Molecular analysis of local relapse in high-risk breast cancer patients: can radiotherapy fractionation and time factors make a difference?

Abstract

Large primary breast tumours and extensive lymph node involvement are linked to a high rate of local recurrence after surgery. In 10 -20% of such high-risk breast cancer patients, local relapse will occur despite postoperative radiotherapy. In the present study, we investigated whether molecular features, such as angiogenesis, cancer cell proliferation, steroid receptor expression, c-erbB-2 oncoprotein overexpression, p53 protein nuclear accumulation or bcl-2 antiapoptotic protein expression, can predict failure of local therapy. We further examined as to which subgroups of patients could benefit from altered fractionation schemes of radiotherapy. In univariate analysis, high intratumoural angiogenesis, c-erbB overxpression and mutant-p53 nuclear accumulation were significantly associated with increased relapse rate (P ¼ 0.0002, 0.009 and 0.05, respectively). In multivariate analysis, the microvessel density and the c-erbB-2 status were independent and significant factors related to local relapse (P ¼ 0.001, t-ratio 3.36 and P ¼ 0.02, t-ratio 2.26, respectively). Hypofractionated and accelerated radiotherapy supported with amifostine (HypoARC regimen) was significantly more effective than standard radiotherapy in cases with high cancer cell proliferation index, c-erbB-2 and p53 overexpression. High angiogenesis, however, was linked with local relapse regardless of the radiotherapy regimen.

Young age is associated with ipsilateral breast tumor recurrence after breast conserving surgery and radiation therapy in patients with HER2-positive/ER-negative subtype

“…Previous studies have assessed the usefulness of biomarkers, such as Ki-67 and p53, and multi-gene signatures, such as wound response signature and the Oncotype DX assay, as indicators of local recurrence [38][39][40]. We suggest that the interaction of patient age with these and other biomarkers be considered in future studies.…”

Hypofractionated and Accelerated Radiotherapy With Subcutaneous Amifostine Cytoprotection as Short Adjuvant Regimen After Breast-Conserving Surgery: Interim Report

“…A previous pilot study showed that hypofractionated accelerated RT with cytoprotection using intravenously administered amifostine (HypoARC) provided encouraging results, with minimal early and late toxicity and improved efficacy in specific subgroups of patients (8,9). Since 2003, a prospective study has been on-going, recruiting patients with early-stage breast cancer to receive HypoARC to the breast and/or axilla and supported with high-dose, daily, subcutaneously administered, amifostine.…”

“…An immunohistochemical streptavidin-biotin technique was used for the detection of c-erbB-2 and estrogen receptor (ER) expression, as previously described (9). The percentage of tumor cells with membrane c-erbB-2 staining was recorded in all optical fields, and a mean value of $20% was considered positive.…”

“…Patients received a daily fraction of 3.5 Gy to a total dose of 35 Gy (10 consecutive fractions) within 12 days. An additional dose of 8 Gy (4 Gy/fraction) was given to the tumor-residing breast quadrant using electrons (8)(9)(10)(11)(12). A posterior axillary field delivered an additional fraction of 3.5 Gy to the axilla.…”

Histological quantitation of tumour angiogenesis

“…In oesophageal, head and neck tumours, microvessel density or vascular grade was predictive of response (178–181). Recurrences after wide local excision and radiation therapy showed no association with tumour VEGF expression (182) and highly vascular tumours recurred after aggressive regimens such as hypofractionated and accelerated radiotherapy despite being more effective in tumours with high proliferation, c‐erbB‐2 and p53 overexpression (183).…”