Abemaciclib plus trastuzumab with or without fulvestrant versus trastuzumab plus standard-of-care chemotherapy in women with hormone receptor-positive, HER2-positive advanced breast cancer (monarcHER): a randomised, open-label, phase 2 trial.

BACKGROUND: Patients with HER2-positive breast cancer who have received two or more previous therapies for advanced disease have few effective treatment options. The monarcHER trial aimed to compare the efficacy of abemaciclib plus trastuzumab with or without fulvestrant with standard-of-care chemotherapy of physician's choice plus trastuzumab in women with advanced breast cancer. METHODS: This phase 2, three-group, open-label trial was done across 75 hospitals, clinics, and medical centres in 14 countries. Eligible patients were women aged 18 years or older, who had hormone receptor-positive, HER2-positive advanced breast cancer with unresectable, locally advanced, recurrent or metastatic disease, Eastern Cooperative Oncology Group performance status of 0 or 1, and who had previously received at least two HER2-targeted therapies for advanced disease. Patients were randomly assigned 1:1:1 to the abemaciclib, trastuzumab, and fulvestrant (group A), abemaciclib and trastuzumab (group B), or standard-of-care chemotherapy and trastuzumab (group C). Oral abemaciclib 150 mg 12 hourly was administered on days 1-21 of a 21-day cycle, intravenous trastuzumab 8 mg/kg on cycle 1 day 1, followed by 6 mg/kg on day 1 of each subsequent 21-day cycle, and intramuscular fulvestrant 500 mg on days 1, 15, and 29 and once every 4 weeks thereafter. Standard-of-care chemotherapy was administered as specified by the product label. Randomisation was by a computer-generated random sequence by means of an interactive web-response system and stratified by number of previous systemic therapies for advanced breast cancer and measurable versus non-measurable disease. The primary endpoint was investigator-assessed progression-free survival in the intention-to-treat population, first testing group A versus group C and, if this result was significant, then group B versus group C. Safety was assessed in all patients who had received at least one dose of study treatment. This trial is registered at ClinicalTrials.gov (NCT02675231) and is ongoing for long-term survival follow-up. FINDINGS: Between May 31, 2016, and Feb 28, 2018, 325 patients were screened, of whom 237 eligible patients were enrolled and randomly assigned to groups A (n=79), B (n=79), and C (n=79). Median follow-up was 19·0 months (IQR 14·7-25·1). The study met its primary endpoint, showing a significant difference at the prespecified two-sided α of 0·2 in median progression-free survival between group A (8·3 months, 95% CI 5·9-12·6) and group C (5·7 months, 5·4-7·0; HR 0·67 [95% CI 0·45-1·00]; p=0·051). No difference was observed between median progression-free survival in group B (5·7 months, 95% CI 4·2-7·2) and group C (HR 0·94 [0·64-1·38]; p=0·77). The most common grade 3-4 treatment-emergent adverse event in groups A, B, and C was neutropenia (21 [27%] of 78 patients, 17 [22%] of 77, and 19 [26%] of 72). The most common serious adverse events were: in group A, pyrexia (three [4%]), diarrhoea (two [3%]), urinary tract infection (two [3%]), and acute kidney injury (two [3%]); in group B, diarrhoea (two [3%]) and pneumonitis (two [3%]); and in group C, neutropenia (four [6%]) and pleural effusion (two [3%]). Two deaths were attributed to treatment: one due to pulmonary fibrosis in group B and one due to febrile neutropenia in group C. INTERPRETATION: The combination of abemaciclib, fulvestrant, and trastuzumab significantly improved progression-free survival versus standard-of-care chemotherapy plus trastuzumab while showing a tolerable safety profile. Our results suggest that a chemotherapy-free regimen might potentially be an alternative treatment option for patients with hormone receptor-positive, HER2-positive advanced breast cancer. FUNDING: Eli Lilly and Company.

Circulating tumour DNA analysis to direct therapy in advanced breast cancer (plasmaMATCH): a multicentre, multicohort, phase 2a, platform trial.

BACKGROUND: Circulating tumour DNA (ctDNA) testing might provide a current assessment of the genomic profile of advanced cancer, without the need to repeat tumour biopsy. We aimed to assess the accuracy of ctDNA testing in advanced breast cancer and the ability of ctDNA testing to select patients for mutation-directed therapy. METHODS: We did an open-label, multicohort, phase 2a, platform trial of ctDNA testing in 18 UK hospitals. Participants were women (aged ≥18 years) with histologically confirmed advanced breast cancer and an Eastern Cooperative Oncology Group performance status 0-2. Patients had completed at least one previous line of treatment for advanced breast cancer or relapsed within 12 months of neoadjuvant or adjuvant chemotherapy. Patients were recruited into four parallel treatment cohorts matched to mutations identified in ctDNA: cohort A comprised patients with ESR1 mutations (treated with intramuscular extended-dose fulvestrant 500 mg); cohort B comprised patients with HER2 mutations (treated with oral neratinib 240 mg, and if oestrogen receptor-positive with intramuscular standard-dose fulvestrant); cohort C comprised patients with AKT1 mutations and oestrogen receptor-positive cancer (treated with oral capivasertib 400 mg plus intramuscular standard-dose fulvestrant); and cohort D comprised patients with AKT1 mutations and oestrogen receptor-negative cancer or PTEN mutation (treated with oral capivasertib 480 mg). Each cohort had a primary endpoint of confirmed objective response rate. For cohort A, 13 or more responses among 78 evaluable patients were required to infer activity and three or more among 16 were required for cohorts B, C, and D. Recruitment to all cohorts is complete and long-term follow-up is ongoing. This trial is registered with ClinicalTrials.gov, NCT03182634; the European Clinical Trials database, EudraCT2015-003735-36; and the ISRCTN registry, ISRCTN16945804. FINDINGS: Between Dec 21, 2016, and April 26, 2019, 1051 patients registered for the study, with ctDNA results available for 1034 patients. Agreement between ctDNA digital PCR and targeted sequencing was 96-99% (n=800, kappa 0·89-0·93). Sensitivity of digital PCR ctDNA testing for mutations identified in tissue sequencing was 93% (95% CI 83-98) overall and 98% (87-100) with contemporaneous biopsies. In all cohorts, combined median follow-up was 14·4 months (IQR 7·0-23·7). Cohorts B and C met or exceeded the target number of responses, with five (25% [95% CI 9-49]) of 20 patients in cohort B and four (22% [6-48]) of 18 patients in cohort C having a response. Cohorts A and D did not reach the target number of responses, with six (8% [95% CI 3-17]) of 74 in cohort A and two (11% [1-33]) of 19 patients in cohort D having a response. The most common grade 3-4 adverse events were raised gamma-glutamyltransferase (13 [16%] of 80 patients; cohort A); diarrhoea (four [25%] of 20; cohort B); fatigue (four [22%] of 18; cohort C); and rash (five [26%] of 19; cohort D). 17 serious adverse reactions occurred in 11 patients, and there was one treatment-related death caused by grade 4 dyspnoea (in cohort C). INTERPRETATION: ctDNA testing offers accurate, rapid genotyping that enables the selection of mutation-directed therapies for patients with breast cancer, with sufficient clinical validity for adoption into routine clinical practice. Our results demonstrate clinically relevant activity of targeted therapies against rare HER2 and AKT1 mutations, confirming these mutations could be targetable for breast cancer treatment. FUNDING: Cancer Research UK, AstraZeneca, and Puma Biotechnology.

6 versus 12 months of adjuvant trastuzumab for HER2-positive early breast cancer (PERSEPHONE): 4-year disease-free survival results of a randomised phase 3 non-inferiority trial.

BACKGROUND: Adjuvant trastuzumab significantly improves outcomes for patients with HER2-positive early breast cancer. The standard treatment duration is 12 months but shorter treatment could provide similar efficacy while reducing toxicities and cost. We aimed to investigate whether 6-month adjuvant trastuzumab treatment is non-inferior to the standard 12-month treatment regarding disease-free survival. METHODS: This study is an open-label, randomised phase 3 non-inferiority trial. Patients were recruited from 152 centres in the UK. We randomly assigned patients with HER2-positive early breast cancer, aged 18 years or older, and with a clear indication for chemotherapy, by a computerised minimisation process (1:1), to receive either 6-month or 12-month trastuzumab delivered every 3 weeks intravenously (loading dose of 8 mg/kg followed by maintenance doses of 6 mg/kg) or subcutaneously (600 mg), given in combination with chemotherapy (concurrently or sequentially). The primary endpoint was disease-free survival, analysed by intention to treat, with a non-inferiority margin of 3% for 4-year disease-free survival. Safety was analysed in all patients who received trastuzumab. This trial is registered with EudraCT (number 2006-007018-39), ISRCTN (number 52968807), and ClinicalTrials.gov (number NCT00712140). FINDINGS: Between Oct 4, 2007, and July 31, 2015, 2045 patients were assigned to 12-month trastuzumab treatment and 2044 to 6-month treatment (one patient was excluded because they were double randomised). Median follow-up was 5·4 years (IQR 3·6-6·7) for both treatment groups, during which a disease-free survival event occurred in 265 (13%) of 2043 patients in the 6-month group and 247 (12%) of 2045 patients in the 12-month group. 4-year disease-free survival was 89·4% (95% CI 87·9-90·7) in the 6-month group and 89·8% (88·3-91·1) in the 12-month group (hazard ratio 1·07 [90% CI 0·93-1·24], non-inferiority p=0·011), showing non-inferiority of the 6-month treatment. 6-month trastuzumab treatment resulted in fewer patients reporting severe adverse events (373 [19%] of 1939 patients vs 459 [24%] of 1894 patients, p=0·0002) or stopping early because of cardiotoxicity (61 [3%] of 1939 patients vs 146 [8%] of 1894 patients, p<0·0001). INTERPRETATION: We have shown that 6-month trastuzumab treatment is non-inferior to 12-month treatment in patients with HER2-positive early breast cancer, with less cardiotoxicity and fewer severe adverse events. These results support consideration of reduced duration trastuzumab for women at similar risk of recurrence as to those included in the trial. FUNDING: UK National Institute for Health Research, Health Technology Assessment Programme.

Health-related quality of life and work productivity in UK patients with HER2-positive breast cancer: a cross-sectional study evaluating the relationships between disease and treatment stage.

BACKGROUND: The impact of different disease stages and treatment for human epidermal growth factor 2 positive (HER2-positive) breast cancer (BC) on work productivity and health-related quality of life (HRQoL) is poorly understood. METHODS: This was a UK cross-sectional study of 299 adult patients with HER2-positive early or metastatic BC (NCT03099200). Productivity was assessed using the work productivity and activity impairment scale; HRQoL was measured using EuroQol-5 Dimensions-5 levels (EQ-5D-5L), and Functional Assessment of Cancer Therapy Breast (FACT-G and -B) instruments. Three balanced patient groups were recruited: (1) early BC on treatment post-surgery, (2) early BC after completion of adjuvant treatment, (3) during metastatic BC treatment. Between-group comparisons were performed using an analysis of variance. RESULTS: Group 1 comprised 89 patients, Group 2, 108 and Group 3, 102. Age, ethnicity and comorbidities were similar across groups. Patients in Group 3 reported more often being unable to work (significant Bonferroni adjusted p < 0.003). Proportions of employed patients were 50.6%, 50.9% and 27.5% in Groups 1, 2 and 3, respectively. For patients in part-time employment, the number of hours worked was significantly higher in Group 2 patients versus Group 3 (p = 0.002). Group 2 also had significantly lower levels of work absenteeism and overall work impairment compared with Group 1 (p < 0.001). Patients in Group 3 reported worse health utility scores (p ≤ 0.002), moderate or worse problems in the EQ-5D-5L self-care and usual activity domains (p ≤ 0.001), and lower HRQoL as assessed by FACT summary scores (p < 0.001 for FACT-B and -G) than Groups 1 and 2. Poorer HRQoL was significantly associated with higher work impairment (p < 0.001), with the strongest relationships being observed between activity impairment and HRQoL (Pearson's r: 0.67). CONCLUSIONS: Metastatic disease and treatment of HER2-positive BC adversely impacted on work productivity and HRQoL. The results of this study support the idea that being able to delay or prevent the metastatic recurrence of BC, for example by extending the time patients are in remission or at early stage of BC, has wider benefits in terms of patient productivity and HRQoL.

Adjuvant trastuzumab duration trials in HER2 positive breast cancer - what results would be practice-changing? Persephone investigator questionnaire prior to primary endpoint results.

BACKGROUND: Twelve months treatment is the current standard of care for adjuvant trastuzumab in patients with HER2 positive early breast cancer however the optimal duration is not known. Persephone is a non-inferiority randomised controlled trial comparing 6- to 12-months of trastuzumab. In this trial there will be a trade-off between a possible small decrease in disease-free survival (DFS) with 6-months and reduced cardiotoxicity and cost. METHODS: A structured questionnaire asked clinicians who had recruited patients into the Persephone trial about their prior beliefs with regards to the clinical effectiveness of trastuzumab and cardiotoxicity profile, in the comparison of 6- and 12-month durations. RESULTS: Fifty-one clinicians from 40 of the 152 Persephone sites completed the questionnaire. 30/50 responders (60%) believed that 6-months trastuzumab would give the same 4-year DFS rate as 12-months trastuzumab, with 21/50 (42%) holding this belief across all breast cancer subsets. In addition, 46/49 responders (94%) reported expecting to change their clinical practice to 6-months, with their prior beliefs (most commonly 85% 4-year DFS rate with 6-months) being greater than their lowest acceptable rate (most commonly 83% 4-year DFS rate with 6-months). Low levels of cardiotoxicity were expected with both 6 and 12-months trastuzumab, with the majority expecting lower levels with 6-months. With increasing hypothesised differences of cardiotoxicity rates between the two durations, significantly lower levels of 4-year DFS with 6-months trastuzumab were deemed acceptable (p < 0.0001). CONCLUSION: Most responders believe that 6-months trastuzumab is adequate, both overall and within each subset of breast cancer, and plan to change their clinical practice if the Persephone results support their prior belief. An individual patient meta-analysis of the duration trials would give greater precision to estimates of the differences in efficacy and toxicity, and adequate statistical power to establish a 2% level of non-inferiority for 6-months adjuvant trastuzumab.

Addition of gemcitabine to paclitaxel, epirubicin, and cyclophosphamide adjuvant chemotherapy for women with early-stage breast cancer (tAnGo): final 10-year follow-up of an open-label, randomised, phase 3 trial.

BACKGROUND: The tAnGo trial was designed to investigate the potential role of gemcitabine when added to anthracycline and taxane-containing adjuvant chemotherapy for early breast cancer. When this study was developed, gemcitabine had shown significant activity in metastatic breast cancer, and there was evidence of a favourable interaction with paclitaxel. METHODS: tAnGo was an international, open-label, randomised, phase 3 superiority trial that enrolled women aged 18 years or older with newly diagnosed, early-stage breast cancer who had a definite indication for chemotherapy, any nodal status, any hormone receptor status, Eastern Cooperative Oncology Group performance status of 0-1, and adequate bone marrow, hepatic, and renal function. Women were recruited from 127 clinical centres and hospitals in the UK and Ireland, and randomly assigned (1:1) to one of two treatment regimens: epirubicin, cyclophosphamide, and paclitaxel (four cycles of 90 mg/m2 intravenously administered epirubicin and 600 mg/m2 intravenously administered cyclophosphamide on day 1 every 3 weeks, followed by four cycles of 175 mg/m2 paclitaxel as a 3 h infusion on day 1 every 3 weeks) or epirubicin, cyclophosphamide, and paclitaxel plus gemcitabine (the same chemotherapy regimen as the other group, with the addition of 1250 mg/m2 gemcitabine to the paclitaxel cycles, administered intravenously as a 0·5 h infusion on days 1 and 8 every 3 weeks). Patients were randomly assigned by a central computerised deterministic minimisation procedure, with stratification by country, age, radiotherapy intent, nodal status, and oestrogen receptor and HER-2 status. The primary endpoint was disease-free survival and the trial aimed to detect 5% differences in 5-year disease-free survival between the treatment groups. Recruitment completed in 2004 and this is the final, intention-to-treat analysis. This trial is registered with EudraCT (2004-002927-41), ISRCTN (51146252), and ClinicalTrials.gov (NCT00039546). FINDINGS: Between Aug 22, 2001, and Nov 26, 2004, 3152 patients were enrolled and randomly assigned to epirubicin, cyclophosphamide, paclitaxel, and gemcitabine (gemcitabine group; n=1576) or to epirubicin, cyclophosphamide, and paclitaxel (control group; n=1576). 11 patients (six in the gemcitabine group and five in the control group) were ineligible because of pre-existing metastases and were therefore excluded from the analysis. At this protocol-specified final analysis (median follow-up 10 years [IQR 10-10]), 1087 disease-free survival events and 914 deaths had occurred. Disease-free survival did not differ significantly between the treatment groups at 10 years (65% [63-68] in the gemcitabine group vs 65% [62-67] in the control group), and median disease-free survival was not reached (adjusted hazard ratio 0·97 [95% CI 0·86-1·10], p=0·64). Toxicity, dose intensity, and a detailed safety substudy showed both regimens to be safe, deliverable, and tolerable. Grade 3 and 4 toxicities were reported at expected levels in both groups. The most common were neutropenia (527 [34%] of 1565 patients in the gemcitabine group vs 412 [26%] of 1567 in the control group), myalgia and arthralgia (207 [13%] vs 186 [12%]), fatigue (207 [13%] vs 152 [10%]), infection (202 [13%] vs 141 [9%]), vomiting (143 [9%] vs 108 [7%]), and nausea (132 [8%] vs 102 [7%]). INTERPRETATION: The addition of gemcitabine to anthracycline and taxane-based adjuvant chemotherapy at this dose and schedule confers no therapeutic advantage in terms of disease-free survival in early breast cancer, although it can cause increased toxicity. Therefore, gemcitabine has not been added to standard adjuvant chemotherapy in breast cancer for any subgroup. FUNDING: Cancer Research UK core funding for Clinical Trials Unit at the University of Birmingham, Eli Lilly, Bristol-Myers Squibb, and Pfizer.

Patient-derived Mammosphere and Xenograft Tumour Initiation Correlates with Progression to Metastasis.

Breast cancer specific mortality results from tumour cell dissemination and metastatic colonisation. Identification of the cells and processes responsible for metastasis will enable better prevention and control of metastatic disease, thus reducing relapse and mortality. To better understand these processes, we prospectively collected 307 patient-derived breast cancer samples (n = 195 early breast cancers (EBC) and n = 112 metastatic samples (MBC)). We assessed colony-forming activity in vitro by growing isolated cells in both primary (formation) and secondary (self-renewal) mammosphere culture, and tumour initiating activity in vivo through subcutaneous transplantation of fragments or cells into mice. Metastatic samples formed primary mammosphere colonies significantly more frequently than early breast cancers and had significantly higher primary mammosphere colony formation efficiency (0.9 % vs. 0.6 %; p < 0.0001). Tumour initiation in vivo was significantly higher in metastatic than early breast cancer samples (63 % vs. 38 %, p = 0.04). Of 144 breast cancer samples implanted in vivo, we established 20 stable patient-derived xenograft (PDX) models at passage 2 or greater. Lung metastases were detected in mice from 14 PDX models. Mammosphere colony formation in vitro significantly correlated with the ability of a tumour to metastasise to the lungs in vivo (p = 0.05), but not with subcutaneous tumour initiation. In summary, the breast cancer stem cell activities of colony formation and tumour initiation are increased in metastatic compared to early samples, and predict metastasis in vivo. These results suggest that breast stem cell activity will predict for poor outcome tumours, and therapy targeting this activity will improve outcomes for patients with metastatic disease.

Fulvestrant plus anastrozole or placebo versus exemestane alone after progression on non-steroidal aromatase inhibitors in postmenopausal patients with hormone-receptor-positive locally advanced or metastatic breast cancer (SoFEA): a composite, multicentre, phase 3 randomised trial.

BACKGROUND: The optimum endocrine treatment for postmenopausal women with advanced hormone-receptor-positive breast cancer that has progressed on non-steroidal aromatase inhibitors (NSAIs) is unclear. The aim of the SoFEA trial was to assess a maximum double endocrine targeting approach with the steroidal anti-oestrogen fulvestrant in combination with continued oestrogen deprivation. METHODS: In a composite, multicentre, phase 3 randomised controlled trial done in the UK and South Korea, postmenopausal women with hormone-receptor-positive breast cancer (oestrogen receptor [ER] positive, progesterone receptor [PR] positive, or both) were eligible if they had relapsed or progressed with locally advanced or metastatic disease on an NSAI (given as adjuvant for at least 12 months or as first-line treatment for at least 6 months). Additionally, patients had to have adequate organ function and a WHO performance status of 0-2. Participants were randomly assigned (1:1:1) to receive fulvestrant (500 mg intramuscular injection on day 1, followed by 250 mg doses on days 15 and 29, and then every 28 days) plus daily oral anastrozole (1 mg); fulvestrant plus anastrozole-matched placebo; or daily oral exemestane (25 mg). Randomisation was done with computer-generated permuted blocks, and stratification was by centre and previous use of an NSAI as adjuvant treatment or for locally advanced or metastatic disease. Participants and investigators were aware of assignment to fulvestrant or exemestane, but not of assignment to anastrozole or placebo. The primary endpoint was progression-free survival (PFS). Analyses were by intention to treat. This trial is registered with ClinicalTrials.gov, numbers NCT00253422 (UK) and NCT00944918 (South Korea). FINDINGS: Between March 26, 2004, and Aug 6, 2010, 723 patients underwent randomisation: 243 were assigned to receive fulvestrant plus anastrozole, 231 to fulvestrant plus placebo, and 249 to exemestane. Median PFS was 4·4 months (95% CI 3·4-5·4) in patients assigned to fulvestrant plus anastrozole, 4·8 months (3·6-5·5) in those assigned to fulvestrant plus placebo, and 3·4 months (3·0-4·6) in those assigned to exemestane. No difference was recorded between the patients assigned to fulvestrant plus anastrozole and fulvestrant plus placebo (hazard ratio 1·00, 95% CI 0·83-1·21; log-rank p=0·98), or between those assigned to fulvestrant plus placebo and exemestane (0·95, 0·79-1·14; log-rank p=0·56). 87 serious adverse events were reported: 36 in patients assigned to fulvestrant plus anastrozole, 22 in those assigned to fulvestrant plus placebo, and 29 in those assigned to exemestane. Grade 3-4 adverse events were rare; the most frequent were arthralgia (three in the group assigned to fulvestrant plus anastrozole; seven in that assigned to fulvestrant plus placebo; eight in that assigned to exemestane), lethargy (three; 11; 11), and nausea or vomiting (five; two; eight). INTERPRETATION: After loss of response to NSAIs in postmenopausal women with hormone-receptor-positive advanced breast cancer, maximum double endocrine treatment with 250 mg fulvestrant combined with oestrogen deprivation is no better than either fulvestrant alone or exemestane.

Genomic analysis of advanced breast cancer tumors from talazoparib-treated gBRCA1/2mut carriers in the ABRAZO study.

These analyses explore the impact of homologous recombination repair gene mutations, including BRCA1/2 mutations and homologous recombination deficiency (HRD), on the efficacy of the poly(ADP-ribose) polymerase (PARP) inhibitor talazoparib in the open-label, two-cohort, Phase 2 ABRAZO trial in germline BRCA1/2-mutation carriers. In the evaluable intent-to-treat population (N = 60), 58 (97%) patients harbor ≥1 BRCA1/2 mutation(s) in tumor sequencing, with 95% (53/56) concordance between germline and tumor mutations, and 85% (40/47) of evaluable patients have BRCA locus loss of heterozygosity indicating HRD. The most prevalent non-BRCA tumor mutations are TP53 in patients with BRCA1 mutations and PIK3CA in patients with BRCA2 mutations. BRCA1- or BRCA2-mutated tumors show comparable clinical benefit within cohorts. While low patient numbers preclude correlations between HRD and efficacy, germline BRCA1/2 mutation detection from tumor-only sequencing shows high sensitivity and non-BRCA genetic/genomic events do not appear to influence talazoparib sensitivity in the ABRAZO trial.ClinicalTrials.gov identifier: NCT02034916.

Olaparib and Ceralasertib (AZD6738) in Patients with Triple-Negative Advanced Breast Cancer: Results from Cohort E of the plasmaMATCH Trial (CRUK/15/010).

PURPOSE: Approximately 10% to 15% of triple-negative breast cancers (TNBC) have deleterious mutations in BRCA1 and BRCA2 and may benefit from PARP inhibitor treatment. PARP inhibitors may also increase exogenous replication stress and thereby increase sensitivity to inhibitors of ataxia telangiectasia and Rad3-related (ATR) protein. This phase II study examined the activity of the combination of PARP inhibitor, olaparib, and ATR inhibitor, ceralasertib (AZD6738), in patients with advanced TNBC. PATIENTS AND METHODS: Patients with TNBC on most recent biopsy who had received 1 or 2 lines of chemotherapy for advanced disease or had relapsed within 12 months of (neo)adjuvant chemotherapy were eligible. Treatment was olaparib 300 mg twice a day continuously and celarasertib 160 mg on days 1-7 on a 28-day cycle until disease progression. The primary endpoint was confirmed objective response rate (ORR). Tissue and plasma biomarker analyses were preplanned to identify predictors of response. RESULTS: 70 evaluable patients were enrolled. Germline BRCA1/2 mutations were present in 10 (14%) patients and 3 (4%) patients had somatic BRCA mutations. The confirmed ORR was 12/70; 17.1% (95% confidence interval, 10.4-25.5). Responses were observed in patients without germline or somatic BRCA1/2 mutations, including patients with mutations in other homologous recombination repair genes and tumors with functional homologous recombination deficiency by RAD51 foci. CONCLUSIONS: The response rate to olaparib and ceralasertib did not meet prespecified criteria for activity in the overall evaluable population, but responses were observed in patients who would not be expected to respond to olaparib monotherapy.

A randomised, pragmatic clinical trial of ACUpuncture plus standard care versus standard care alone FOr Chemotherapy Induced peripheral Neuropathy (ACUFOCIN).

PURPOSE: Chemotherapy-induced peripheral neuropathy (CIPN) is a dose limiting toxicity posing a major clinical challenge for managing patients receiving specific chemotherapy regimens (e.g., Taxanes). There is a growing body of literature suggesting acupuncture can improve CIPN symptoms. The purpose of the ACUFOCIN trial was to collect preliminary data on the safety, feasibility, acceptability and initial effectiveness of acupuncture as a treatment for CIPN, comparing use of acupuncture plus standard care (Acupuncture) against standard care alone (Control). METHOD: At a tertiary cancer centre, a pragmatic, randomised, parallel group design study was used to investigate the effectiveness of a 10-week course of acupuncture. Participants experiencing CIPN of ≥ Grade II, recording a 'Most Troublesome' CIPN symptom score of ≥3 using the "Measure Yourself Medical Outcome Profile" (MYMOP 2), were randomised to 'Acupuncture' or 'Control' arms. Clinicians were blinded to allocated groups, however as it was not possible to blind participants, it cannot be guaranteed they did not disclose study allocation within their clinic assessments. The primary outcome measure was the number of patients reporting a ≥ 2-point improvement (success) in their MYMOP2 score at week 10. 100 participants (120 to allow for attrition) were required for a hypothesised improvement in success proportions from 30% to 55% using a primary analysis model with logistic regression adjusted for stratification factors and baseline MYMOP2 scores. Feasibility and acceptability of study design was addressed through percentage return of primary outcome, retention rate and a nested qualitative study. RESULTS: Primary MYMOP2 outcome data at week 10 was available for 108/120 randomised participants; this is greater than the 100 participants required to adequately power the study. There were 36/53 (68%) successes in 'Acupuncture' compared to 18/55 (33%) in 'Control'. Beneficial effects were seen in the secondary outcome data, including clinicians' grading of neuropathy, EORTC, QLQ-CIPN20, QLQ-C30 summary scores and patient reported pain scores. There were no serious adverse events reported within the study and only 16 acupuncture associated events, none of which required intervention. CONCLUSION: A 10-week course of acupuncture resulted in measurable improvement in participants symptoms of CIPN. The results warrant further investigation.

Facilitating reproductive choices: the impact of health services on the experiences of young women with breast cancer.

OBJECTIVE: Chemotherapy and hormone treatments carry significant implications on the fertility of young women with breast cancer. Increasingly, nulliparous women experience fertility dilemmas due to rising survival rates and pregnancy delay. This qualitative study investigated women's responses to being told that treatments affected their fertility and how their interactions with health services impacted on their experiences. METHODS: Twenty-four women under 40 years participated in three focus groups using a flexible interview structure. Data were analysed using content analysis and participants subsequently member checked the themes generated. RESULTS: The priority for most women was survival, although women without children were more willing to take risks. Many women felt that pregnancy after breast cancer and methods of egg harvesting carried a significant risk to survival and fears appeared to be increased by conflicting advice from health professionals. Overall, the women felt the cancer, its treatment options and the health service itself had each robbed them of choice. Hence, with hindsight, many said they would have welcomed an open and honest discussion with a fertility expert to maximise their options. CONCLUSIONS: Young women with breast cancer face complex decisions regarding their fertility and treatment options. Survival remains the priority for the majority of women. Although there is a paucity of evidence concerning many fertility issues, it is essential that available options and any potential risks are discussed in a coherent, objective fashion. Early referral to specialist fertility services that provide clear, cohesive advice can aid informed decision making.

Genomic profile of advanced breast cancer in circulating tumour DNA.

The genomics of advanced breast cancer (ABC) has been described through tumour tissue biopsy sequencing, although these approaches are limited by geographical and temporal heterogeneity. Here we use plasma circulating tumour DNA sequencing to interrogate the genomic profile of ABC in 800 patients in the plasmaMATCH trial. We demonstrate diverse subclonal resistance mutations, including enrichment of HER2 mutations in HER2 positive disease, co-occurring ESR1 and MAP kinase pathway mutations in HR + HER2- disease that associate with poor overall survival (p = 0.0092), and multiple PIK3CA mutations in HR + disease that associate with short progression free survival on fulvestrant (p = 0.0036). The fraction of cancer with a mutation, the clonal dominance of a mutation, varied between genes, and within hotspot mutations of ESR1 and PIK3CA. In ER-positive breast cancer subclonal mutations were enriched in an APOBEC mutational signature, with second hit PIK3CA mutations acquired subclonally and at sites characteristic of APOBEC mutagenesis. This study utilises circulating tumour DNA analysis in a large clinical trial to demonstrate the subclonal diversification of pre-treated advanced breast cancer, identifying distinct mutational processes in advanced ER-positive breast cancer, and novel therapeutic opportunities.

Detection of PIK3CA mutations in circulating free DNA in patients with breast cancer.

Somatic mutations in PIK3CA (encoding a class I phosphoinositide 3 kinase (PI3K) subunit) modulate PI3K signalling to influence tumour behaviour and occur in up to 40% of breast cancers. Inhibitors of PI3K signalling are entering clinical trials, but the impact of PIKC3A mutation on tumour response has yet to be clarified. This study investigated the potential utility of circulating free DNA (cfDNA) as a source for PIK3CA mutation detection in patients with breast cancer. cfDNA extracted (QIAamp Virus spin kit) from blood and matched archival tumour from 46 patients with metastatic breast cancer and 30 patients with localised, operable breast cancer was assessed for hotspot PIK3CA mutations using Amplification Refractory Mutation System (ARMS()) allele-specific PCR and Scorpion probes. PIK3CA mutations were detected in 13/46 (28%) plasma-derived and 10/46 (21%) serum-derived cfDNA samples from metastatic breast cancer patients. In 41 cases with matched tumour and plasma-derived cfDNA data, concordance (same mutation status in plasma and tumour) was 95%. Where a PIK3CA mutation was present in tumour, the 'pick up' in plasma-derived cfDNA was 80%. PIK3CA mutations were present in tumours from 14/30 (47%) localised breast cancers, but no PIK3CA mutations were detected in matched cfDNA. These data demonstrate feasibility and potential utility of cfDNA for PIK3CA mutation detection in patients with metastatic breast cancer. Studies are underway to qualify PIK3CA mutation in cfDNA as a predictive biomarker allowing patient stratification in clinical trials of mechanism-based therapeutics that target PI3K signalling pathways.

Six versus 12 months' adjuvant trastuzumab in patients with HER2-positive early breast cancer: the PERSEPHONE non-inferiority RCT.

BACKGROUND: The addition of adjuvant trastuzumab to chemotherapy has significantly improved outcomes for people with human epidermal growth factor receptor 2 (HER2)-positive, early, potentially curable breast cancer. Twelve months' trastuzumab, tested in registration trials, was adopted as standard adjuvant treatment in 2006. Subsequently, similar outcomes were demonstrated using 9 weeks of trastuzumab. Shorter durations were therefore tested for non-inferiority. OBJECTIVES: To establish whether or not 6 months' adjuvant trastuzumab is non-inferior to 12 months' in the treatment of HER2-positive early breast cancer using a primary end point of 4-year disease-free survival. DESIGN: This was a Phase III randomised controlled non-inferiority trial. SETTING: The setting was 152 NHS hospitals. PARTICIPANTS: A total of 4088 patients with HER2-positive early breast cancer who it was planned would receive both chemotherapy and trastuzumab took part. INTERVENTION: Randomisation (1 : 1) to 6 months' or 12 months' trastuzumab treatment. MAIN OUTCOMES: The primary end point was disease-free survival. The secondary end points were overall survival, cost-effectiveness and cardiac function during treatment with trastuzumab. Assuming a 4-year disease-free survival rate of 80% with 12 months' trastuzumab, 4000 patients were required to demonstrate non-inferiority of 6 months' trastuzumab (5% one-sided significance, 85% power), defining the non-inferiority limit as no worse than 3% below the standard arm. Costs and quality-adjusted life-years were estimated using a within-trial analysis and a lifetime decision-analytic model. RESULTS: Between 4 October 2007 and 31 July 2015, 2045 patients were randomised to 12 months' trastuzumab and 2043 were randomised to 6 months' trastuzumab. Sixty-nine per cent of patients had ER-positive disease; 90% received anthracyclines (49% with taxanes; 41% without taxanes); 10% received taxanes without anthracyclines; 54% received trastuzumab sequentially after chemotherapy; and 85% received adjuvant chemotherapy (58% were node negative). At 6.1 years' median follow-up, with 389 (10%) deaths and 566 (14%) disease-free survival events, the 4-year disease-free survival rates for the 4088 patients were 89.5% (95% confidence interval 88.1% to 90.8%) in the 6-month group and 90.3% (95% confidence interval 88.9% to 91.5%) in the 12-month group (hazard ratio 1.10, 90% confidence interval 0.96 to 1.26; non-inferiority p = 0.01), demonstrating non-inferiority of 6 months' trastuzumab. Congruent results were found for overall survival (non-inferiority p = 0.0003) and landmark analyses 6 months from starting trastuzumab [non-inferiority p = 0.03 (disease-free-survival) and p = 0.006 (overall survival)]. Six months' trastuzumab resulted in fewer patients reporting adverse events of severe grade [365/1929 (19%) vs. 460/1935 (24%) for 12-month patients; p = 0.0003] or stopping early because of cardiotoxicity [61/1977 (3%) vs. 146/1941 (8%) for 12-month patients; p < 0.0001]. Health economic analysis showed that 6 months' trastuzumab resulted in significantly lower lifetime costs than and similar lifetime quality-adjusted life-years to 12 months' trastuzumab, and thus there is a high probability that 6 months' trastuzumab is cost-effective compared with 12 months' trastuzumab. Patient-reported experiences in the trial highlighted fatigue and aches and pains most frequently. LIMITATIONS: The type of chemotherapy and timing of trastuzumab changed during the recruitment phase of the study as standard practice altered. CONCLUSIONS: PERSEPHONE demonstrated that, in the treatment of HER2-positive early breast cancer, 6 months' adjuvant trastuzumab is non-inferior to 12 months'. Six months' treatment resulted in significantly less cardiac toxicity and fewer severe adverse events. FUTURE WORK: Ongoing translational work investigates patient and tumour genetic determinants of toxicity, and trastuzumab efficacy. An individual patient data meta-analysis with PHARE and other trastuzumab duration trials is planned. TRIAL REGISTRATION: Current Controlled Trials ISRCTN52968807, EudraCT 2006-007018-39 and ClinicalTrials.gov NCT00712140. FUNDING: This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 24, No. 40. See the NIHR Journals Library website for further project information.

THE BACKGROUND: There are several different types of breast cancer and some are called 'HER2 positive'. These cancers can often be cured by treatment with chemotherapy and a drug called trastuzumab (also known as Herceptin®; Roche, Basel, Switzerland). Although the first trials of trastuzumab used 12 months treatment, we did not know if less treatment could work as well. A small trial in Finland showed that giving trastuzumab for just 9 weeks was also effective. We know that trastuzumab can have some side effects, including heart problems, so it was important to see if we could reduce the length of treatment time, which is usually 12 months. WHAT DID WE DO?: We wanted to find out if we could treat patients safely with 6 months rather than 12 months of trastuzumab. We carried out a clinical trial called PERSEPHONE, in which over 4000 patients with this type of early breast cancer took part. Half of the patients were given 12 months of trastuzumab and half were given 6 months of trastuzumab. WHAT DID WE FIND?: We found that the two groups of patients had very similar benefit from treatment. At 4 years after diagnosis 90.3% of those who had received 12 months of trastuzumab were alive and free of any breast cancer recurrence, compared with 89.5% of those who had received 6 months. In other words, 125 patients would need to be treated with 12 months' trastuzumab rather than 6 months' trastuzumab for one more person to be alive and cancer-free 4 years from diagnosis. THE SIDE EFFECTS?: Severe side effects of trastuzumab were seen on at least one occasion in 24% of 12-month patients compared with 19% of 6-month patients. More patients receiving 12 months of trastuzumab had to stop trastuzumab early because of heart problems (8% of 12-month patients compared with 3% of 6-month patients). WHAT DOES THIS ALL MEAN?: We have shown that 6 months of trastuzumab has similar outcomes to 12 months in treating patients with HER2-positive early breast cancer but with fewer severe side effects, including heart problems, fewer visits to hospital for patients and significant cost savings for the NHS.

A Phase II Study of Talazoparib after Platinum or Cytotoxic Nonplatinum Regimens in Patients with Advanced Breast Cancer and Germline BRCA1/2 Mutations (ABRAZO).

PURPOSE: To assess talazoparib activity in germline BRCA1/2 mutation carriers with advanced breast cancer. PATIENTS AND METHODS: ABRAZO (NCT02034916) was a two-cohort, two-stage, phase II study of talazoparib (1 mg/day) in germline BRCA mutation carriers with a response to prior platinum with no progression on or within 8 weeks of the last platinum dose (cohort 1) or ≥3 platinum-free cytotoxic regimens (cohort 2) for advanced breast cancer. Primary endpoint was confirmed objective response rate (ORR) by independent radiological assessment. RESULTS: We enrolled 84 patients (cohort 1, n = 49; cohort 2, n = 35) from May 2014 to February 2016. Median age was 50 (range, 31-75) years. Triple-negative breast cancer (TNBC) incidence was 59% (cohort 1) and 17% (cohort 2). Median number of prior cytotoxic regimens for advanced breast cancer was two and four, respectively. Confirmed ORR was 21% [95% confidence interval (CI), 10-35; cohort 1] and 37% [95% CI, 22-55; cohort 2]. Median duration of response was 5.8 and 3.8 months, respectively. Confirmed ORR was 23% (BRCA1), 33% (BRCA2), 26% (TNBC), and 29% (hormone receptor-positive). The most common all-grade adverse events (AE) included anemia (52%), fatigue (45%), and nausea (42%). Talazoparib-related AEs led to drug discontinuation in 3 (4%) patients. In an exploratory analysis, longer platinum-free interval was associated with higher response rate in cohort 1 (0% ORR with interval <8 weeks; 47% ORR with interval >6 months). CONCLUSIONS: Talazoparib exhibited promising antitumor activity in patients with advanced breast cancer and germline BRCA mutation.

A phase II, randomized, blinded study of the farnesyltransferase inhibitor tipifarnib combined with letrozole in the treatment of advanced breast cancer after antiestrogen therapy.

BACKGROUND: This study assessed the clinical efficacy of the farnesyltransferase inhibitor, tipifarnib, combined with letrozole in patients with advanced breast cancer and disease progression following antiestrogen therapy. PATIENTS AND METHODS: Postmenopausal women with estrogen-receptor-positive advanced breast cancer that had progressed after tamoxifen were given 2.5 mg letrozole once daily and were randomly assigned (2:1) to tipifarnib 300 mg (TL) or placebo (L) twice daily for 21 consecutive days in 28-day cycles. The primary endpoint was objective response rate. RESULTS: Of 120 patients treated with TL (n = 80) or L (n = 40), 113 were evaluable for response. Objective response rate was 30% (95% CI; 20-41%) for TL and 38% (95% CI; 23-55%) for L. There was no significant difference in response duration, time to disease progression or survival. Clinical benefit rates were 49% (TL) and 62% (L). Tipifarnib was generally well tolerated; a higher incidence of drug-related asymptomatic grade 3/4 neutropenia was observed for TL (18%) than for L (0%). Tipifarnib population pharmacokinetics were similar to previous studies, with no significant difference in trough letrozole concentrations between the TL and L groups. CONCLUSIONS: Adding tipifarnib to letrozole did not improve objective response rate in this population of patients with advanced breast cancer.

Understanding the BIG results: Insights from the BIG 1-98 trial analyses.

Third-generation aromatase inhibitors (AIs), including letrozole, are now standard therapy for initial adjuvant endocrine treatment of postmenopausal women with early breast cancer. The International Breast Cancer Study Group's Breast International Group (BIG) 1-98 trial is examining efficacy and safety of letrozole or tamoxifen, whether used upfront or sequentially, for postmenopausal with hormone receptor-positive breast cancer. Women in the BIG 1-98 trial were randomized to either 5 years' monotherapy with tamoxifen or letrozole (trial arms A and B, respectively), or to 5 years' sequential therapy with 2 years of tamoxifen followed by 3 years of letrozole, or 2 years of letrozole followed by 3 years of tamoxifen (arms C and D, respectively). Results of the primary core analysis (PCA) of BIG 1-98, at a median follow-up of 25.8 months, showed a significant improvement in disease-free survival for patients treated with initial adjuvant letrozole relative to those on tamoxifen (P=0.003). Of interest, there was an important reduction in distant metastases, the most common and ultimately fatal type of early recurrence, for patients allocated to initial letrozole compared with initial tamoxifen. Since the PCA, there have been further analyses of BIG 1-98 with variations in the cohorts analyzed and follow-up period. The first and largest central pathology review in an adjuvant AI trial to date was also performed in the BIG 1-98 trial. In light of the impending sequence analysis, expected in late 2008, the goal of this article is to describe and summarize the breadth of information learned to date and highlight the key findings regarding the efficacy and safety of letrozole in the initial adjuvant setting.