Adrian Harnett

Randomised controlled trial of conservation therapy for breast cancer: 6-year analysis of the Scottish trial

Summary Background To determine whether, when primary breast cancer is treated by local excision supported by systemic therapy appropriate to the oestrogen receptor status (ER) of the tumour, local radiotherapy can be avoided. Methods We carried out a randomised controlled trial in 585 patients aged less than 70 years with primary breast cancers of 4 cm or less in size in four specialist units and seven other hospitals in Scotland. After local excision of the tumour (1 cm margin) and an axillary lymph-node clearance or sample, all patients received systemic therapy with oral tamoxifen 20 mg daily or six 3-weekly intravenous bolus injections of cyclophosphamide 600 mg, methotrexate 50 mg, and fluorouracil 600 mg per m 2 , depending upon the ER concentration in the primary tumour. Patients were then randomly allocated to postoperative radical radiotherapy (50 Gy to breast with boost to the tumour bed) or to no further local treatment. The median follow-up of living patients was 5·7 years. The primary analysis was by intention to treat but since some patients did not receive systemic therapy appropriate to their ER status, a subsidiary analysis was restricted to 464 patients in whom all details of the protocol had been observed. Findings In the primary analysis survival was equal in the radiotherapy and non-radiotherapy groups (hazard ratio [HR] 0·98, 95% CI 0 67–1·44). Event-free survival showed an advantage in the irradiated patients (HR 0·54, 95% CI 0·39–0·74), largely due to fewer loco-regional relapses (HR 0·20, 95% CI 0·12–0·33). The relapse rate in the ipsilateral breast was 24·5% in the non-irradiated group and 5·8% following breast irradiation. The subsidiary analysis confirmed these findings and indicated the advantage of radiotherapy irrespective of ER concentration. There was a non-significant trend towards fewer distant metastases in the irradiated group. Interpretation After local excision of a primary breast cancer, we conclude that radiotherapy to the residual breast tissue is advisable even when selective adjuvant systemic therapy is given.

First results of the randomised UK FAST Trial of radiotherapy hypofractionation for treatment of early breast cancer (CRUKE/04/015).

BACKGROUND AND PURPOSE Randomised trials testing 15- or 16-fraction regimens of adjuvant radiotherapy in women with early breast cancer have reported favourable outcomes compared with standard fractionation. To evaluate hypofractionation further, two 5-fraction schedules delivering 1 fraction per week have been tested against a 25-fraction regimen. MATERIALS AND METHODS Women aged ⩾50years with node negative early breast cancer were randomly assigned after microscopic complete tumour resection to 50Gy in 25 fractions versus 28.5 or 30Gy in 5 once-weekly fractions of 5.7 or 6.0Gy, respectively, to the whole breast. The primary endpoint was 2-year change in photographic breast appearance. RESULTS Nine hundred and fifteen women were recruited from 2004 to 2007. Seven hundred and twenty-nine patients had 2-year photographic assessments. Risk ratios for mild/marked change were 1.70 (95% CI 1.26-2.29, p<0.001) for 30Gy and 1.15 (0.82-1.60, p=0.489) for 28.5Gy versus 50Gy. Three-year rates of physician-assessed moderate/marked adverse effects in the breast were 17.3% (13.3-22.3%, p<0.001) for 30Gy and 11.1% (7.9-15.6%, p=0.18) for 28.5Gy compared with 9.5% (6.5-13.7%) after 50Gy. With a median follow-up in survivors of 37.3months, 2 local tumour relapses and 23 deaths have occurred. CONCLUSIONS At 3years median follow-up, 28.5Gy in 5 fractions is comparable to 50Gy in 25 fractions, and significantly milder than 30Gy in 5 fractions, in terms of adverse effects in the breast.

Diagnosis and treatment of early breast cancer, including locally advanced disease--summary of NICE guidance.

Breast cancer is the commonest cancer in women, with over 40 500 new cases diagnosed each year in England and Wales.1 2 Despite a steady decline in age standardised mortality rates owing to screening and better management, the disease still causes 10 900 deaths each year in England and Wales,1 2 with a huge social and emotional impact. This article outlines the most important recent recommendations from the National Institute for Health and Clinical Excellence (NICE) on the diagnosis and treatment of early and locally advanced breast cancer.3 NICE recommendations are based on systematic reviews of best available evidence. When minimal evidence is available, recommendations are based on the Guideline Development Group’s opinion of what constitutes good practice. Evidence levels for the recommendations are given in italic in square brackets. This new guideline covers women presenting with breast cancer in whom the primary tumour may have been non-palpable and detected by screening mammography through to women with cancers over 5 cm but in whom there is no evidence of spread beyond the breast and axillary lymph nodes. The guideline includes a large spectrum of disease, ranging from ductal carcinoma in situ (DCIS) to inflammatory breast cancer, and also includes breast cancer in men, which is rare. Advanced breast cancer is the subject of another guideline.4 ### Diagnosis and preoperative assessment

Partial-breast radiotherapy after breast conservation surgery for patients with early breast cancer (UK IMPORT LOW trial): 5-year results from a multicentre, randomised, controlled, phase 3, non-inferiority trial

Summary Background Local cancer relapse risk after breast conservation surgery followed by radiotherapy has fallen sharply in many countries, and is influenced by patient age and clinicopathological factors. We hypothesise that partial-breast radiotherapy restricted to the vicinity of the original tumour in women at lower than average risk of local relapse will improve the balance of beneficial versus adverse effects compared with whole-breast radiotherapy. Methods IMPORT LOW is a multicentre, randomised, controlled, phase 3, non-inferiority trial done in 30 radiotherapy centres in the UK. Women aged 50 years or older who had undergone breast-conserving surgery for unifocal invasive ductal adenocarcinoma of grade 1–3, with a tumour size of 3 cm or less (pT1–2), none to three positive axillary nodes (pN0–1), and minimum microscopic margins of non-cancerous tissue of 2 mm or more, were recruited. Patients were randomly assigned (1:1:1) to receive 40 Gy whole-breast radiotherapy (control), 36 Gy whole-breast radiotherapy and 40 Gy to the partial breast (reduced-dose group), or 40 Gy to the partial breast only (partial-breast group) in 15 daily treatment fractions. Computer-generated random permuted blocks (mixed sizes of six and nine) were used to assign patients to groups, stratifying patients by radiotherapy treatment centre. Patients and clinicians were not masked to treatment allocation. Field-in-field intensity-modulated radiotherapy was delivered using standard tangential beams that were simply reduced in length for the partial-breast group. The primary endpoint was ipsilateral local relapse (80% power to exclude a 2·5% increase [non-inferiority margin] at 5 years for each experimental group; non-inferiority was shown if the upper limit of the two-sided 95% CI for the local relapse hazard ratio [HR] was less than 2·03), analysed by intention to treat. Safety analyses were done in all patients for whom data was available (ie, a modified intention-to-treat population). This study is registered in the ISRCTN registry, number ISRCTN12852634. Findings Between May 3, 2007, and Oct 5, 2010, 2018 women were recruited. Two women withdrew consent for use of their data in the analysis. 674 patients were analysed in the whole-breast radiotherapy (control) group, 673 in the reduced-dose group, and 669 in the partial-breast group. Median follow-up was 72·2 months (IQR 61·7–83·2), and 5-year estimates of local relapse cumulative incidence were 1·1% (95% CI 0·5–2·3) of patients in the control group, 0·2% (0·02–1·2) in the reduced-dose group, and 0·5% (0·2–1·4) in the partial-breast group. Estimated 5-year absolute differences in local relapse compared with the control group were −0·73% (−0·99 to 0·22) for the reduced-dose and −0·38% (−0·84 to 0·90) for the partial-breast groups. Non-inferiority can be claimed for both reduced-dose and partial-breast radiotherapy, and was confirmed by the test against the critical HR being more than 2·03 (p=0·003 for the reduced-dose group and p=0·016 for the partial-breast group, compared with the whole-breast radiotherapy group). Photographic, patient, and clinical assessments recorded similar adverse effects after reduced-dose or partial-breast radiotherapy, including two patient domains achieving statistically significantly lower adverse effects (change in breast appearance [p=0·007 for partial-breast] and breast harder or firmer [p=0·002 for reduced-dose and p<0·0001 for partial-breast]) compared with whole-breast radiotherapy. Interpretation We showed non-inferiority of partial-breast and reduced-dose radiotherapy compared with the standard whole-breast radiotherapy in terms of local relapse in a cohort of patients with early breast cancer, and equivalent or fewer late normal-tissue adverse effects were seen. This simple radiotherapy technique is implementable in radiotherapy centres worldwide. Funding Cancer Research UK.

Acute skin toxicity associated with a 1-week schedule of whole breast radiotherapy compared with a standard 3-week regimen delivered in the UK FAST-Forward Trial

Background and purpose FAST-Forward is a phase 3 clinical trial testing a 1-week course of whole breast radiotherapy against the UK standard 3-week regimen after primary surgery for early breast cancer. Two acute skin toxicity substudies were undertaken to test the safety of the test schedules with respect to early skin reactions. Material and methods Patients were randomly allocated to 40 Gy/15 fractions (F)/3-weeks, 27 Gy/5F/1-week or 26 Gy/5F/1-week. Acute breast skin reactions were graded using RTOG (first substudy) and CTCAE criteria v4.03 (second substudy) weekly during treatment and for 4 weeks after treatment ended. Primary endpoint was the proportion of patients within each treatment group with grade ⩾3 toxicity (RTOG and CTCAE, respectively) at any time from the start of radiotherapy to 4 weeks after completion. Results 190 and 162 patients were recruited. In the first substudy, evaluable patients with grade 3 RTOG toxicity were: 40 Gy/15F 6/44 (13.6%); 27 Gy/5F 5/51 (9.8%); 26 Gy/5F 3/52 (5.8%). In the second substudy, evaluable patients with grade 3 CTCAE toxicity were: 40 Gy/15F 0/43; 27 Gy/5F 1/41 (2.4%); 26 Gy/5F 0/53. Conclusions Acute breast skin reactions with two 1-week schedules of whole breast radiotherapy under test in FAST-Forward were mild.

Trastuzumab-associated cardiac events in the Persephone trial

Background:We report cardiac events in the Persephone trial which compares 6–12 months of adjuvant trastuzumab in women with confirmed HER2-positive, early-stage breast cancer.Methods:Clinical cardiac events were defined as any of the following: symptoms and/or signs of congestive heart failure (CHF) and new or altered CHF medication. In addition, left ventricular ejection fraction (LVEF) was measured at baseline and then 3 monthly for 12 months.Results:A total of 2500 patients, aged 22–82, were included: 1251 randomised to 12 months and 1249 to 6 months of trastuzumab treatment. A total of 93% (2335/2500) received anthracyclines, 49% of these (1136/2335) with taxanes. Cardiotoxicity delayed treatment in 6% of 12-month and 4% of 6-month patients (P=0.01), and stopped treatment early in 8% (96/1214) of 12-month and 4% (45/1216) of 6-month patients (P<0.0001). Between 7 and 12 months, more 12-month than 6-month patients had LVEFs<50% (8% vs 5%; P=0.004). LVEFs showed quadratic change over time, and 6-month patients had a more rapid recovery (P=0.02). In a landmark analysis twice as many 12-month patients, free of cardiac events at 6 months, had cardiac problems in months 7–12 (6% (66/1046) vs 3% (29/1035) of 6-month patients (P=0.0002)). Lower baseline LVEF predicted more cardiac dysfunction in both arms (reference ⩾65%: 55 to <65% OR 1.61 (95% CI 1.26–2.04); <55% OR 5.22 (3.42–7.95)) as did increasing age (reference <50: 50–59 OR 1.58 (1.17–2.12), 60–69 OR 1.91 (1.42–2.57)) 70+ OR 2.72 (1.82–4.08)) and prior use of cardiac medication (OR 8.46 (4.69–15.25)). >3 cycles of anthracycline was associated with higher risk of cardiac events only for 12-month patients (OR 1.41 (1.04–1.90)), and not for 6-month patients (OR 1.28 (0.91–1.79)).Conclusions:We demonstrate significantly fewer cardiac events from 6 months of adjuvant trastuzumab compared with that from 12 months. This cardiac signal adds importance to the question of the optimum duration of adjuvant trastuzumab treatment. If 6 months is proven to have non-inferior outcomes to 12 months treatment, these data would support 6 months as the standard of care.

First results of the randomised UK FAST Trial of radiotherapy hypofractionation for treatment of early breast cancer (CRUKE/04/015): The FAST Trialists group

BACKGROUND AND PURPOSE Randomised trials testing 15- or 16-fraction regimens of adjuvant radiotherapy in women with early breast cancer have reported favourable outcomes compared with standard fractionation. To evaluate hypofractionation further, two 5-fraction schedules delivering 1 fraction per week have been tested against a 25-fraction regimen. MATERIALS AND METHODS Women aged ⩾50years with node negative early breast cancer were randomly assigned after microscopic complete tumour resection to 50Gy in 25 fractions versus 28.5 or 30Gy in 5 once-weekly fractions of 5.7 or 6.0Gy, respectively, to the whole breast. The primary endpoint was 2-year change in photographic breast appearance. RESULTS Nine hundred and fifteen women were recruited from 2004 to 2007. Seven hundred and twenty-nine patients had 2-year photographic assessments. Risk ratios for mild/marked change were 1.70 (95% CI 1.26-2.29, p<0.001) for 30Gy and 1.15 (0.82-1.60, p=0.489) for 28.5Gy versus 50Gy. Three-year rates of physician-assessed moderate/marked adverse effects in the breast were 17.3% (13.3-22.3%, p<0.001) for 30Gy and 11.1% (7.9-15.6%, p=0.18) for 28.5Gy compared with 9.5% (6.5-13.7%) after 50Gy. With a median follow-up in survivors of 37.3months, 2 local tumour relapses and 23 deaths have occurred. CONCLUSIONS At 3years median follow-up, 28.5Gy in 5 fractions is comparable to 50Gy in 25 fractions, and significantly milder than 30Gy in 5 fractions, in terms of adverse effects in the breast.

Abstract P4-11-03: Androgen receptor expression is an independent marker of lower residual risk in the TACT2 trial (CRUK/05/019)

Introduction: TACT2 (CRUK/05/019), a multicentre randomized phase III trial in patients with node +ve or high risk node -ve invasive EBC with E-CMF as control tested two hypotheses in a 2x2 factorial design, with previously presented results showing: i) no evidence of a benefit from accelerated 2-weekly epirubicin (aE) compared to standard 3-weekly epirubicin (E) (Cameron 2012); and ii) capecitabine (X) gives equivalent efficacy but preferential side-effect profile to CMF (Canney 2014). Studies suggest that Androgen receptor (AR) expression may be associated with improved outcome in early breast cancer. We performed an analysis of AR expression in TACT2 patients to test the hypothesis that AR would represent an independent predictor of residual risk following adjuvant therapy. Methods: Tumour samples were collected prospectively from 3803/4391 TACT2 patients, Tissue micro-arrays were constructed as per published guidelines and central AR, ER, PgR, HER2, Ki67, CK5/6, EGFr and BCL2 staining performed and quantified by imaged analysis for ER, PgR, HER2, Ki67 and BCL2. EGFr and CK5/6 were dichotomised by light microscopy evaluation of cores. After planned biomarker analyses had been performed, a subset of TACT2 cases for whom remaining tissue was available were analysed for AR expression. Data for 1878 cases was available for this analysis (49% of those consenting to tissue collection). AR expression was dichotomised as AR-ve ( 10%). Log-rank tests were used to explore the prognostic value of AR on time to recurrence (TTR). Cox-regression models were used to test the independent prognostic value of AR in the presence of tumour size, grade, nodal status, and biological subtypes. Marker by treatment interaction terms were included in models to test the predictive value of AR for both randomised treatment comparisons. Results: 1398/1878 (74%) patients were classed as AR+ve and 480/1878 (26%) as AR-ve. The proportion of AR+ve patients differed significantly between biological subtypes (Luminal A 269/293 (92%); Luminal B 784/928 (84%); HER+ve 86/111 (77%); Basal-like 37/216 (17%); 5-marker-ve 37/93 (40%); χ2 p 117/480 (24%) AR-ve patients had a TTR event compared with 183/1398 (13%) AR+ve patients (HR for AR-ve compared to AR+ve =2.05 95%CI 1.63-2.59; p No differential treatment effect between AR subtypes was observed for either randomised treatment comparison (E/aE or CMF/X). Conclusion: AR is an independent prognostic marker for residual risk following chemotherapy in this large study which included patients with both luminal and non-luminal cancers. AR expression patterns differ between molecular subtypes of early breast cancer, with evidence suggesting the impact of AR on residual risk may also differ between subtypes. AR is currently being explored as another potential target for therapy so these data could have future clinical relevance. Citation Format: Jane Bayani, James Morden, Sunil Skaria, Peter Bliss, Robert Grieve, Adrian Harnett, Chris Bradley, Diana Ritchie, Peter Barrett-Lee, Peter Canney, David Cameron, Judith Bliss, John Bartlett. Androgen receptor expression is an independent marker of lower residual risk in the TACT2 trial (CRUK/05/019) [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P4-11-03.

RAPID RESPONSES FROM BMJ.COM: Increased cardiovascular deaths following radiotherapy over 10 years ago - nothing new

Following is an edited excerpt from one of the Rapid Responses generated by this article, which can be read in their entirety at http://bmj.com/cgi/eletters/326/7383/256—Editor