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Capivasertib (AZD5363) is a potent selective oral inhibitor of all three isoforms of the serine/threonine kinase AKT. The FAKTION trial investigated whether the addition of capivasertib to fulvestrant improved progression-free survival in patients with aromatase inhibitor-resistant advanced breast cancer. In this randomised, double-blind, placebo-controlled, phase 2 trial, postmenopausal women aged at least 18 years with an Eastern Cooperative Oncology Group performance status of 0–2 and oestrogen receptor-positive, HER2-negative, metastatic or locally advanced inoperable breast cancer who had relapsed or progressed on an aromatase inhibitor were recruited from 19 hospitals in the UK. Enrolled participants were randomly assigned (1:1) to receive intramuscular fulvestrant 500 mg (day 1) every 28 days (plus a loading dose on day 15 of cycle 1) with either capivasertib 400 mg or matching placebo, orally twice daily on an intermittent weekly schedule of 4 days on and 3 days off (starting on cycle 1 day 15) until disease progression, unacceptable toxicity, loss to follow-up, or withdrawal of consent. Treatment allocation was done using an interactive web-response system using a minimisation method (with a 20% random element) and the following minimisation factors: measurable or non-measurable disease, primary or secondary aromatase inhibitor resistance, PIK3CA status, and PTEN status. The primary endpoint was progression-free survival with a one-sided alpha of 0·20. Analyses were done by intention to treat. Recruitment is complete, and the trial is in follow-up. This trial is registered with ClinicalTrials.gov, number NCT01992952. Between March 16, 2015, and March 6, 2018, 183 patients were screened for eligibility, of whom 140 (76%) were eligible and were randomly assigned to receive fulvestrant plus capivasertib (n=69) or fulvestrant plus placebo (n=71). Median follow-up for progression-free survival was 4·9 months (IQR 1·6–11·6). At the time of primary analysis for progression-free survival (Jan 30, 2019), 112 progression-free survival events had occurred, 49 (71%) in 69 patients in the capivasertib group compared with 63 (89%) of 71 in the placebo group. Median progression-free survival was 10·3 months (95% CI 5·0–13·2) in the capivasertib group versus 4·8 months (3·1–7·7) in the placebo group, giving an unadjusted hazard ratio (HR) of 0·58 (95% CI 0·39–0·84) in favour of the capivasertib group (two-sided p=0·0044; one-sided log rank test p=0·0018). The most common grade 3–4 adverse events were hypertension (22 [32%] of 69 patients in the capivasertib group vs 17 [24%] of 71 in the placebo group), diarrhoea (ten [14%] vs three [4%]), rash (14 [20%] vs 0), infection (four [6%] vs two [3%]), and fatigue (one [1%] vs three [4%]). Serious adverse reactions occurred only in the capivasertib group, and were acute kidney injury (two), diarrhoea (three), rash (two), hyperglycaemia (one), loss of consciousness (one), sepsis (one), and vomiting (one). One death, due to atypical pulmonary infection, was assessed as possibly related to capivasertib treatment. One further death in the capivasertib group had an unknown cause; all remaining deaths in both groups (19 in the capivasertib group and 31 in the placebo group) were disease related. Progression-free survival was significantly longer in participants who received capivasertib than in those who received placebo. The combination of capivasertib and fulvestrant warrants further investigation in phase 3 trials. AstraZeneca and Cancer Research UK.

Capivasertib, an AKT inhibitor, added to fulvestrant, was previously reported to improve progression-free survival in women with aromatase inhibitor-resistant oestrogen receptor (ER)-positive, HER2-negative advanced breast cancer. The benefit appeared to be independent of the phosphoinositide 3-kinase (PI3K)/AKT/phosphatase and tensin homologue (PTEN) pathway alteration status of tumours, as ascertained using assays available at the time. Here, we report updated progression-free survival and overall survival results, and a prespecified examination of the effect of PI3K/AKT/PTEN pathway alterations identified by an expanded genetic testing panel on treatment outcomes. This randomised, multicentre, double-blind, placebo-controlled, phase 2 trial recruited postmenopausal adult women aged at least 18 years with ER-positive, HER2-negative, metastatic or locally advanced inoperable breast cancer and an Eastern Cooperative Oncology Group performance status of 0–2, who had relapsed or progressed on an aromatase inhibitor, from across 19 hospitals in the UK. Participants were randomly assigned (1:1) to receive intramuscular fulvestrant 500 mg (day 1) every 28 days (plus a 500 mg loading dose on day 15 of cycle 1) with either capivasertib 400 mg or matching placebo, orally twice daily on an intermittent weekly schedule of 4 days on and 3 days off, starting on cycle 1 day 15. Treatment continued until disease progression, unacceptable toxicity, loss to follow-up, or withdrawal of consent. Treatment was allocated by an interactive web-response system using a minimisation method (with a 20% random element) and the following minimisation factors: measurable or non-measurable disease, primary or secondary aromatase inhibitor resistance, PIK3CA status, and PTEN status. The primary endpoint was progression-free survival in the intention-to-treat population. Secondary endpoints shown in this Article were overall survival and safety in the intention-to-treat population, and the effect of tumour PI3K/AKT/PTEN pathway status identified by an expanded testing panel that included next-generation sequencing assays. Recruitment is complete. The trial is registered with ClinicalTrials.gov, number NCT01992952. Between March 16, 2015, and March 6, 2018, 183 participants were screened for eligibility and 140 (77%) were randomly assigned to receive fulvestrant plus capivasertib (n=69) or fulvestrant plus placebo (n=71). Median follow-up at the data cut-off of Nov 25, 2021, was 58·5 months (IQR 45·9–64·1) for participants treated with fulvestrant plus capivasertib and 62·3 months (IQR 62·1–70·3) for fulvestrant plus placebo. Updated median progression-free survival was 10·3 months (95% CI 5·0–13·4) in the group receiving fulvestrant plus capivasertib compared with 4·8 months (3·1–7·9) for fulvestrant plus placebo (adjusted hazard ratio [HR] 0·56 [95% CI 0·38–0·81]; two-sided p=0·0023). Median overall survival in the capivasertib versus placebo groups was 29·3 months (95% CI 23·7–39·0) versus 23·4 months (18·7–32·7; adjusted HR 0·66 [95% CI 0·45–0·97]; two-sided p=0·035). The expanded biomarker panel identified an expanded pathway-altered subgroup that contained 76 participants (54% of the intention-to-treat population). Median progression-free survival in the expanded pathway-altered subgroup for participants receiving capivasertib (n=39) was 12·8 months (95% CI 6·6–18·8) compared with 4·6 months (2·8–7·9) in the placebo group (n=37; adjusted HR 0·44 [95% CI 0·26–0·72]; two-sided p=0·0014). Median overall survival for the expanded pathway-altered subgroup receiving capivasertib was 38·9 months (95% CI 23·3–50·7) compared with 20·0 months (14·8–31·4) for those receiving placebo (adjusted HR 0·46 [95% CI 0·27–0·79]; two-sided p=0·0047). By contrast, there were no statistically significant differences in progression-free or overall survival in the expanded pathway non-altered subgroup treated with capivasertib (n=30) versus placebo (n=34). One additional serious adverse event (pneumonia) in the capivasertib group had occurred subsequent to the primary analysis. One death, due to atypical pulmonary infection, was assessed as possibly related to capivasertib treatment. Updated FAKTION data showed that capivasertib addition to fulvestrant extends the survival of participants with aromatase inhibitor-resistant ER-positive, HER2-negative advanced breast cancer. The expanded biomarker testing suggested that capivasertib predominantly benefits patients with PI3K/AKT/PTEN pathway-altered tumours. Phase 3 data are needed to substantiate the results, including in patients with previous CDK4/6 inhibitor exposure who were not included in the FAKTION trial. AstraZeneca and Cancer Research UK.

Review of the spectrum of breast cancer tumor subtypes, which include basal-like, triple-negative and BRCA1-positive tumors, suggest that they have overlapping clinical, pathologic and molecular features, which are different from endocrine responsive breast cancers. Although response to chemotherapy is high in the neoadjuvant setting, the overall prognosis of this subset of tumors remains poor. Gene-profiling studies of this heterogeneous subset have lead to a better understanding of the molecular pathology of these aggressive tumors and the identification of possible therapeutic targets. Ongoing clinical studies of newer targeted agents, along with optimal chemotherapy, portend an improved clinical outcome for patients with aggressive basal-like/triple-negative breast cancer in the future.

IntroductionThe diagnosis and quantification of chemotherapy‐induced peripheral neuropathy (CIPN) remains a challenge. Conventional methods including quantitative sensory testing (QST), nerve conduction tests, and biopsy are unable to detect subclinical changes, and do not consistently correlate with severity of patients' symptoms and functional impairment. This study aims to determine the utility of the LDI (laser Doppler imager) FLARE technique in the diagnosis of CIPN and whether it correlates with symptom severity.Materials and MethodsWe assessed 24 patients with established CIPN [12 due to platinum analogs (PA) and 12 to Taxanes (TX)] and 24 matched healthy controls (HC). All underwent neurophysiological examination including vibration perception threshold (VPT), sural nerve amplitude (SNAP) and conduction velocity (SNCV), LDIFLARE, and fasting biochemistry. The QLQ‐CIPN20 questionnaire was used to assess symptom severity.ResultsHC, combined chemotherapy (CG), PA, and TX groups were matched for age, sex, BMI, and blood pressure. The LDIFLARE was significantly reduced in CG compared to HC (P =< 0.0001), whereas SNAP (P = 0.058) and SNCV (P = 0.054) were not. The LDIFLARE correlated with the QLQ‐CIPN20 symptom scores in all three categories namely, CG (P =< 0.0001), PA (P = 0.001) and TX (P = 0.027) whilst, VPT, SNAP, and SNCV did not.ConclusionOur findings suggest that the LDIFLARE technique is more helpful in confirming the diagnosis of CIPN in patients with distal sensory symptoms than current commonly used methods. Moreover, this novel test fulfils the unmet need for a diagnostic test that relates to the severity of symptoms. This may be useful in quantifying early changes in small fibre function indicating early CIPN.

Introduction The diagnosis and quantification of chemotherapy‐induced peripheral neuropathy (CIPN) remains a challenge. Conventional methods including quantitative sensory testing (QST), nerve conduction tests, and biopsy are unable to detect subclinical changes, and do not consistently correlate with severity of patients' symptoms and functional impairment. This study aims to determine the utility of the LDI (laser Doppler imager) FLARE technique in the diagnosis of CIPN and whether it correlates with symptom severity. Materials and Methods We assessed 24 patients with established CIPN [12 due to platinum analogs (PA) and 12 to Taxanes (TX)] and 24 matched healthy controls (HC). All underwent neurophysiological examination including vibration perception threshold (VPT), sural nerve amplitude (SNAP) and conduction velocity (SNCV), LDIFLARE, and fasting biochemistry. The QLQ‐CIPN20 questionnaire was used to assess symptom severity. Results HC, combined chemotherapy (CG), PA, and TX groups were matched for age, sex, BMI, and blood pressure. The LDIFLARE was significantly reduced in CG compared to HC (P =< 0.0001), whereas SNAP (P = 0.058) and SNCV (P = 0.054) were not. The LDIFLARE correlated with the QLQ‐CIPN20 symptom scores in all three categories namely, CG (P =< 0.0001), PA (P = 0.001) and TX (P = 0.027) whilst, VPT, SNAP, and SNCV did not. Conclusion Our findings suggest that the LDIFLARE technique is more helpful in confirming the diagnosis of CIPN in patients with distal sensory symptoms than current commonly used methods. Moreover, this novel test fulfils the unmet need for a diagnostic test that relates to the severity of symptoms. This may be useful in quantifying early changes in small fibre function indicating early CIPN. The LDIFLARE (Laser doppler imager) technique is a sensitive method of assessing early C‐fibre dysfunction by measuring the axon‐reflex mediated skin hyperaemic response to heating of the foot skin.

PARTNER is a prospective, phase II-III, randomised controlled clinical trial, which recruited patients with Triple Negative Breast Cancer (TNBC) , who were gBRCA wild type (gBRCAwt) . Patients (n=559) were randomised on a 1:1 basis to neoadjuvant carboplatin with paclitaxel +/- olaparib 150mg twice daily, days 3 to 14, for 4 cycles (gap schedule olaparib, research arm) followed by 3 cycles of anthracycline chemotherapy before surgery. The primary endpoint was pathological complete response (pCR) , and secondary endpoints included event-free survival (EFS), and overall survival (OS) . pCR was achieved in 51% in the research arm and 52% in the control arm (p=0.753). Estimated EFS at 36 months in research and control arms were 80% and 79% (log-rank p>0.9); OS were 90% and 87.2% (log-rank p=0.8) respectively. In patients with pCR, estimated EFS at 36 months was 90%, and with non-pCR was 70% (log-rank p < 0.001) and OS was 96% and 83% (log-rank p < 0.001) respectively. Neo-adjuvant olaparib did not improve pCR rates, EFS or OS when added to carboplatin/paclitaxel and anthracycline chemotherapy in patients with TNBC (gBRCAwt). This is in marked contrast to the major benefit of olaparib (gap schedule) in those with gBRCA pathogenic variants (gBRCAm) which is reported separately (gBRCAm article). ClinicalTrials.gov ID NCT03150576.

Isolated testicular metastasis from rectal cancer is rare. We describe the case of a patient who presented with a locally advanced rectal malignancy and underwent multimodality treatment with low anterior resection, postoperative radiotherapy and adjuvant chemotherapy. He developed a painless testicular nodule while on follow-up, five years after the diagnosis of primary rectal cancer. Histopathology and immunohistochemistry of orchidectomy specimen were compatible with a metastatic adenocarcinoma of rectal origin. We hypothesize that this phenomenon of isolated relapse in a sanctuary site could be due to the altered biology and pattern of metastasis as a result of effective adjuvant systemic chemotherapy. Treatment of late isolated relapse in the testis needs to be ascertained.

Context: Radiotherapy is the cornerstone of treatment in nasopharyngeal cancer (NPC); the addition of chemotherapy has shown improved results. Aims: To compare the results of concurrent chemoradiation with that of radiotherapy alone in NPC. Materials and Methods: One hundred and ninety consecutive NPC patients, without distant metastasis, who reported to the institute from January 1992 to December 2001, received external-beam radiation to 66 Gy in 33 fractions. Seventy-five of these patients received concurrent chemotherapy with cisplatin and 5-fluorouracil (5-FU) for four cycles. We compared the results of treatment in these two groups. Results: The 5-year disease-free survival rates were 40% and 60%, respectively, for patients who had radiotherapy alone and those who had chemoradiation (P = 0.002), while the median survival was 45 months and 60 months, respectively (P = 0.0028). Conclusion: A significant improvement in local control and survival was observed by the addition of concurrent chemotherapy with cisplatin and 5-FU to radical radiation in this nonrandomized study on patients with NPC.

The aim of this study was to determine whether serum concentrations of micronutrients, antioxidants and vitamins predict rate of disease progression in untreated, localised prostate cancer. Patients with localised prostatic adenocarcinoma on a prospective study of active surveillance underwent monitoring with serial PSA levels and repeat prostate biopsies. Disease progression was defined as either adverse histology on repeat biopsy (primary Gleason grade ≥4 or >50% positive cores of total) or radical treatment for PSA velocity >1 ng ml −1 year −1 . Time to disease progression was analysed with respect to baseline levels of alpha-tocopherol, gamma-tocopherol, alpha-carotene and beta-carotene, lycopene, retinol and selenium. One hundred four patients were evaluable, with a median follow-up of 2.5 years. Thirty-eight patients experienced disease progression, 13 biochemical and 25 histologic progression. Median time to disease progression was 2.62 years. No significant association was seen between time to disease progression and baseline serum levels of alpha-tocopherol ( p  = 0.86), gamma-tocopherol ( p  = 0.84), alpha-carotenoid ( p  = 0.66), beta-carotene ( p  = 0.65), lycopene ( p  = 0.0.15), retinol ( p  = 0.76) or selenium ( p  = 0.76). No significant association was seen between serum levels of the micronutrients, antioxidants or vitamins and either adverse histology on repeat biopsy or PSA velocity. Our data do not support the hypothesis that high serum concentrations of micronutrients, antioxidants and vitamins prevent disease progression in men with localised prostate cancer.

Objectives: To use an electroglottography (EGG)-based videostroboscopy tool to assess the anatomical and morphologic characteristics of the pharyngoesophageal (PE) segment in tracheoesophageal (TO) speakers. Study design: Cross-sectional cohort study. Subjects: Fifty-two post-laryngectomy patients with no recurrence and using prosthetic (Blom-Singer) speech. Intervention: An electroglottography (EGG)-based videostroboscopy tool EGG-based rigid videostroboscopy as well as perceptual evaluation. Outcome measures: Stroboscopic protocol included nine subjective/visual parameters to evaluate the neoglottis and study correlation of the G (GRBAS scale) and the overall voice quality (OVQ) with the treatment variables. Results: Of the 52 laryngectomees, videostroboscopic recordings were possible in 46 patients (36 males and 10 females) with a mean age of 63.4 ±10.5 (SD) an electroglottography (EGG)-based videostroboscopy tool years. All used the Blom-Singer valve and the median time since Total Laryngectomy was 2 years. The neoglottis was assessable in 26 patients. We were able to strobe only 9 patients. There was excellent correlation between G and OVQ (Spearman rho > 0.9). Statistically significant correlation was found between G1 and saliva (P = 0.03) and between good OVQ and saliva (P = 0.02); similarly, there was significant correlation between G1 and LVV (P = 0.05) and between good OVQ and LVV (P = 0.03). Conclusions: This study is the first to examine the use of an EGG-based stroboscopy instrument to evaluate TO speech. Our observations suggest that from the standpoint of functional voice, saliva and the LVV had statistically significant effect in determining voice quality.