidental finding of prostate cancer in transurethral resection of prostate (TURP) specimens: A retrospective analysis from a tertiary care hospital in Pakistan

    Memon, Shahbaz Mustafa (The Pan African Medical Journal, 2021-05)
    Introduction: incidental prostate cancer findings reflect the great burden of prostatic cancer across the globe. Our 10 year retrospective analysis aimed to identify the incidence and clinic-pathologic features of prostate cancer incidentally detected in patients undergoing transurethral resection of the prostate (TURP) for benign prostatic hyperplasia (BPH), and to estimate the clinical value of pathologic review of all TURP specimens. Methods: after excluding patients with a known diagnosis of prostate cancer prior to TURP a total of 2,386 men (ages 25-98) were identified by pathology (TURP) specimens. Yearly incidences, Gleason score, grade, pathologic stage were recorded for all incidental prostate cancer patients. Results: a total of 256 (10.7%) patients were found to have prostate cancer. Mean Age was 68.51±9.22 years. T1a and T1b stage prostatic carcinoma was found in 9.9% and 90.1% of these patients respectively. Forty-nine percent (49%) patients had higher Gleason scores (>7). After subtracting average incidences between 5-year intervals, a statistical rise of almost 4% was found. Conclusion: our analysis concludes that a large proportion (10.7%) of patients had incidental prostate cancer and the incidence was increasing in recent years in Pakistan and in comparison, to Asian countries. In Pakistan there is a scarcity of updated national cancer registries. The growing incidence of high Gleason scores requires keen and prompt attention. The diverse ethnic and socioeconomic background of patients propels their propensity towards loss of follow up with already limited tertiary healthcare institutes in Pakistan. This pathologic review of TURP specimens is valuable for Asiatic and non-Asiatic populations.
  • Parathyroid carcinoma presenting with ventricular bigeminy in pregnancy.

    Sivasankaran, Karthikeyan (BMJ Case Reports, 2022-02)
    Parathyroid carcinoma is very rare in pregnancy. Clinical features are similar to primary hyperparathyroidism. A 38-year-old pregnant woman had repeated hospital admissions for palpitations, headaches, dizziness and polydipsia. Blood investigations showed severe hypercalcaemia with raised parathyroid hormone and 24-hour ECG showed ventricular bigeminy and premature ventricular contractions. Neck ultrasound showed a lesion in the right thyroid lobe. Consequently, she underwent an en bloc resection of the right parathyroid and thyroid lobe at 23 weeks gestation. Histology results confirmed parathyroid cancer. This case highlights the complexities of identifying hypercalcaemia in pregnancy due to the overlapping features with common disorders of pregnancy. Early recognition and timely surgical management can prevent maternal and fetal complications. Also, the case demonstrates the value of interprofessional collaboration between different specialities in providing quality care and improving outcomes. An abridged version of this case was presented at European Congress of Endocrinology 2021.
  • Finding the needle in the haystack: the diagnostic accuracy of the faecal immunochemical test for colorectal cancer in younger symptomatic patients

    Foley, Stephen (2021-10)
    Aim: Detection of early onset colorectal cancer is challenging, and remains a rare diagnosis amongst younger people with gastrointestinal symptoms. We investigated whether faecal immunochemical testing (FIT) could identify younger patients at higher risk of colorectal cancer or serious bowel disease including colorectal cancer, inflammatory bowel disease or advanced adenomas. Methods: A subgroup analysis was performed of symptomatic patients under 50 years of age (<50) from the NICE FIT study, a multicentre, prospective diagnostic accuracy study of FIT conducted between October 2017 and December 2019. The diagnostic accuracy of FIT for colorectal cancer and serious bowel disease was investigated in younger patients at different faecal haemoglobin (f-Hb) cut-offs of 2, 10 and 150 µg blood/g faeces (µg/g). Results: Early onset colorectal cancer was diagnosed in 1.5% (16/1103) of younger symptomatic patients. The sensitivity of FIT for younger patients aged <50 was 87.5% (95% CI 61.7%-98.4%), 81.3% (54.4%-96.0%) and 68.8% (41.3%-89.0%) at f-Hb cut-offs of 2, 10 and 150 µg/g, respectively. The positive predictive value for colorectal cancer increased from 4.2% (2.3%-6.9%) to 11.5% (5.9%-19.6%) at cut-offs of 2 and 150 µg/g, while the positive predictive value for serious bowel disease increased from 31.3% (26.3%-36.5%) to 65.6% (55.2%-75.0%) at the same cut-offs. The negative predictive value of FIT for colorectal cancer remained above 99.5% at all cut-offs. Conclusion: Detectable f-Hb on FIT in symptomatic younger patients may indicate referral for investigation of colorectal cancer and serious bowel disease.
  • Factors associated with psychological distress for couples facing head and neck cancer: A systematic literature review

    Biswas, Sanchia (2021-08)
    Objectives: Cancer patients in supportive relationships display improved health and survival outcomes. Identifying factors that might respond to intervention for Head and Neck Cancer (HNC) dyads is important as HNC patients and their partners experience heightened distress. This article systematically reviewed and evaluated the research findings and methodological quality of studies which identified factors influencing psychological distress for couples facing HNC. Methods: PsycINFO, Medline, and CINAHL were searched. Studies were included if they used validated psychological distress measures and quantitative data collection methods. Eleven studies satisfied inclusion criteria. Results: Studies identified factors associated with the psychological distress experienced by couples facing HNC, with substantial effect size variation. These factors included clinical, sociodemographic, relational, and psychological variables. Factors associated with increased psychological distress included disease burden, reduced social contact, perception of reduced relationship quality, and less adaptive/assimilative coping although the effect sizes displayed considerable heterogeneity. Overall, studies possessed good methodological quality but generally could have been improved by minimising the risk of non-response bias and fully reporting relational characteristics. Conclusions: The implications of these results for clinical practice and future research are discussed. Further research is recommended to report effect sizes more consistently for both dyad members to gain greater insight into couple-level distress and to perform moderator analyses to identify which variables influence the magnitude of psychological distress.
  • Imaging techniques in breast cancer

    Beremauro, Stebia (Surgery, 2022-01)
    Imaging is the mainstay in breast cancer diagnosis, with mammography being the primary screening tool used to detect small/asymptomatic cancers. Symptomatic patients undergo triple assessment which includes a clinical assessment, imaging and, if indicated, an image-guided biopsy for histological diagnosis. We discuss current and emerging breast imaging techniques used in breast cancer care. These include mammography, digital breast tomosynthesis, ultrasound and magnetic resonance. We also discuss image-guided biopsy and miscellaneous image-guided interventions that influence the management of breast cancer care.
  • A prospective evaluation of the American College of Surgeons Surgical Risk Calculator as a predictor of complications for breast surgery

    Dube, Mukul
    Background: The infection rates for operative management of breast cancer are often unpredictable and higher than average for a clean surgical procedure (0.8% and 28%). We aimed to assess the effectiveness of the American College of Surgeons (ACS) Surgical Risk Calculator (SRC), a preoperative scoring system to calculate the risk of surgical site infection (SSI) and serious complications following breast surgery. Methods: Prospective risk scoring using the SRC on 213 patients in the preoperative clinic and the incidence of SSI and serious complications within 30 days postoperatively was prospectively collected. Results: The overall SSI rate in our sample was 5% (n=11/210 patients). For a one-unit increase in SRC score, the odds of having SSI increased by a factor of 1.88 (95% CI 1.33 to 2.74). Odds of developing SSI were higher in patients with high Body Mass Index (OR 1.25; 95% 1.13 to 1.40) and American Society of Anesthesiologists score 3 (OR 11.54; 95% CI 2.98 to 43.65). The odds of developing an SSI were ∼19 times higher if a patient had an SRC score >3.0 versus those with an SRC score <3.0. Only 3% (n=4) of patients who had an SRC score of <3.0 experienced SSI, compared with 33% (n=7) for those with a risk score of >3.0. Out of 210 patients, 9 had serious complications (4.2%). Conclusions: ACS SRC Score of more than 3 was associated with a higher likelihood of SSI. SRC was able to predict the risk of SSI and serious complications and can be used preoperatively for identification and risk minimisation.
  • EBV-positive mucocutaneous ulceration.

    Reza, M; Qureshi, A (Annals of the Royal College of Surgeons of England, 2021-11)
    Ulceration of the oral cavity is common and a frequent reason for referral to secondary and tertiary centres. Epstein-Barr virus (EBV)-related mucocutaneous ulceration, however, is a rare cause of oral ulceration that has been described only recently. Histologically these lesions resemble lymphomas; however, their management and prognosis differ significantly. We present a case of EBV-induced oral ulceration and discuss the diagnosis and management of and available literature for the condition, which was treated successfully through conservative measures alone.
  • Outcomes from elective colorectal cancer surgery during the SARS-CoV-2 pandemic

    Sapre; Watson
    Aim: This study aimed to describe the change in surgical practice and the impact of SARS-CoV-2 on mortality after surgical resection of colorectal cancer during the initial phases of the SARS-CoV-2 pandemic. Method: This was an international cohort study of patients undergoing elective resection of colon or rectal cancer without preoperative suspicion of SARS-CoV-2. Centres entered data from their first recorded case of COVID-19 until 19 April 2020. The primary outcome was 30-day mortality. Secondary outcomes included anastomotic leak, postoperative SARS-CoV-2 and a comparison with prepandemic European Society of Coloproctology cohort data. Results: From 2073 patients in 40 countries, 1.3% (27/2073) had a defunctioning stoma and 3.0% (63/2073) had an end stoma instead of an anastomosis only. Thirty-day mortality was 1.8% (38/2073), the incidence of postoperative SARS-CoV-2 was 3.8% (78/2073) and the anastomotic leak rate was 4.9% (86/1738). Mortality was lowest in patients without a leak or SARS-CoV-2 (14/1601, 0.9%) and highest in patients with both a leak and SARS-CoV-2 (5/13, 38.5%). Mortality was independently associated with anastomotic leak (adjusted odds ratio 6.01, 95% confidence interval 2.58-14.06), postoperative SARS-CoV-2 (16.90, 7.86-36.38), male sex (2.46, 1.01-5.93), age >70 years (2.87, 1.32-6.20) and advanced cancer stage (3.43, 1.16-10.21). Compared with prepandemic data, there were fewer anastomotic leaks (4.9% versus 7.7%) and an overall shorter length of stay (6 versus 7 days) but higher mortality (1.7% versus 1.1%). Conclusion: Surgeons need to further mitigate against both SARS-CoV-2 and anastomotic leak when offering surgery during current and future COVID-19 waves based on patient, operative and organizational risks.
  • Effectiveness of percutaneous vacuum-assisted excision (VAE) of breast lesions of uncertain malignant potential (B3 lesions) as an alternative to open surgical biopsy

    Yemm, Julia
    Traditionally B3 breast lesions are treated surgically, but overtreatment is a concern, as the majority have a final benign diagnosis. A national screening program introduced vacuum-assisted excision (VAE) for managing B3 lesions in late 2016. This retrospective study aimed to assess the outcomes associated with this approach.
  • A Randomized, Open-label, Presurgical, Window-of-Opportunity Study Comparing the Pharmacodynamic Effects of the Novel Oral SERD AZD9496 with Fulvestrant in Patients with Newly Diagnosed ER+ HER2- Primary Breast Cancer.

    Jahan, Ali (2020-08)
    Purpose: Fulvestrant, the first-in-class selective estrogen receptor (ER) degrader (SERD), is clinically effective in patients with ER+ breast cancer, but it has administration and pharmacokinetic limitations. Pharmacodynamic data suggest complete ER degradation is not achieved at fulvestrant's clinically feasible dose. This presurgical study (NCT03236974) compared the pharmacodynamic effects of fulvestrant with AZD9496, a novel, orally bioavailable, nonsteroidal, potent SERD, in treatment-naïve patients with ER+ HER2- primary breast cancer awaiting curative intent surgery. Patients and methods: Patients were randomized 1:1 to receive AZD9496 250 mg twice daily from day 1 for 5-14 days, or fulvestrant 500 mg on day 1. On-treatment imaging-guided core tumor biopsies were taken between day 5 and 14 and compared with pretreatment diagnostic biopsies. The primary objective was to compare the effects of AZD9496 and fulvestrant on ER expression. Secondary objectives included changes in progesterone receptor (PR) and Ki-67 pharmacokinetic/pharmacodynamic relationships and safety. Results: Forty-six women received treatment (AZD9496 n = 22; fulvestrant n = 24); 35 paired biopsies were evaluable (AZD9496 n = 15; fulvestrant n = 20). The least square mean estimate for ER H-score reduction was 24% after AZD9496 versus 36% after fulvestrant treatment (P = 0.86). AZD9496 also reduced PR H-scores (-33.3%) and Ki-67 levels (-39.9%) from baseline, but was also not superior to fulvestrant (PR: -68.7%, P = 0.97; Ki-67: -75.4%, P = 0.98). No new safety findings were identified. Conclusions: This was the first presurgical study to demonstrate that an oral SERD affects its key biological targets. However, AZD9496 was not superior to fulvestrant at the dose tested.
  • Pulmonary Metastasectomy in Colorectal Cancer: updated analysis of 93 randomized patients - control survival is much better than previously assumed.

    Sherwood Forest Hospitals NHS Foundation Trust (2020-05)
    Aim: Lung metastases from colorectal cancer are resected in selected patients in the belief that this confers a significant survival advantage. It is generally assumed that the 5-year survival of these patients would be near zero without metastasectomy. We tested the clinical effectiveness of this practice in Pulmonary Metastasectomy in Colorectal Cancer (PulMiCC), a randomized, controlled noninferiority trial. Method: Multidisciplinary teams in 14 hospitals recruited patients with resectable lung metastases into a two-arm trial. Randomization was remote and stratified according to site, with minimization for age, sex, primary cancer stage, interval since primary resection, prior liver involvement, number of metastases and carcinoembryonic antigen level. The trial management group was blind to patient allocation until after intention-to-treat analysis. Results: From 2010 to 2016, 93 participants were randomized. These patients were 35-86 years of age and had between one and six lung metastases at a median of 2.7 years after colorectal cancer resection; 29% had prior liver metastasectomy. The patient groups were well matched and the characteristics of these groups were similar to those of observational studies. The median survival after metastasectomy was 3.5 (95% CI: 3.1-6.6) years compared with 3.8 (95% CI: 3.1-4.6) years for controls. The estimated unadjusted hazard ratio for death within 5 years, comparing the metastasectomy group with the control group, was 0.93 (95% CI: 0.56-1.56). Use of chemotherapy or local ablation was infrequent and similar in each group. Conclusion: Patients in the control group (who did not undergo lung metastasectomy) have better survival than is assumed. Survival in the metastasectomy group is comparable with the many single-arm follow-up studies. The groups were well matched with features similar to those reported in case series.
  • Timing of radiotherapy after radical prostatectomy (RADICALS-RT): a randomised, controlled phase 3 trial.

    Sherwood Forest Hospitals NHS Foundation Trust (2020-09-28)
    Background: The optimal timing of radiotherapy after radical prostatectomy for prostate cancer is uncertain. We aimed to compare the efficacy and safety of adjuvant radiotherapy versus an observation policy with salvage radiotherapy for prostate-specific antigen (PSA) biochemical progression. Methods: We did a randomised controlled trial enrolling patients with at least one risk factor (pathological T-stage 3 or 4, Gleason score of 7-10, positive margins, or preoperative PSA ≥10 ng/mL) for biochemical progression after radical prostatectomy (RADICALS-RT). The study took place in trial-accredited centres in Canada, Denmark, Ireland, and the UK. Patients were randomly assigned in a 1:1 ratio to adjuvant radiotherapy or an observation policy with salvage radiotherapy for PSA biochemical progression (PSA ≥0·1 ng/mL or three consecutive rises). Masking was not deemed feasible. Stratification factors were Gleason score, margin status, planned radiotherapy schedule (52·5 Gy in 20 fractions or 66 Gy in 33 fractions), and centre. The primary outcome measure was freedom from distant metastases, designed with 80% power to detect an improvement from 90% with salvage radiotherapy (control) to 95% at 10 years with adjuvant radiotherapy. We report on biochemical progression-free survival, freedom from non-protocol hormone therapy, safety, and patient-reported outcomes. Standard survival analysis methods were used. A hazard ratio (HR) of less than 1 favoured adjuvant radiotherapy. This study is registered with, NCT00541047. Findings: Between Nov 22, 2007, and Dec 30, 2016, 1396 patients were randomly assigned, 699 (50%) to salvage radiotherapy and 697 (50%) to adjuvant radiotherapy. Allocated groups were balanced with a median age of 65 years (IQR 60-68). Median follow-up was 4·9 years (IQR 3·0-6·1). 649 (93%) of 697 participants in the adjuvant radiotherapy group reported radiotherapy within 6 months; 228 (33%) of 699 in the salvage radiotherapy group reported radiotherapy within 8 years after randomisation. With 169 events, 5-year biochemical progression-free survival was 85% for those in the adjuvant radiotherapy group and 88% for those in the salvage radiotherapy group (HR 1·10, 95% CI 0·81-1·49; p=0·56). Freedom from non-protocol hormone therapy at 5 years was 93% for those in the adjuvant radiotherapy group versus 92% for those in the salvage radiotherapy group (HR 0·88, 95% CI 0·58-1·33; p=0·53). Self-reported urinary incontinence was worse at 1 year for those in the adjuvant radiotherapy group (mean score 4·8 vs 4·0; p=0·0023). Grade 3-4 urethral stricture within 2 years was reported in 6% of individuals in the adjuvant radiotherapy group versus 4% in the salvage radiotherapy group (p=0·020). Interpretation: These initial results do not support routine administration of adjuvant radiotherapy after radical prostatectomy. Adjuvant radiotherapy increases the risk of urinary morbidity. An observation policy with salvage radiotherapy for PSA biochemical progression should be the current standard after radical prostatectomy.
  • Proliferation and AKT Activity Biomarker Analyses after Capivasertib (AZD5363) Treatment of Patients with ER+ Invasive Breast Cancer (STAKT).

    Jahan, Ali (Clinical Cancer Research, 2020-04)
    Purpose: The STAKT study examined short-term exposure (4.5 days) to the oral selective pan-AKT inhibitor capivasertib (AZD5363) to determine if this drug can reach its therapeutic target in sufficient concentration to significantly modulate key biomarkers of the AKT pathway and tumor proliferation. Patients and Methods: STAKT was a two-stage, double-blind, randomized, placebo-controlled, "window-of-opportunity" study in patients with newly diagnosed ER + invasive breast cancer. Stage 1 assessed capivasertib 480 mg b.i.d. (recommended monotherapy dose) and placebo, and stage 2 assessed capivasertib 360 and 240 mg b.i.d. Primary endpoints were changes from baseline in AKT pathway markers pPRAS40, pGSK3β, and proliferation protein Ki67. Pharmacologic and pharmacodynamic properties were analyzed from blood sampling, and tolerability by adverse-event monitoring. Results: After 4.5 days' exposure, capivasertib 480 mg b.i.d. ( n = 17) produced significant decreases from baseline versus placebo ( n = 11) in pGSK3β (H-score absolute change: -55.3, P = 0.006) and pPRAS40 (-83.8, P < 0.0001), and a decrease in Ki67 (absolute change in percentage positive nuclei: -9.6%, P = 0.031). Significant changes also occurred in secondary signaling biomarker pS6 (-42.3, P = 0.004), while pAKT (and nuclear FOXO3a) also increased in accordance with capivasertib's mechanism (pAKT: 81.3, P = 0.005). At doses of 360 mg b.i.d. ( n = 5) and 240 mg b.i.d. ( n = 6), changes in primary and secondary biomarkers were also observed, albeit of smaller magnitude. Biomarker modulation was dose and concentration dependent, and no new safety signals were evident. Conclusions: Capivasertib 480 mg b.i.d. rapidly modulates key biomarkers of the AKT pathway and decreases proliferation marker Ki67, suggesting future potential as an effective therapy in AKT-dependent breast cancers.

View more