Dataset Information

Breast cancer hypoxia in relation to prognosis and benefit from radiotherapy after breast-conserving surgery in a large, randomised trial with long-term follow-up.

ABSTRACT:

Background

Breast-conserving surgery followed by radiotherapy is part of standard treatment for early-stage breast cancer. Hypoxia is common in cancer and may affect the benefit of radiotherapy. Cells adapt to hypoxic stress largely via the transcriptional activity of hypoxia-inducible factor (HIF)-1α. Here, we aim to determine whether tumour HIF-1α-positivity and hypoxic gene-expression signatures associated with the benefit of radiotherapy, and outcome.

Methods

Tumour HIF-1α-status and expression of hypoxic gene signatures were retrospectively analysed in a clinical trial where 1178 women with primary T1-2N0M0 breast cancer were randomised to receive postoperative radiotherapy or not and followed 15 years for recurrence and 20 years for breast cancer death.

Results

The benefit from radiotherapy was similar in patients with HIF-1α-positive and -negative primary tumours. Both ipsilateral and any breast cancer recurrence were more frequent in women with HIF-1α-positive primary tumours (hazard ratio, HR_{0-5 yrs}1.9 [1.3-2.9], p = 0.003 and HR_{0-5 yrs} = 2.0 [1.5-2.8], p < 0.0001). Tumour HIF-1α-positivity is also associated with increased breast cancer death (HR_{0-10 years} 1.9 [1.2-2.9], p = 0.004). Ten of the 11 investigated hypoxic gene signatures correlated positively to HIF-1α-positivity, and 5 to increased rate/risk of recurrence.

Conclusions

The benefit of postoperative radiotherapy persisted in patients with hypoxic primary tumours. Patients with hypoxic primary breast tumours had an increased risk of recurrence and breast cancer death.

SUBMITTER: Tutzauer J

PROVIDER: S-EPMC9023448 | biostudies-literature | 2022 May

REPOSITORIES: biostudies-literature

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Publications

Breast cancer hypoxia in relation to prognosis and benefit from radiotherapy after breast-conserving surgery in a large, randomised trial with long-term follow-up.

Tutzauer Julia J Sjöström Martin M Holmberg Erik E Karlsson Per P Killander Fredrika F Leeb-Lundberg L M Fredrik LMF Malmström Per P Niméus Emma E Fernö Mårten M Jögi Annika A

British journal of cancer 20220209 8

<h4>Background</h4>Breast-conserving surgery followed by radiotherapy is part of standard treatment for early-stage breast cancer. Hypoxia is common in cancer and may affect the benefit of radiotherapy. Cells adapt to hypoxic stress largely via the transcriptional activity of hypoxia-inducible factor (HIF)-1α. Here, we aim to determine whether tumour HIF-1α-positivity and hypoxic gene-expression signatures associated with the benefit of radiotherapy, and outcome.<h4>Methods</h4>Tumour HIF-1α-sta ...[more]

PMID: 35140341

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Project description:Background The rapid development of early diagnostic methods and systematic treatment for breast cancer have shed lights on the insight of prognosis of breast-conserving therapy versus mastectomy. However, there are relatively few studies with long-term follow-up, large patient cohort and under the contemporary setting in China on the subject of survival of patients undergoing breast conserving therapy versus mastectomy. Methods Data on the cases of breast-conserving therapy and mastectomy for breast cancer from October 1, 2005 to September 31, 2010 were retrieved from the breast cancer database of Chinese PLA General Hospital. The clinicopathological characteristics of patients were compared by chi-square test or Fisher’s exact test. Breast cancer-specific survival, disease-free survival, local recurrence-free survival, loco-regional recurrence-free survival, and distant metastasis-free survival were calculated and compared by Kaplan-Meier survival analysis and log-rank test firstly. And then Cox Proportional-Hazards model was used for multivariate analysis. Results There were 296 patients in the breast-conserving surgery group and 675 patients in the mastectomy group. For patients with invasive breast cancer in the entire cohort, the 10-year breast cancer-specific survival rate of patients in the breast-conserving surgery group at stage I-II was significantly higher than that of the mastectomy group. However, surgical method was not an independent prognostic factor for breast cancer-specific survival, disease-free survival and local recurrence-free survival. Moreover, N stage and luminal B-like subtype were independent prognostic factors for the breast cancer-specific survival of invasive breast cancer in the entire cohort. Conclusions This study suggests that there is no significant difference in breast cancer-specific survival between breast cancer patients undergoing breast-conserving surgery and mastectomy after adjusting for confounding factors. Lymph node staging is the major risk factor affecting patients’ survival. In this case, choosing patients with smaller tumor size, avoiding patients with stage N3, and removing a smaller volume of breast tissue including tumors while ensuring negative margins may reduce the patient’s risk of local recurrence and loco-regional recurrence.

Project description:BackgroundBC2001 showed combining chemotherapy (5-FU + mitomycin-C) with radiotherapy improves loco-regional disease-free survival in patients with muscle-invasive bladder cancer (MIBC). We previously showed a 24-gene hypoxia-associated signature predicted benefit from hypoxia-modifying radiosensitisation in BCON and hypothesised that only patients with low hypoxia scores (HSs) would benefit from chemotherapy in BC2001. BC2001 allowed conventional (64Gy/32 fractions) or hypofractionated (55Gy/20 fractions) radiotherapy. An exploratory analysis tested an additional hypothesis that hypofractionation reduces reoxygenation and would be detrimental for patients with hypoxic tumours.MethodsRNA was extracted from pre-treatment biopsies (298 BC2001 patients), transcriptomic data generated (Affymetrix Clariom-S arrays), HSs calculated (median expression of 24-signature genes) and patients stratified as hypoxia-high or -low (cut-off: cohort median).Primary endpointinvasive loco-regional control (ILRC); secondary overall survival.FindingsHypoxia affected overall survival (HR = 1.30; 95% CI 0.99-1.70; p = 0.062): more uncertainty for ILRC (HR = 1.29; 95% CI 0.82-2.03; p = 0.264). Benefit from chemotherapy was similar for patients with high or low HSs, with no interaction between HS and treatment arm. High HS associated with poor ILRC following hypofractionated (n = 90, HR 1.69; 95% CI 0.99-2.89 p = 0.057) but not conventional (n = 207, HR 0.70; 95% CI 0.28-1.80, p = 0.461) radiotherapy. The finding was confirmed in an independent cohort (BCON) where hypoxia associated with a poor prognosis for patients receiving hypofractionated (n = 51; HR 14.2; 95% CI 1.7-119; p = 0.015) but not conventional (n = 24, HR 1.04; 95% CI 0.07-15.5, p = 0.978) radiotherapy.InterpretationTumour hypoxia status does not affect benefit from BC2001 chemotherapy. Hypoxia appears to affect fractionation sensitivity. Use of HSs to personalise treatment needs testing in a biomarker-stratified trial.FundingCancer Research UK, NIHR, MRC.

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Project description:The aim of the present paper is to update the practical guidelines for postoperative adjuvant radiotherapy of breast cancer published in 2007 by the breast cancer expert panel of the German Society for Radiooncology (Deutsche Gesellschaft für Radioonkologie, DEGRO). The present recommendations are based on a revision of the German interdisciplinary S-3 guidelines published in July 2012.A comprehensive survey of the literature concerning radiotherapy following breast conserving therapy (BCT) was performed using the search terms "breast cancer", "radiotherapy", and "breast conserving therapy". Data from lately published meta-analyses, recent randomized trials, and guidelines of international breast cancer societies, yielding new aspects compared to 2007, provided the basis for defining recommendations according to the criteria of evidence-based medicine. In addition to the more general statements of the DKG (Deutsche Krebsgesellschaft), this paper addresses indications, target definition, dosage, and technique of radiotherapy of the breast after conservative surgery for invasive breast cancer.Among numerous reports on the effect of radiotherapy during BCT published since the last recommendations, the recent EBCTCG report builds the largest meta-analysis so far available. In a 15 year follow-up on 10,801 patients, whole breast irradiation (WBI) halves the average annual rate of disease recurrence (RR 0.52, 0.48-0.56) and reduces the annual breast cancer death rate by about one sixth (RR 0.82, 0.75-0.90), with a similar proportional, but different absolute benefit in prognostic subgroups (EBCTCG 2011). Furthermore, there is growing evidence that risk-adapted dose augmentation strategies to the tumor bed as well as the implementation of high precision RT techniques (e.g., intraoperative radiotherapy) contribute substantially to a further reduction of local relapse rates. A main focus of ongoing research lies in partial breast irradiation strategies as well as WBI hypofractionation schedules. The potential of both in replacing normofractionated WBI has not yet been finally clarified.After breast conserving surgery, no subgroup even in low risk patients has yet been identified for whom radiotherapy can be safely omitted without compromising local control and, hence, cancer-specific survival. In most patients, this translates into an overall survival benefit.

Dataset Information

Breast cancer hypoxia in relation to prognosis and benefit from radiotherapy after breast-conserving surgery in a large, randomised trial with long-term follow-up.

Background

Methods

Results

Conclusions

Publications

Breast cancer hypoxia in relation to prognosis and benefit from radiotherapy after breast-conserving surgery in a large, randomised trial with long-term follow-up.

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