THE COMPARISON OF PROGNOSIS BETWEEN FOUR SUBTYPES UNDER VARIOUS RADIOTHERAPY CONDITIONS
Conventional whole-breast irradiation
For the majority of patients with ESBC or ductal carcinoma in situ (DCIS) in the case of intended breast preservation, standard and widely adopted treatment is CWBI at 50.0 Gy irradiation typically administered at the daily dose of 2.0 Gy via 25 fractions over 5 weeks;2,22 this treatment can reduce the risk of LR by 60–70% and 50–60% in invasive and noninvasive breast carcinoma, respectively.2,23–26 Two independent pioneering randomized trials (The British Columbia Randomized Radiation (BCRR) trial27 and The Danish Breast Cancer Group (DBCG) protocol 82b28) demonstrated the benefits of CWBI combined with polychemotherapy in breast cancer. After follow-up of 15 years, the BCRR trial found a reduction in the rate of locoregional recurrence (LRR) and mortality of 33% and 29%, respectively, which was approximately similar to the outcomes of DBCG 82b trial that demonstrated a reduction in the LRR rate by 23% and 9%, respectively, after 10-years follow-up. These findings have a far-reaching impact on the clinical application of CWBI.
The median time of disease relapse in breast cancer after systemic adjuvant therapy may be 2–4 years or can be significantly prolonged to 5–8 years;24,29,30 this delay is linked to tumor biology and molecular subtypes. Compared to luminal breast cancer, TNBC, and HER2-amplified breast carcinomas commonly have strong invasiveness, shortened survival31 and a 2–3-fold increase in the tumor relapse rate.32,33 Moreover, the risk of DM in TNBC during the initial 2–3 years is higher than that in other subtypes of the disease thus emphasizing unfavorable prognosis.34 Multiple studies have corroborated that the prognosis varies depending on the subtype of breast tumor receiving CWBI.12,35–37 A significantly lengthened overall survival (OS) is observed in luminal A and TNBC but not in other tumor phenotypes. In breast cancer patients treated with BCS combined with CWBI, the 5 years and 10 years LR risk in TNBC and HER2-positive subtypes (without anti-HER2 targeted therapy) is up to twofold higher than that in luminal A subset and the relapse-free survival in luminal B molecular phenotype is lower than that in other intrinsic subtypes; however, the 10 years ipsilateral breast tumor relapse (IBTR) among different subtypes is not significantly different (Table 2). In recent years, alongside with introduction of trastuzumab, the LRR rate of HER2-positive breast cancer has been significantly decreased;38 however, this high LRR rate remains a major threat in TNBC due to the lack of suitable targeted therapy.
Accelerated partial-breast irradiation
Currently, APBI is gradually becoming a surrogate to CWBI due to its discernible advantages including curtailed curative time, superior local control,39 low toxicity, and favorable cosmetic outcomes.40 The American Brachytherapy Society has published a consensus statement on APBI treatment for breast cancer by taking the following factors into consideration and enacted appropriate criteria for patient selection: age ≥45 years, tumor size ≤3 cm, negative lymph nodes, no invasion of lymph-vascular space, all invasive histology and DCIS, positive/negative ER status, and no infiltration of surgical margins.41
Recently, the correlations of molecular subtypes with the prognosis of breast cancer patients who were treated with APBI have been extensively investigated. In the study of Wadasadawala et al, who evaluated the treatment outcomes of ESBC patients after receiving APBI,42 it was shown that the 3 years LR and LRR across different molecular subtypes were not significantly different whereas the 3 years DM-free survival, OS, and disease-free survival (DFS) of HER2-positive subtype were significantly lower than those of luminal A and B phenotypes. Moreover, in 2016, Dr. Wilkinson introduced a 5-year follow-up clinical results of APBI treatment in 278 ESBC patients,43 which indicated no significant difference in the incidence rates of IBTR, DM, DFS, and OS between four phenotypes of breast tumors (Table 2). In contrast, Pashtan and colleagues evaluated 98 ESBC patients who underwent three-dimensional conformal external beam APBI and discovered partial inconsistencies.44 The multivariate analysis indicated that TNBC was the only predictor for the inferior outcome of 5 years IBTR with a high risk of 33% compared to that of 2% in other pooled subtypes. There may be some connotative explanations for different conclusion in both trails; for example, the majority of TNBC patients in the latter study receives chemotherapy prior to APBI, thereby delaying the initiation of radiotherapy.
It should be noted that for breast cancer patients >50 years of age undergoing APBI, HER2-enriched subtype has a significantly higher risk of 5 years IBTR and 5 years regional nodal recurrence (RNR) than that in all other subtypes, whereas luminal A subtype has the lowest risk of all subtypes.45 A similar conclusion was reached in some clinical trials following multi-catheter APBI (mAPBI)42 and single-entry catheter APBI (sAPBI).46 In the mAPBI trial, HER2-positive status was associated with the shortened DM-free survival, DFS, and OS and the 5 years IBTR of HER2-enriched breast tumors and 5 years RNR of TNBC were significantly higher than those in luminal A disease in the sAPBI trial (Table 2).
Hypofractionated whole-breast irradiation
Radiobiological models indicate that an alternative regimen, known as HWBI, with a larger daily dose per fraction within a shorter duration may achieve efficacy similar to that of CWBI47 and has distinct advantages including higher convenience, lower resource expenditure, and decreased LR rate and radiation-related morbidity.48–50 In 2002, a randomized trial investigated a 5-year follow-up outcomes with reference to BCS followed by CWBI or HWBI at the 42.5 Gy dose divided into 16 fractions over a period of 22 days in the treatment of breast cancer patients with negative status of axillary lymph nodes.51 The two cohorts had identical LR rate of 3% and similar cosmetic outcomes reflecting irradiation-associated complications. Considering possible magnification of the radiation-related toxicity at an extended time,52 women with breast tumors may be inclined to receive HWBI instead of CWBI.
HWBI has become the standard surrogate of CWBI for a large proportion of breast cancer patients;53however, it is less effective in high-grade tumors regardless of positive or negative lymph nodes leading to curtailed DFS and deterioration of DM.54,55 The highest incidence of LR is observed in HER2-enriched breast cancer patients with lymph node negativity;56 however, no substantial differences in IBTR rate are detected across four intrinsic subtypes.57,58 A study in 752 elderly breast cancer patients (age ≥65 years) who were categorized as having grade 3 primary tumors with positive surgical margins administered a tumor bed boost (n=190).59 The 5 years DFS of TNBC was significantly lower than that in other subtypes of the tumors (p<0.01) without a significant difference in 5 years LR rate (p=0.83); the univariate and multivariate analysis indicated that HER2-positive breast cancer and TNBC were positively correlated with the unfavorable DFS (p<0.05). A total number of 989 node-negative breast cancer women who underwent HWBI following BCS were finally enrolled in the trial of Dr. Bane and colleagues,56 demonstrating that the HER2-positive breast tumor was associated with significantly higher 10 years LR than that of Luminal A breast cancer and TNBC (p<0.01) (Table 2). Collectively, the results from these studies demonstrated variable benefit of different phenotypes of breast tumors from CWBI, APBI, and HWBI treatments, which may be attributed to disparate radiosensitivity of the subtypes.
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