Targeted intraoperative radiotherapy tumour bed boost during breast conserving surgery after neoadjuvant chemotherapy in HER2 positive and triple negative breast cancer

Introduction: Targeted intraoperative radiotherapy (TARGIT - IORT) as a tumour bed boost after breast conserving surgery is well established for women with early breast cancer. A previous study from our group shows a beneficial effect of TARGIT-IORT on overall survival (OS) but not diseasefree survival (DFS) after neoadjuvant chemotherapy compared to an external boost suggesting a potential non-inferiority of TARGIT-IORT. In this study, we present results regarding the high-risk subset of patients (i.e. with triple negative (TN) and HER2 positive tumours) from this cohort. Method: In this non-randomized cohort study involving patients with HER2 positive (n= 28) and triple negative (n=42) tumours after NACT we compared outcomes of 40 patients with tumour bed boost applied with TARGIT IORT during lumpectomy versus 30 patients treated in the previous 13 months with external (EBRT) boost. All patients received whole breast radiotherapy. Rates of DFS and OS were compared. Results: Median follow up was 49 months. In comparison of TARGIT-IORT vs. EBRT 5-year Kaplan- Meier estimates of OS showed no significant difference among patients with HER2 positive tumours (100% vs. 91.7%, log rank p = 0.22). The same was seen for DFS (83.3% vs. 77.0%, log rank p=0.38). The results for TN cases were similar (OS : 87.5% vs. 74.1%, log rank p=0.488; DFS 87.5% vs. 60%, log rank p=0.22). Conclusion: Although survival estimates trended towards favouring TARGIT-IORT, no significant differences could be observed and the significantly positive result for OS favoring TARGIT-IORT in the whole cohort of 116 patients could not be reproduced in this subset analysis of patients with TN and HER2 positive tumours. This may be contributable to the limited number of patients but may also indicate that effects seen in the whole cohort were mainly driven by ER and/or PR positive and HER2 negative tumours. Most importantly, non-inferiority of TARGIT-IORT as an intraoperative boost could be reproduced in these high-risk patients

Targeted intraoperative radiotherapy tumour bed boost during breast conserving surgery after neoadjuvant chemotherapy

Introduction: The use of targeted intraoperative radiotherapy (TARGIT-IORT) as a tumour bed boost during breast conserving surgery (BCS) for breast cancer has been reported since 1998. We present its use in patients undergoing breast conservation following neoadjuvant therapy (NACT). / Method: In this retrospective study involving 116 patients after NACT we compared outcomes of 61 patients who received a tumour bed boost with IORT during lumpectomy versus 55 patients treated in the previous 13 months with external (EBRT) boost. All patients received whole breast radiotherapy. Local recurrence free survival (LRFS), disease free survival (DFS), distant disease free survival (DDFS), breast-cancer mortality (BCM), non-breast-cancer mortality (NBCM) and overall mortality (OS) were compared. / Results: Median follow up was 49 months. The differences in LRFS, DFS and BCM were not statistically significant. The 5-year Kaplan-Meier estimate of OS was significantly better by 15% with IORT: IORT 2 events 96.7%(95%CI 87.5 – 99.2), EBRT 9 events 81.7% (95%CI 67.6 – 90.1), HR 0.19 (0.04 – 0.87), log rank p = 0.016, mainly due to a reduction of 10.1% in NBCM: IORT 100%, EBRT 89.9% (77.3 – 95.7), HR (not calculable), log rank p=0.015. The DDFS was: IORT 3 events, 95.1% (85.5-98.4), EBRT 12 events, 69.0% (49.1 – 82.4), HR 0.23 (0.06-0.80), log rank p=0.012. Conclusion: IORT during lumpectomy after neoadjuvant chemotherapy as a tumour bed boost appears to give results that are not worse than external beam radiotherapy boost. These data give further support to the inclusion of such patients in the TARGIT-B (Boost) randomised trial that is testing whether IORT Boost is superior to EBRT Boost

Targeted Intraoperative Radiotherapy Tumour Bed Boost during Breast-Conserving Surgery after Neoadjuvant Chemotherapy - a Subgroup Analysis of Hormone Receptor-Positive HER2-Negative Breast Cancer

INTRODUCTION: In a previous study our group showed a beneficial effect of targeted intraoperative radiotherapy (TARGIT-IORT) as an intraoperative boost on overall survival after neoadjuvant chemotherapy (NACT) compared to an external boost (EBRT). In this study we present the results of a detailed subgroup analysis of the hormone receptor (HR)-positive HER2-negative patients. METHODS: In this cohort study involving 46 patients with HR-positive HER2-negative breast cancer after NACT, we compared the outcomes of 21 patients who received an IORT boost to those of 25 patients treated with an EBRT boost. All patients received whole breast radiotherapy. RESULTS: Median follow-up was 49 months. Whereas disease-freesurvival and breast cancer-specific mortality were not significantly different between the groups, the 5-year Kaplan-Meier estimate of overall mortality was significantly lower by 21% with IORT, p = 0.028. Non-breast cancer-specific mortality was significantly lower by 16% with IORT, p = 0.047. CONCLUSION: Although our results have to be interpreted with caution, we have shown that the improved overall survival demonstrated previously could be reproduced in the HR-positive HER2-negative subgroup. These data give further support to the inclusion of such patients in the TARGIT-B (Boost) randomised trial that is testing whether IORT boost is superior to EBRT boost

Anastrozole versus tamoxifen for the prevention of locoregional and contralateral breast cancer in postmenopausal women with locally excised ductal carcinoma in situ (IBIS-II DCIS): a double-blind, randomised controlled trial

Background Third-generation aromatase inhibitors are more effective than tamoxifen for preventing recurrence in postmenopausal women with hormone-receptor-positive invasive breast cancer. However, it is not known whether anastrozole is more effective than tamoxifen for women with hormone-receptor-positive ductal carcinoma in situ (DCIS). Here, we compare the efficacy of anastrozole with that of tamoxifen in postmenopausal women with hormone-receptor-positive DCIS. Methods In a double-blind, multicentre, randomised placebo-controlled trial, we recruited women who had been diagnosed with locally excised, hormone-receptor-positive DCIS. Eligible women were randomly assigned in a 1:1 ratio by central computer allocation to receive 1 mg oral anastrozole or 20 mg oral tamoxifen every day for 5 years. Randomisation was stratified by major centre or hub and was done in blocks (six, eight, or ten). All trial personnel, participants, and clinicians were masked to treatment allocation and only the trial statistician had access to treatment allocation. The primary endpoint was all recurrence, including recurrent DCIS and new contralateral tumours. All analyses were done on a modified intention-to-treat basis (in all women who were randomised and did not revoke consent for their data to be included) and proportional hazard models were used to compute hazard ratios and corresponding confidence intervals. This trial is registered at the ISRCTN registry, number ISRCTN37546358. Results Between March 3, 2003, and Feb 8, 2012, we enrolled 2980 postmenopausal women from 236 centres in 14 countries and randomly assigned them to receive anastrozole (1449 analysed) or tamoxifen (1489 analysed). Median follow-up was 7·2 years (IQR 5·6–8·9), and 144 breast cancer recurrences were recorded. We noted no statistically significant difference in overall recurrence (67 recurrences for anastrozole vs 77 for tamoxifen; HR 0·89 [95% CI 0·64–1·23]). The non-inferiority of anastrozole was established (upper 95% CI <1·25), but its superiority to tamoxifen was not (p=0·49). A total of 69 deaths were recorded (33 for anastrozole vs 36 for tamoxifen; HR 0·93 [95% CI 0·58–1·50], p=0·78), and no specific cause was more common in one group than the other. The number of women reporting any adverse event was similar between anastrozole (1323 women, 91%) and tamoxifen (1379 women, 93%); the side-effect profiles of the two drugs differed, with more fractures, musculoskeletal events, hypercholesterolaemia, and strokes with anastrozole and more muscle spasm, gynaecological cancers and symptoms, vasomotor symptoms, and deep vein thromboses with tamoxifen. Conclusions No clear efficacy differences were seen between the two treatments. Anastrozole offers another treatment option for postmenopausal women with hormone-receptor-positive DCIS, which may be be more appropriate for some women with contraindications for tamoxifen. Longer follow-up will be necessary to fully evaluate treatment differences

Supplementary Material for: Systemic Therapy of Advanced/Metastatic Breast Cancer - Current Evidence and Future Concepts

Systemic therapy of metastatic breast cancer may include chemotherapy, endocrine therapy, and targeted therapies (e.g., antibody-based approaches). These agents may be employed alone or in combination based on the patient’s breast cancer subtype. Therefore, characterization of the disease phenotype is necessary and may include biopsy of the metastatic site. Novel therapeutic approaches include immunologic therapies, PARP inhibitors, PI3K inhibitors, and CDK4/6 inhibitors, which are currently under investigation in clinical trials