Helena Earl

aTTom: Long-term effects of continuing adjuvant tamoxifen to 10 years versus stopping at 5 years in 6,953 women with early breast cancer.

5 Background: In estrogen-receptor-positive (ER+) early breast cancer, 5 years of tamoxifen reduces breast cancer death rates by about a third throughout years 0-14. It has been uncertain how 10 years of tamoxifen compares with this. METHODS During 1991-2005, 6,953 women with ER+ (n=2755), or ER untested (4198, estimated 80% ER+ if status known) invasive breast cancer from 176 UK centres were, after 5 years of tamoxifen, randomized to stop tamoxifen or continue to year 10. Annual follow-up recorded compliance, recurrence, mortality, and hospital admissions. RESULTS Allocation to continue tamoxifen reduced breast cancer recurrence (580/3468 vs 672/3485, p=0.003). This reduction was time dependent: rate ratio 0.99 during years 5-6 [95%CI 0.86-1.15], 0.84 [0.73-0.95] during years 7-9, and 0.75 [0.66-0.86] later. Longer treatment also reduced breast cancer mortality (392 vs 443 deaths after recurrence, p=0.05), rate ratio 1.03 [0.84-1.27] during years 5-9 and 0.77 [0.64-0.92] later; and overall mortality (849 vs 910 deaths, p=0.1), rate ratio 1.05 [0.90-1.22] during years 5-9 and 0.86 [0.75-0.97] later. Non-breast-cancer mortality was little affected (457 vs 467 deaths, rate ratio 0.94 [0.82-1.07]). There were 102 vs 45 endometrial cancers RR=2.20 (1.31-2.34, p<0.0001) with 37 (1.1%) vs 20 (0.6%) deaths (absolute hazard 0.5%, p=0.02). Combining the similar results of aTTom and its international counterpart ATLAS (Lancet 2013) enhances statistical significance of recurrence (p<0.0001), breast cancer mortality (p=0.002) and overall survival (p=0.005) benefits. CONCLUSIONS aTTom confirms that, in ER+ disease, continuing tamoxifen to year 10 rather than just to year 5 produces further reductions in recurrence, from year 7 onward, and breast cancer mortality after year 10. Taken together with the reduction in breast cancer deaths seen in trials of 5 years of tamoxifen vs none, these results indicate that 10 years of adjuvant tamoxifen, compared to no tamoxifen, reduces breast cancer mortality by about one third in the first 10 years following diagnosis and by a half subsequently. CLINICAL TRIAL INFORMATION ISRCTN17222211.

Laboratory handling and histology reporting of breast specimens from patients who have received neoadjuvant chemotherapy

Neoadjuvant chemotherapy is increasingly being offered to patients with invasive breast carcinoma but surgical excision specimens following such therapy may be difficult to interpret in the pathology laboratory, both macroscopically and histologically. We provide here some guidelines for handling such postneoadjuvant chemotherapy samples and describe the histopathological features which may be encountered in both the breast and lymph nodes received. We also present a brief review of the literature and suggest a simple method for quantifying the degree of response to neoadjuvant chemotherapy in both the primary breast carcinoma and the lymph nodes.

Predicting Anthracycline Benefit: TOP2A and CEP17—Not Only but Also

PURPOSE Evidence supporting the clinical utility of predictive biomarkers of anthracycline activity is weak, with a recent meta-analysis failing to provide strong evidence for either HER2 or TOP2A. Having previously shown that duplication of chromosome 17 pericentromeric alpha satellite as measured with a centromere enumeration probe (CEP17) predicted sensitivity to anthracyclines, we report here an individual patient-level pooled analysis of data from five trials comparing anthracycline-based chemotherapy with CMF (cyclophosphamide, methotrexate, and fluorouracil) as adjuvant chemotherapy for early breast cancer. PATIENTS AND METHODS Fluorescent in situ hybridization for CEP17, HER2, and TOP2A was performed in three laboratories on samples from 3,846 of 4,864 eligible patients from five trials evaluating anthracycline-containing chemotherapy versus CMF. Methodologic differences did not affect HER2-to-CEP17 ratios but necessitated different definitions for CEP17 duplication: > 1.86 observed copies per cell for BR9601, NEAT, Belgian, and DBCG89D trials and > 2.25 for the MA.5 trial. RESULTS Fluorescent in situ hybridization data were available in 89.3% (HER2), 83.9% (CEP17), and 80.6% (TOP2A) of 3,846 patient cases with available tissue. Both CEP17and TOP2A treatment-by-marker interactions remained significant in adjusted analyses for recurrence-free and overall survival, whereas HER2 did not. A combined CEP17 and TOP2A-adjusted model predicted anthracycline benefit across all five trials for both recurrence-free (hazard ratio, 0.64; 95% CI, 0.51 to 0.82; P = .001) and overall survival (hazard ratio, 0.66; 95% CI, 0.51 to 0.85; P = .005). CONCLUSION This prospectively planned individual-patient pooled analysis of patient cases from five adjuvant trials confirms that patients whose tumors harbor either CEP17 duplication or TOP2A aberrations, but not HER2 amplification, benefit from adjuvant anthracycline chemotherapy.

Etoposide protein binding in cancer patients

The protein binding of etoposide was studied in vivo in 36 cancer patients receiving etoposide therapy. Free etoposide was separated from plasma using an ultrafiltration method and the etoposide concentrations (free and total) were measured by high-performance liquid chromatography (HPLC). Considerable interpatient variation in the protein binding of etoposide was observed. The protein binding of etoposide varied from 80% to 97% (mean, 93%). Univariate analysis showed a significant inverse correlation between the free fraction of etoposide and serum albumin (r=−0.74), daily dose (r=−0.37) and age (r=−0.34). Multivariate analysis demonstrated that serum albumin and age were independent predictors of the etoposide free fraction. Serum bilirubin showed no correlation with etoposide protein binding. There is wide variation in etoposide protein binding in cancer patients, which is mostly dependent on serum albumin concentration.

Long-Term Neurotoxicity of Chemotherapy in Adolescents and Young Adults Treated for Bone and Soft Tissue Sarcomas

Purpose. To study the long-term neurotoxicity of chemotherapy in adolescents and young adults treated for bone and soft tissue sarcomas. Patients and Methods. Thirty-six adolescents and young adults (median age 17 years) were examined following chemotherapy for bone and soft tissue sarcomas. Twenty-nine (29/36) had received cisplatin (median 400 mg/m2), 15/36 ifosfamide (median 20 g/m2), and 12/36 vincristine (median 16 mg). Neurotoxicity was assessed at a median of 8 months (range, 1–54 months) after completion of chemotherapy by clinical examination, nerve conduction studies, audiograms and autonomic function tests. The same nerve conduction studies were carried out in 20 normal volunteers to define normal ranges in this age group. Results. Sixteen patients (44%) had a significant reduction in deep tendon reflexes, and this clinical parameter correlated well with abnormalities detected in nerve conduction studies. Vibration perception threshold (VPT) was raised in 20/36 patients (55%) and this was the most sensitive single test in the assessment of neuropathy. There was a significant correlation between VPT and cumulative cisplatin dose received in mg/m-2 (r=0.607, p<0.01). Ten of 29 patients (35%) had abnormal nerve conduction studies with a pattern characteristic of sensory axonal neuropathy. No patient complained of auditory symptoms, but minor high tone hearing loss was detected by audiograms in 5/28 patients who had received cisplatin. No patients had symptoms of autonomic neuropathy, but autonomic function tests showed minor abnormalities in 4/22 patients tested, and all had received cisplatin. Conclusions. This study demonstrates significant, although asymptomatic, long-term neurotoxicity of cisplatin in adolescents and young adults receiving chemotherapy for bone and soft tissue sarcomas. Follow-up studies are planned to assess whether these neurological deficits improve with time.

Abstract S3-3: The UK TACT2 Trial: comparison of standard vs accelerated epirubicin in patients requiring chemotherapy for early breast cancer (EBC) (CRUK/05/019)

Introduction: TACT2, a multicentre randomized phase III trial in patients with node +ve or high risk node -ve invasive EBC with E-CMF as control (Poole NEJM 2006), tests two hypotheses in a 2×2 factorial design: A) accelerated epirubicin (aE) improves outcomes compared to standard epirubicin (E) (CALGB9741 Citron JCO 2003); and B) capecitabine (X) gives similar efficacy but preferential side-effect profile to CMF. Here we focus on the impact of accelerating epirubicin treatment on patient outcome. Tolerability and toxicity of this regimen have already been presented (Cameron 2010, SABCS); 33/4391 pts did not start chemotherapy. 4261 (97%) completed the initial 4 cycles (E 2143 (96%), aE 2118 (98%)) with RDI >85% for E 2061 (93%) and aE 1985 (91%). Serious CTCAE toxicity was less common with aE compared with E, however patients report poorer global QL, fatigue & role function which does not appear to be explained by impact on daily activities due to individual side-effects. Patients & Methods: Between December 2005 and December 2008, 4391 patients (4371 women, 20 men) were randomized to receive either E (100mg/m2 × 4) q3wk or aE (100mg/m2 × 4 plus pegfilgrastim, 6mg d2) q2wk followed by classical CMF q4wk × 4 or X (2500mg/m2/day × 14) q3wk × 4. Other adjuvant treatment was delivered according to local practice (HER2+ve – sequential trastuzumab for 1 year from June 2006; ER/PgR+ve - endocrine therapy for 5 years). Tumor blocks were collected prospectively to enable central biomarker testing. Median age of patients was 52 years (IQR 46–59). 53% patients had node +ve disease; 59% had tumors >2cm; 57% were grade 3. According to local assessment, of 4366 patients where both ER and HER2 status were known, 60% had ER+ve/HER2-ve tumors, 19% HER2+ve, 21% ER-ve/HER2-ve. Primary endpoint was time to recurrence (TTR), defined as time to loco-regional or distant relapse, or breast cancer-death. Secondary endpoints included disease-free survival (DFS), overall survival (OS), tolerability of regimens and quality of life. TACT2 has over 90% power to detect a clinically meaningful 4% difference in TTR between standard and accelerated epirubicin schedules (from 80% to 84% at 5 years). Survival estimates will be compared using stratified log-rank tests and Cox regression. Results: At 1st June 2012, median follow up was 49 months (interquartile range: 46–60) with 553 TTR events reported. The Independent Data Monitoring Committee consider these data sufficiently mature for presentation of analyses relating to the accelerated epirubicin hypothesis. A further data snapshot, after query resolution, for the main analysis will be taken in Q3 2012. Data to be presented, by treatment group, include TTR, DFS, OS, late toxicity and pre-planned subgroup analyses according to ER, PgR and HER2 status and Ki67 levels. Discussion: TACT2 will provide a definitive analysis to confirm or refute benefits previously reported for accelerating anthracycline chemotherapy in early breast cancer including, via pre-planned subgroup analyses, exploration of the potential benefits in phenotypic subtypes. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr S3-3.

Multidisciplinary management of malignant ovarian germ cell tumours

OBJECTIVES Malignant ovarian germ cell tumours (MOGCT) are rare cancers of young women. Limited prospective trials exist from which evidence-based management can be developed. This review summarizes the available literature concerning MOGT in order to provide the clinician with information relevant to their multidisciplinary management. METHODS MEDLINE was searched between 1966 and 2010 for all publications in English where the studied population included women diagnosed with malignant ovarian germ cell tumours. RESULTS The majority of patients can be cured with fertility-preserving surgery with or without combination chemotherapy. Long term survival approaches 100% in early stage disease and is approximately 75% in advanced stage disease. Most studies suggest that the treatment has little, if any, effect on future fertility and limited data suggest that there is no adverse effect on the future quality of life. CONCLUSION MOGCTs are rare tumours of young women the majority of which can be successfully treated with fertility-preserving surgery with or without chemotherapy with preservation of reproductive function. Minimisation of chemotherapy in good prognostic groups and improved treatment in resistant and relapsed MOGCT are important goals for the future. Further studies are needed to quantify the late adverse effects of treatment in long term survivors.

Acetazolamide for alkalinisation of urine in patients receiving high-dose methotrexate

SummaryAcetazolamide, 500 mg 6 hourly, has been used to alkalinise the urine in patients receiving high dose methotrexate. A urinary pH of >7.5 was achieved in every cycle (13 cycles in 10 patients). In 6 cycles a single supplementary dose of sodium bicarbonate was necessary. Plasma methotrexate levels fell satisfactorily at 24 and 48 h. Acetazolamide is a simple and effective method of achieving urinary alkalinisation with advantages over oral and intravenous bicarbonate.

Abstract P1-13-03: Mature analysis of UK Taxotere as Adjuvant Chemotherapy (TACT) trial (CRUK 01/001); effects of treatment and characterisation of patterns of breast cancer relapse.

Introduction: TACT, an investigator-led study in 4162 women with node positive (N+ve) or high risk node negative (N-ve) early breast cancer (EBC), is the largest taxane trial unconfounded by treatment (trt) duration. At principal analysis, with 5 years follow-up (fup), no evidence of improved disease-free survival (DFS) was observed by switching to 4 cycles of docetaxel (D) after 4 cycles of FEC (Ellis, Lancet 2009). Results were provocative in suggesting differential effects according to ER & HER2 status. Longer fup provides opportunity to detect emergence of late trt effects overall & within phenotypic subgroups & explore patterns of recurrence, by tumor characteristics. Patients & methods: TACT recruited women with histologically confirmed completely resected invasive EBC from 104 centers (UK (103), Belgium (1)) between 02/2001 & 07/2003. Centers chose FEC (600/60/600 mg/m 2 q3wk × 8) or E-CMF (E 100mg/m 2 q3wk × 4 → CMF 100mg/m 2 PO d1-14 or 600mg/m 2 IV d1&8/40/600 mg/m 2 q4wk × 4) as their control, reflecting standard UK practice. Patients (pts) were randomized to FEC-D (FEC q3wk × 4 → D 100 mg/m 2 q3wk × 4) or control. 2523 pts were from FEC centers (FEC = 1265: FEC-D = 1258) & 1639 from E-CMF centers (E-CMF = 824; FEC-D = 815). Endocrine therapy was given for 5 years. Few pts received HER2 directed therapy; 589 pts had unknown HER2 status. Median fup is now 97.5 months; this analysis updates DFS & overall survival in the ITT population. It also explores patterns of relapse by phenotypic & clinical characteristics. Analyses of trt effect are stratified by ER status due to issues of non-proportionality of hazard associated with length of fup. Results: DFS events have been reported for 1329 pts (FEC-D=640, Control=689) giving an unadjusted hazard ratio (HR) & 95%CI (stratified by control regimen & ER status) of 0.93 (0.83, 1.03) overall; p = 0.16 in favor of FEC-D & for ER+ve/HER2-ve of 0.99 (0.84, 1.17), for ER+ve/HER2+ve) 0.97 (0.73, 1.30), for ER-ve/HER2+ve 0.74 (0.53, 1.03), & ER-ve/HER2-ve 0.93 (0.73, 1.17). 1017 patients have died (FEC-D=500, Control=517); unadjusted HR=0.98 (95%CI: 0.86, 1.10); p = 0.69 with intercurrent deaths (prior to distant relapse) reported for 80 pts (FEC-D=40, Control=40). Annual event rates show different pattern of disease relapse by phenotypic subgroup Graphical representation will further explore these patterns & associated sites of relapse. Discussion: With a median fup of >8 years no clear benefit has emerged for D over standard anthracyclines within the TACT pt group. Differential effects associated with different patterns of relapse remain of interest. TACT precedes use of antiHER2 therapy which is known to have impacted on early relapse risk in HER2+ve pts. The high relapse risk observed for pts with ER-ve/HER2-ve disease remains a current clinical challenge. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P1-13-03.

Abstract OT3-02-02: ROSCO: A randomised phase III, stratified CEP17/TOP2A biomarker trial of neo-adjuvant 5-flourouracil, epirubicin and cyclophosphamide vs docetaxel and cyclophosphamide chemotherapy

Background: Patients with high risk early breast cancer undergoing chemotherapy are frequently treated with both anthracycline and taxane-based chemotherapy exposing patients to multiple toxicities. Molecular predictors of response to specific chemotherapy agents are emerging. Abnormal duplication of the centromeric region of chromosome 17 (CEP17) and either Topoisomerase 2A (TOP2A) gene amplification or deletion, have been identified in a recent meta-analysis as potent markers of anthracycline sensitivity (Bartlett et al JCO 2015). The ROSCO study has been designed to prospectively test the utility of these markers to select anthracycline or taxane based chemotherapy in the neoadjuvant setting. Key entry criteria: Confirmed invasive breast cancer; centrally confirmed CEP17 duplication and TOP2A status; primary tumour>2cms or documented axillary node metastasis Exclusion criteria include breast cancer with good risk features i.e. Grade 1/2 ER PR rich (Q score 7/8), HER2 negative tumours. Study treatment: Patients will undergo central testing for CEP-17 and TOP2A and be randomised to 4 cycles of FEC100 (5-Flourouracil 500mg/m2 Epirubicin 100mg/m2 cyclophosphamide 600mg/m2) or 4 cycles of TC (Docetaxel 75mg/m2 Cyclophosphamide 600 mg/m2). Following chemotherapy patients will undergo surgical resection, (Institutional standard). Patients with residual invasive cancer will receive 4 cycles of the alternative chemotherapy to that received in the neoadjuvant setting. HER2 positive patients will receive concurrent trastuzumab and continue standard adjuvant trastuzumab. . Patients with biopsy proven axillary node metastases will undergo combined blue dye and radioisotope tracer guided sentinel lymph node biopsy (SLNB) and axillary lymph node clearance as a single procedure during breast surgery. Adjuvant endocrine and radiation therapy will be Institutional standard Endpoints: The primary endpoint is pathological complete response (no invasive disease in breast or axilla (pCR)). Secondary endpoints include: clinical and radiological response; rate of breast conservation; patient reported outcomes; safety, tolerability and long term outcomes. In patients with proven nodal involvement the false negative rate of a negative post treatment SLNB compared to axillary node clearance will be reported. Sample size and stratification: 1050 patients will be randomised in a 1:1 ratio stratified by nodal status, ER, HER2, and biomarker status (CEP-17 amplified or TOP2A amplified/deleted) vs normal (CEP-17 normal TOP2A normal). Analysis: The primary analysis will assess the interaction between the treatment effect and CEP17/TOP2A status to determine if a differential treatment effect exists between CEP17/TOP2A Normal and CEP17/TOP2A Abnormal patients. pCR will be analysed using a logistic regression model including co-variates for treatment, CEP17/TOP2A status and an interaction term of the two effects Sample size is based on the ability to detect an absolute improvement in pCR in the biomarker abnormal group from 21% in the TC treated group to 30% in the FEC treated group. With 90% power at 10% significance level. Contact Information: the ROSCO Trial Office ROSCO@trials.bham.ac.uk. Citation Format: Rea DW, Haywood L, Francis AM, Bowden SJ, Brookes CM, MacKenzie M, Cameron D, Stein R, Earl HM, Thomas J, Abraham J, Stanley A, Starczinski J, McGoldrick T, Treharne-Jones P, Billingham L, Bartlett JM. ROSCO: A randomised phase III, stratified CEP17/TOP2A biomarker trial of neo-adjuvant 5-flourouracil, epirubicin and cyclophosphamide vs docetaxel and cyclophosphamide chemotherapy. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr OT3-02-02.