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Originally published as JCO Early Release 10.1200/JCO.2007.14.5565 on February 19 2008 © 2008 American Society of Clinical Oncology. Estrogen Receptor, Progesterone Receptor, HER-2, and Response to Postmastectomy Radiotherapy in High-Risk Breast Cancer: The Danish Breast Cancer Cooperative Group
From the Departments of Experimental Clinical Oncology, Oncology, and Pathology, Aarhus University Hospital, Århus; and the Department of Pathology, Herlev Hospital, Herlev, Denmark Corresponding author: Marianne Kyndi, MD, Department of Experimental Clinical Oncology, Aarhus University Hospital, Århus Sygehus, Noerrebrogade 44, Building 5, 2, DK-8000 Aarhus C, Denmark; e-mail: kyndi{at}oncology.dk
Purpose To examine the importance of estrogen receptor (ER), progesterone receptor (PgR), human epidermal growth factor receptor 2 (HER-2), and constructed subtypes in a large study randomly assigning patients to receive or not receive postmastectomy radiotherapy (PMRT). Patients and Methods The present analysis included 1,000 of the 3,083 high-risk breast cancer patients randomly assigned to PMRT in the Danish Breast Cancer Cooperative Group (DBCG) protocol 82 trials b and c. Tissue microarray sections were stained for ER, PgR, and HER-2. Median follow-up time for patients alive was 17 years. End points were locoregional recurrence as isolated first event, distant metastases, and overall survival. For statistical analyses four subgroups were constructed from hormonal receptors (Rec). Rec+ was defined as ER+ and/or PgR+. Rec–as both ER–and PgR–. The four subgroups were Rec+/HER-2–, Rec+/HER-2+, Rec–/HER-2–(triple negative), and Rec–/HER-2+. Results A significantly improved overall survival after PMRT was seen only among patients characterized by good prognostic markers such as hormonal receptor–positive and HER-2– patients (including the two Rec+ subtypes). No significant overall survival improvement after PMRT was found among patients with an a priori poor prognosis, the hormonal receptor–negative and HER-2+ patients, and in particular the Rec–/HER-2+ subtype. Furthermore, comparing hazard ratios and 95% CIs, significantly smaller improvements in locoregional recurrence control after PMRT were found for ER–and PgR–tumors compared with the ER+ and PgR+ tumors (P = .003 and .04, respectively), and for the triple-negative (P = .02), and the Rec–/HER-2+ subtypes (P = .003) compared with the Rec+/HER-2–subtype. Conclusion Hormonal receptor status, HER-2, and the constructed subtypes may be predictive of locoregional recurrence and survival after postmastectomy radiotherapy.
In the late 1970s, adjuvant chemotherapy became the standard treatment of choice for high-risk premenopausal breast cancer patients1-3 with a subsequent decline in use of adjuvant radiotherapy. In the late 1990s, results from the Danish Breast Cancer Cooperative Group (DBCG) protocol 82 trials b and c and the British Columbia Randomized Radiation trials showed an improved overall survival (OS) after postmastectomy radiotherapy (PMRT) both among premenopausal4,5 and postmenopausal high-risk breast cancer patients also treated with systemic therapy.6 In the late 1990s and early 2000, it was concluded in international consensus reports that postmastectomy radiotherapy (PMRT) was to be considered for patients with an increased risk of locoregional recurrence (LRR) after adequate surgery and adjuvant systemic therapy,7-15 which was defined as patients with more than three positive lymph nodes. So far, patients and tumors in the DBCG82 b and c studies have been described with classical clinical factors only, such as nodal status and tumor size. However, when examined as single factors, neither nodal status nor tumor size revealed any subgroups of patients lacking effect from radiotherapy.4 In fact, both the DBCG82 and the British Columbia Randomized Radiation trials showed a significantly improved overall survival after PMRT, also among patients with one to three positive lymph nodes, which has been indicated in a large overview as well.16-18 It is well-established that breast cancer is a heterogeneous disease and that response to PMRT might be heterogeneous as well. Perhaps different biologic markers describe such heterogeneity. The primary purpose of this study was to examine the impact of hormonal receptors (Rec; estrogen receptor [ER] and progesterone receptor [PgR]), human epidermal growth factor receptor (HER)-2, and different constructed subtypes on PMRT response within what is the largest study including 1,000 breast cancer patients randomly assigned to receive or not receive PMRT to our knowledge to date.
Patients From 1982 to 1990, 3,083 high-risk Danish breast cancer patients were enrolled in the DBCG82 b and c studies. High-risk was defined as either positive lymph nodes and/or tumor size larger than 5 cm and/or invasion of tumor to surrounding skin or pectoral fascia. All women had a total mastectomy and a partial axillary dissection. A median of seven lymph nodes was removed from the axilla. The premenopausal women were enrolled in the DBCG82 b protocol and were randomly assigned to either radiotherapy + CMF (cyclophosphamide, methotrexate, fluorouracil; eight cycles) or to CMF chemotherapy alone (nine cycles).4 The postmenopausal women were enrolled in the DBCG82 c protocol and were randomized either to radiotherapy + tamoxifen (30 mg daily for 1 year) or to tamoxifen alone.6 Long-term clinical follow-up was performed for all patients (described in detail previously19). A total of 1,241 patients were selected for extended biologic analyses. All patients fulfilled the criteria that at least eight lymph nodes had been surgically removed, and consequently the patient subgroup with the most extensive axillary surgery was selected.
Methods
The subgroup of 1,000 patients was well-distributed between the two randomization arms for all classical clinical and pathologic parameters, including ER, PgR, HER-2, and the four different subtypes constructed from hormonal receptor status and HER-2 (Table 1). In agreement with results from the total DBCG82 series, significantly reduced overall mortality (HR = 0.84; 95% CI, 0.72 to 0.97), DM (HR = 0.80; 95% CI, 0.68 to 0.94) and LRR (HR = 0.17; 95% CI, 0.10 to 0.26) probabilities after PMRT were found within the subgroup of 1,000 patients.
Distribution of Clinicopathologic Markers Between Different Biologic Subgroups Rec+/HER-2–tumors were recorded at a frequency of 63%, Rec+/HER-2+ at 10%, triple negative at 15%, and Rec–/HER-2+ tumors at 12%. Women with triple-negative or Rec–/HER-2+ tumors had higher frequencies of other poor prognostic criteria compared with women with Rec+/HER-2–tumors (Table 2). In addition, a slightly higher frequency of premenopausal women was found within the triple-negative subtype and a slightly higher frequency of postmenopausal women within the Rec–/HER-2+ subtype.
Prognostic Value Within the total subgroup of 996 patients with TMA cores assessable for ER, PgR, and HER-2, negative ER and PgR, and positive HER-2 status were significantly associated with increased LRR and DM probability in univariate analyses. PgR and HER-2 retained significance in multivariate analyses of DM (P = .008 and .008, respectively), whereas only PgR retained significance in multivariate testing of LRR (P = .002). Previously, a significant association between PgR and HER-2 and overall mortality was found in multivariate analyses as well.20 Having a triple-negative or a Rec–/HER-2+ tumor was significantly associated with increased overall mortality (P = .02 and < .001), DM (P = .02 and < .001), and LRR (P = .01 and .009) in univariate analyses. Rec–/HER-2+ tumors retained prognostic significance in multivariate analysis for all end points, only outperformed by nodal status. Triple-negative tumors retained prognostic significance for overall mortality and LRR, but not for DM. In multivariate analyses of the subgroup of 510 patients randomly assigned to no PMRT, triple-negative tumors were significantly associated with increased overall mortality and DM and LRR probability (P < .001, < .001, and .01, respectively). Rec–/HER-2+ tumors were significantly associated with increased overall mortality and DM but not with increased LRR probability (P < .001, .01, and .2). In multivariate analyses of the subgroup of 486 patients randomized to PMRT, triple negative tumors were only significantly associated with increased LRR probability (P = .004) but not overall mortality or DM (P = .7 and .99, respectively). Rec–/HER-2+ tumors, however, were significantly associated with all end points (P < .001, .003, and < .001). In fact, triple-negative tumors and Rec–/HER-2+ tumors were the two parameters most strongly associated with increased LRR probability, outperforming both nodal status and tumor size.
Predictive Value Kaplan-Meier probability plots of OS showed significantly improved survival after PMRT within the best prognostic subgroups, the ER+, PgR+, and HER-2–subgroups (Fig 1). Within the poorest prognostic subgroups (ER–, PgR–, and HER-2+) no survival benefit was seen after PMRT. HRs and CIs of overall mortality after PMRT differed significantly between the best and poorest subgroups of ER (P = .04) and PgR (P = .01), but not HER-2 (P = .2). Significantly reduced LRR probabilities after PMRT were found within the best as well as the poorest prognostic subgroups of patients (Fig 2). However, HRs and CIs for LRR probabilities were also significantly less reduced after PMRT for the ER–(P = .003) and PgR–(P = .04) but not HER-2+ (P = .3) subgroups, compared with the ER+ and PgR+ and HER-2–subgroups, respectively.
For the constructed subtypes, a significantly improved OS was found after PMRT for the Rec+/HER-2–subtype, whereas only a borderline improved OS was found for the smaller sized Rec+/HER-2+ subtype. For the triple-negative and Rec–/HER-2+ subtypes, no significant improvements in OS was found after PMRT, with an obvious lack of survival improvement for the Rec–/HER-2+ subtype (Fig 3). HRs and CIs differed significantly only between the Rec–/HER-2+ and the Rec+/HER-2–subtype (P = .01), not between the triple-negative and Rec+/HER-2–subtypes (P = .7). Significantly reduced LRR probabilities were found after PMRT for the Rec+/HER-2–(P < .001), Rec+/HER-2+ (P = .005), and triple-negative subtypes (P = .01), whereas only an insignificant reduction in LRR probability was found for the Rec–/HER-2+ subtype (P = .2; Fig 3). In fact, significantly smaller reductions in LRR probability after PMRT was found comparing hazard ratios and CIs for the triple negative (P = .02) and the Rec–/HER-2+ subtype (P = .003) with the Rec+/HER-2–subtype.
A significantly improved overall survival after PMRT was seen only among patients characterized by good prognostic markers such as Rec+ and HER-2–patients, whereas no significant overall survival improvement after PMRT was found among the Rec–and HER-2+ patients. The subgroup of 1,000 patients was representative of the total cohort of 3,083 patients with patients well-distributed among the two randomization arms and reproducing similar outcome data as seen among the 3,083 patients. The frequency of negative staining for ER (33%) and PgR (40%) in this almost exclusively node-positive patient group was as expected higher than reported for node-negative patients,21 in fact in line with findings among high risk patients with four or more positive nodes in which negative ER and PgR staining has been reported at frequencies of 29% and 43%, respectively.22 Of concern is that use of TMA cores might overestimate the number of ER–and PgR–tumors, in particular in cores with few invasive tumor cells, which was the reason a full tissue section was evaluated if the TMA core contained fewer than 50 invasive tumor cells.20 However, generally a high reproducibility has been reported for ER and PgR stained TMA biopsies and corresponding full sections23-25 and also previously reported for this study.20 Twenty-two percent as HER-2+ tumors might seem low, in particular compared with results obtained by FISH analyses performed in early studies of primarily high-risk cohorts and patients with metastatic disease, suggesting as many as 30% of breast cancers had HER-2 amplification.26,27 However, in two large consecutive cohorts of several thousand patients 19% to 22% of tumors were amplified for HER-2, and 11% percent were scored 3+ by IHC.28-30 In addition, Pritchard et al reported for a node-positive cohort that 26% of tumors were HER-2 amplified and 18% to 20% HER-2 positive by IHC.31 The frequency of 15% triple-negative tumors was in line with previous findings,32-36 as was the higher frequency of triple-negative tumors among premenopausal women and grade 3 malignant tumors.32,34,37 The constructed subtypes may roughly resemble intrinsic subtypes found prognostic of survival in gene microarray studies36,38,39 with the Rec+/HER-2–and Rec+/HER-2+ subtypes resembling the luminal A and B subtypes, respectively, and the triple-negative and the Rec–/HER-2+ subtypes resembling the basal- and HER-2–like subtypes, respectively. A huge number of studies have searched for potential IHC markers describing the intrinsic subtypes. Livasy et al,40 however, showed that IHC determined ER and HER-2 status largely described the subgroups.40 Nevertheless, in this study only slightly separated survival curves were seen for the four different subtypes within the subgroup receiving no PMRT. They all, except from the Rec+/HER-2+ subtype, had a 15-year overall survival probability around 30%. A larger discrepancy, however, was found between 5-year survival probabilities indicating that our definitions of the subtypes may be of largest prognostic relevance within the first years after diagnosis. Applying extra IHC prognostic parameters defining the subtypes, however, may improve the prognostic impact of the subtypes, which has been reported in some studies.34,39 Triple-negative tumors were significantly associated with increased overall mortality and DM probability within the subgroup of patients not receiving PMRT, whereas no significant association was found among patients receiving PMRT indicating an unclear prognostic relevance of this subtype, although findings may owe to the sample size. Gene microarray studies36,39 and studies resembling the intrinsic subtypes with IHC32,34,37 have reported significant associations with OS and DM, but have not distinguished between treatment with radiotherapy. Triple-negative tumors were significantly associated with increased LRR probability in both randomization arms, indicating a strong prognostic relevance, which is in disagreement with findings by Haffty et al37 reporting no significant association between triple negative tumors and increased LRR probability.37 The study by Haffty et al, however, included primarily node-negative patients (75%) treated with breast-conserving surgery and radiotherapy compared with the DBCG82 b and c studies including primarily high-risk, node-positive patients (94%) all treated with mastectomy. The Rec–/HER-2+ subtype was strongly associated with increased mortality and DM probability among patients in both randomization arms, indicating a strong prognostic value. It was, however, only a strong prognostic marker of LRR probability among patients treated with PMRT, indicative of an interaction with radiotherapy, which was also found to be significant. Comparisons of HRs and CIs showed significantly smaller reductions in LRR probability after PMRT among ER–and PgR–and triple-negative patients compared with ER+ and PgR+ and the Rec+HER-2–subtype, respectively, but not among HER-2+ patients compared with HER-2–patients. All together, this may indicate that a possible radioresistance of the triple-negative subtype may predominantly be a result of the inherent Rec negativity within this subtype. Estrogen speeds up cell cycle (transition from G1 to S phase) which, hypothetically, could leave tumor cells with less time to repair DNA damage caused by radiotherapy. This may, at least in theory, render ER+ tumors more sensitive to radiotherapy compared with ER–tumors. Kaplan-Meier LRR plots for HER-2+ and HER-2–patients did not indicate any reduced LRR control after PMRT among HER-2+ patients. Nevertheless, the combined variable of negative hormonal receptors and positive HER-2 (Rec–/HER-2+) showed a significantly reduced LRR improvement after PMRT, indicating some radioresistance associated with HER-2 as well. HER-2 should, among others, also speed up transition from G1 to S phase and increasing radiosensitivity for the HER-2–overexpressing tumors may be expected as well. Preclinical data, however, suggest, in line with our results, that expression of the HER-2 oncogene may be associated with relative resistance to radiation. Transfection of NIH3T3 cells with the HER-2 genomic DNA from an esophageal carcinoma rendered the cells insensitive to radiotherapy.41 In addition, Pietras et al reported that transfectants of MCF-7 cells with HER-2 were resistant to radiotherapy compared with MCF-7 parental cells, and that recombinant humanized monoclonal 4D5 antibody against HER-2 reversed radiation resistance in HER-2–overexpressed cell lines in vitro and in vivo, by modulating DNA repair of radiation induced DNA damage.42 Clinical studies of HER-2 status in patients, randomly assigned radiotherapy, are lacking. Two studies have examined HER-2 status in patients randomized to either adjuvant radiotherapy or to adjuvant chemotherapy but conflicting findings have been reported.43,44 One explanation for the lack of LRR benefits influencing OS among poor prognostic subgroups of patients could be unrecognized distant micrometastases not eliminated by the systemic therapy applied and thereby a high competing risk of clinically detected DM resulting in PMRT affecting the local disease only. This is in line with the spectrum hypothesis, presented by Hellman in 1994.45 This theory suggests that the breast cancer disease encompasses a wide spectrum of diseases, from tumors destined to remain localized to those with the potential to metastasize but without micrometastases at diagnosis to those always presenting with at least distant micrometastases at diagnosis. Rec–tumors respond poorly to tamoxifen46,47 and may also respond poorly to CMF, at least if CMF results in a chemical ovarian ablation resulting in reduced levels of hormones, as has been suggested.48 Positive HER-2 status has been strongly correlated with reduced survival49-51 and associated with both resistance to CMF and tamoxifen, although inconsistent results have been reported.31,52-55 The non–significantly improved OS after PMRT for the triple-negative group, with curves practically overlapping in the first 5 years, may be in line with the presented hypothesis, as well. Triple-negative tumors were only significantly associated with reduced OS among patients not treated with PMRT, and a stronger prognostic association may be needed for a biologic parameter to reveal any lack of survival improvement after PMRT. In agreement with this suggestion, the Rec–/HER-2+ tumors showed a markedly inferior improvement in survival after PMRT and were additionally found strongly associated with reduced OS within both randomization arms. However, attention must be drawn to the retrospective design of this study. Not all subgroup analyses within this 1000 patient cohort had the necessary power to detect significant survival differences and an expected 8% to 10% survival difference may among others not be detected among 156 triple negative patients. In conclusion, in what is to our knowledge the largest study examining Rec and HER-2 among patients randomly assigned to receive or not receive PMRT to date, we found no survival improvement after PMRT among patients with the poorest prognostic biologic criteria such as ER–, PgR–, and HER-2+ tumors and, in particular, the combined Rec–/HER-2+ variable. Our results lend support to the spectrum hypothesis, suggesting that our findings may result from distant unresponsive micrometastases in these biologically defined poor prognostic subgroups. Besides, increased radioresistance among ER–and PgR–, the triple-negative, and particularly the Rec–/HER-2+ subtypes may explain in part the lack of improvement in survival.
The author(s) indicated no potential conflicts of interest.
Conception and design: Marianne Kyndi, Flemming B. Sorensen, Jens Overgaard Financial support: Flemming B. Sorensen, Jens Overgaard Administrative support: Marianne Kyndi, Flemming B. Sorensen, Jens Overgaard Provision of study materials or patients: Marie Overgaard, Jens Overgaard Collection and assembly of data: Marianne Kyndi, Flemming B. Sorensen, Helle Knudsen, Hanne Melgaard Nielsen, Jens Overgaard Data analysis and interpretation: Marianne Kyndi, Jens Overgaard Manuscript writing: Marianne Kyndi, Jens Overgaard Final approval of manuscript: Marianne Kyndi, Flemming B. Sorensen, Helle Knudsen, Marie Overgaard, Hanne Melgaard Nielsen, Jens Overgaard
We thank Stine Walther Nielsen, Tine Bovtrup, Birthe Hermansen, and Mogens M. Johannesen for excellent technical assistance.
published online ahead of print at www.jco.org on February 19, 2008. Supported by grants from the Danish Cancer Society, the University of Aarhus, the Danish Medical Research council, Danish Ministry of Health, and M.L. Jørgensen and Gunnar Hansen's foundation. Presented in part at the 5th European Breast Cancer Conference, March 21-25, 2006, Nice, France. Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.
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Copyright © 2008 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
2 or exact tests were used for testing relationships between variables. Kaplan-Meier probability curves were calculated and tested for differences by log-rank test. Prognostic value was analyzed using Cox uni- and multivariate regression analyses. Tests of interaction were applied to Cox multivariate regression analyses. End points to be considered were isolated LRR, distant metastasis (DM) (including patients presenting with LRR and DM synchronously), and overall survival. End points have been described in detail previously.
