New Frontier for Genomics: Radiotherapy in Early Breast Cancer

Terry P. Mamounas, MD, MPH

In early-stage breast cancer, molecular subtyping and gene expression profiling has improved our ability to estimate risk of distant recurrence above and beyond traditional clinicopathologic factors and biomarkers.^1-7 Despite this considerable progress in refining risk of distant recurrence, risk assessment for locoregional recurrence (LRR) is still primarily based on traditional clinicopathologic factors such as patient age, tumor size, grade, pathologic nodal status, presence of lymphovascular space invasion, and margin width.^8,9

In addition, several studies have shown that tumor subtype alone is strongly predictive of LRR.^5,10-16 Given the solid correlation between the risk of LRR and distant recurrence,^17-19 several investigators have examined whether genomic assays that predict risk of distant recurrence can also predict risk of LRR.^20-28 Increasingly, new genomic classifiers are being developed specific to LRR, in patients with nodenegative and node-positive invasive breast cancer.^29,30 There is also increasing interest in developing gene expression assays to predict response to radiation therapy (XRT).^30-39

Can Genomic Profiling Affect the Surgical Management in the Breast or Axilla?

Local recurrence is also strongly influenced by the surgical approach. To date, molecular subtyping/ genomic profiling has very little to no influence on the extent of surgical therapy, which is traditionally based on the anatomic extent of the tumor and not on underlying tumor biology. Anatomic extent of the tumor in the breast and axilla can be reduced by neoadjuvant therapy, which results in tailoring of the surgical approach. However, in the traditional model of surgery first followed by adjuvant systemic therapy, genomic profiling has very little influence on the extent of surgical therapy.

Can Genomic Profiling Affect the Use of Adjuvant XRT?

By individualizing risk of LRR with molecular subtyping and use of genomic classifiers, it is hoped that use of adjuvant XRT can also be tailored. Currently, there are 2 approaches for tailoring use of XRT. First, is the potential of customizing the use of postmastectomy and regional nodal XRT. Second, is the potential of avoiding breast XRT in selected candidates at low risk of in-breast recurrence after breast-conserving surgery (BCS).

Adjuvant Postmastectomy and Regional Nodal Radiation Therapy

The association between the 21-gene recurrence score (RS) and risk of LRR has been evaluated in patients with node-negative, estrogen receptor (ER)—positive breast cancer treated with either no adjuvant therapy, tamoxifen, or tamoxifen plus adjuvant chemotherapy as part of the National Surgical Adjuvant Breast and Bowel Project (NSABP) B-14 and NSABP B-20 trials.⁴⁰

Patients treated with BCS received breast XRT but patients who underwent a mastectomy received no XRT. RS was a significant predictor of LRR in all 3 groups of patients. In 895 patients treated with tamoxifen, the 10-year estimates of the proportion of patients with LRR were 4.3%, 7.2%, and 15.8% for patients with low, intermediate and high RS, respectively (P <.001).

Similar association between RS and risk of LRR was identified in 424 patients treated with chemotherapy plus tamoxifen in the B-20 trial (10-year LRR rates: 1.6%, 2.7%, and 7.8% for patients with low, intermediate, and high RS, respectively [P = .028]). This 5-fold difference in LRR between low versus high RS in patients treated with chemo-endocrine therapy is biologically interesting but has limited clinical implications for patients with node-negative disease relative to the potential need (or benefit from) postmastectomy or regional nodal XRT.

The previously mentioned observations of low LRR risk in patients with a low RS (<18) were recently confirmed in a large, contemporary cohort of patients with node-negative, ER-positive/HER2- negative breast cancer from Memorial Sloan Kettering Cancer Center in New York, New York.²⁶ Most patients were treated with BCS plus XRT (66.6%) or total mastectomy alone (29.7%), endocrine therapy alone (84.8%), or chemo-endocrine therapy (12.1%). With a median follow-up of 52 months, the LRR rate was 0.9% overall and 0.7% in patients treated with adjuvant endocrine therapy only.

Similar findings have also been reported with other genomic classifiers. Fitzal et al evaluated the PAM50 assay in the ABCSG-8 trial of postmenopausal patients with ER-positive/HER2-negative disease, treated with endocrine therapy⁴¹; 21% of the patients had undergone a mastectomy. With a median follow-up of 11 years, the 10-year local recurrence-free survival (LRFS) risk was significantly associated with PAM50 risk of recurrence (ROR) (98.4% in the low/intermediate ROR group vs 94.4% in the high ROR group). ROR score was the only significant independent predictor of LRR in multivariate analysis. The groups that underwent breast conservation surgery and mastectomy had similar LRR rates (P = .879).

The significant association between genomic classifiers and LRR in patients with node-negative disease provided rationale for evaluating RS in those with node-positive disease, hoping that improved LRR stratification could help to tailor postmastectomy radiation therapy (PMRT) and/or regional nodal XRT use. Three studies have reported such an association based on retrospective assessment of RS in patients with exclusively node-positive breast cancer included in randomized clinical trials of adjuvant chemo-endocrine therapy (NSABP B-28, ECOG 2197, SWOG 8814).^21,22,28

In the NSABP B-28 trial, patients with node-positive disease were randomized to doxorubicin/cyclophosphamide with or without paclitaxel. Patients aged >50 years and those aged <50 years with ER-positive and/or progesterone receptor—positive tumors also received tamoxifen. Patients treated with BCS received breast XRT but patients who underwent mastectomy did not receive XRT. RS was obtained in 1065 patients with ER-positive disease.22 With a median follow-up of 11.2 years, the 10-year cumulative incidence of LRR was 3.3%, 7.2%, and 12.3% for low, intermediate, and high RS, respectively (P <.001).

Table. Clinical Trials Evaluating Genomic Strategies for RT in Early Breast Cancer (Click to Enlarge)

In their study population, 10-year rates of LRR were 3.2%, 2.0%, and 10.1% for low, intermediate, and high RS, respectively, which was not statistically significant (P = .17). However, as a continuous variable, RS was a significant predictor of LRR (HR, 2.66, P = .03). Woodward et al recently reported on the retrospective assessment of RS in SWOG 8814, comparing chemo-endocrine versus endocrine therapy in patients with node-positive, hormone receptor—positive breast cancer.²⁸ Estimated 10-year cumulative LRR rates were 9.7% and 16.5%, for low versus intermediate/high RS, respectively (log-rank P = .018). In an analysis of patients who have undergone mastectomy alone, differences in RS remained significant (7.7% low RS vs 16.8% intermediate/ high RS; P = .03).

These findings suggest that genomic profiling can significantly predict risk of LRR in patients with node-positive breast cancer, and this association could have clinical implications regarding tailoring regional nodal XRT or PMRT. However, before such an approach becomes accepted clinical practice, validation in prospective clinical trials is needed.

One such trial is CCTG MA.39 that is currently accruing patients through the National Cancer Trials Network (TAILOR RT; NCT03488693). MA.39 includes patients with ER-positive/HER2- negative, node-positive breast cancer and a 21-gene RS of <18. Patients who underwent mastectomy are randomized to chest wall plus regional nodal XRT versus no XRT, whereas patients treated with BCS are randomized to breast plus regional nodal XRT versus breast XRT only. A total of 2140 patients will be included in the study (Table).

Adjuvant Breast XRT Following BCS

There have been several attempts to tailor the use of breast XRT following BCS based on primary tumor or patient characteristics.^41,42 A previously reported clinical trial using tumor size of <1 cm as a criterion for selecting patients at low risk of in-breast recurrence, who can then be treated with BCS without breast XRT, demonstrated unacceptably high rates of in-breast recurrence when XRT was omitted, even when adjuvant tamoxifen was used.⁴¹ Another randomized clinical trial that used age >70 years as a criterion for selecting patients in whom breast XRT could be omitted showed significantly higher rates of in-breast recurrence without breast XRT but no overall survival differences.⁴²

Fitzal et al examined the role of EndoPredict (EP) in predicting LRFS after surgery in 1324 postmenopausal patients with endocrine-responsive breast cancer who were primarily treated with adjuvant endocrine therapy as part of a randomized clinical trial conducted by the Austrian Breast and Colorectal Cancer Study Group (ABCSG 8 trial).²³ In addition, 869 women from the ABCSG 8 trial with a low-risk profile (tumor size <3 cm, pN0 and grade 1 and 2) were randomized to breast XRT versus no breast XRT following lumpectomy (ABCSG trial 8a).⁴³ With a median follow-up of 72.3 months, EP was an independent significant predictor of local recurrence (LR) risk.

The risk of LR over a 10-year period was significantly higher in patients with EP high-risk lesions (LRFS, 91%) compared with those who had EP low-risk lesions (LRFS 97.5%; P <.005). On the other hand, EP was not found to be predictive of benefit from breast XRT, as XRT significantly improved LRFS both in the EP low-risk cohort (received XRT: n = 436, 10-year rate of LR, 0.2%; did not receive XRT: n = 63, 10-year rate of LR, 11.1%; P <.005) and in the EP high-risk cohort (received XRT: n = 475; 10-year LRFS, 2.5%; did not receive XRT: n = 75; 10-year LRFS, 12.0%; P <.005).⁴³

Based on these results, there is continuing interest in evaluating whether currently commercially available genomic classifiers can identify subgroups of patients with breast cancer who can be spared breast XRT after BCS. Currently, there are none that can do so. Several prospective trials (both single arm and randomized) are currently under way to address this question in patients with early-stage disease treated with BCS (Table).

The LUMINA trial (NCT01791829) is enrolling patients aged >55 years with T1N0 luminal A tumors, onto a singlearm prospective observation trial, with a primary end point to measure the 5-year ipsilateral breast recurrence rate. The IDEA trial (NCT02400190) completed enrollment of patients who were postmenopausal, with T1N0 ER-positive breast cancer and low RS (<18) onto a single-arm prospective observation trial, with a primary end point of 5-year LRR.

The PRECISION trial (NCT02653755) is enrolling women aged >50 years with T1N0 ER-positive breast cancer and a low PAM50 ROR score to a single-arm prospective observation trial, also with a primary end point of 5-year LRR. The EXPERT trial (NCT02889874) is a randomized study of BCS with or without XRT in T1N0 ER-positive breast cancer in women aged >50 years with a PAM50 ROR of less than 60. Until results from these trials become available, BCS plus XRT remains the standard of care for the majority of patients with invasive breast cancer.

Genomic Profiling for Prediction of XRT Benefit

The aforementioned trials were designed to identify patient populations with very low risk of LRR, where addition of chest/breast XRT or regional nodal XRT would not add substantial absolute benefit in local control. Another approach to tailor use of XRT is development of genomic classifiers predictive of XRT benefit, rather than LRR. Tramm et al³⁰ attempted to develop a genomic predictor of XRT benefit in high-risk patients with breast cancer treated with systemic therapy and randomized to PMRT or not. Seven genes were identified, and the derived gene-expression index (DBCG-RT profile), which then divided patients into high- LRR—risk and low-LRR–risk groups. PMRT significantly reduced risk of LRR in high-LRR– risk patients but not in low-LRR–risk patients.

Other investigators have developed genomic predictors of XRT sensitivity using clonogenic survival assays for breast cancer cell lines. Speers et al³¹ developed a 51-gene radiation sensitivity score enriched for genes involved in cell cycle arrest and DNA damage response, whereas Torres Roca et al⁴⁴ developed and validated a radiosensitivity index in established databases of patients treated with BCS plus XRT or mastectomy without XRT.³²

When combining radiosensitivity index with molecular subtype,³³ patients at the greatest risk of LRR had triple-negative and radioresistant breast cancer (HR, 0.37; P = .02). Sjostrom et al34 utilized fresh frozen tissue from 336 patients undergoing BCS with or without XRT to develop a new radiosensitivity assay with the Nanostring platform, suitable for low-quality RNA analysis. In patients who underwent BCS with a high risk of LRR, investigators identified 3 groups.

In the low-LRR—risk/low-radiosensitivity group, XRT would not reduce risk of LRR. In the second group of patients, XRT was recommended due to high radiosensitivity. In the third group, escalated treatment was recommended, as the patients’ tumors were high risk for LRR that was not significantly reduced by XRT. More recently, the same group of investigators identified a new 27-gene Adjuvant Radiotherapy Intensification Classifier (ARCTIC) using publicly available gene databases with known outcomes. ARCTIC scores were calculated for patients treated with BCS with or without XRT on the SweBCG91 trial and compared with 8 different genomic signature scores from the aforementioned studies.^{20,22,25,31,32,34,35,37} ARCTIC outperformed the other gene expression scores for predicting elevated risk of LRR as well as benefit from XRT.

Future Directions

Although currently available evidence with molecular subtyping/genomic profiling provides great insight on tumor biology and its locoregional behavior, such evidence has not yet translated into meaningful changes in locoregional therapy approaches. In the setting of ER-positive, HER2-negative disease, multiple secondary analyses of randomized studies independently show RS correlates to LRR similar to known prognostic variables, such as lymph vascular space invasion or stage. As such, RS may be incorporated into estimations of LRR risk.

However, care must be taken when omitting XRT off protocol among women with a low RS, given the benefit from breast XRT in reducing in-breast recurrence after BCS and the benefit from PMRT and regional nodal XRT on disease-free survival.

Minimal data are available on the utility of genomic assays for LRR prognosis in the setting of neoadjuvant chemotherapy or with use of trastuzumab, and this remains a significant gap in knowledge. Development of predictive assays are promising, yet unproven. Studies are needed to prospectively correlate pathological response to XRT with the existing genetic assays for radiosensitivity.

Enrollment in prospective studies such as MA.39 is strongly encouraged, and development of new trials to test the hypothesis that genomic assays can predict XRT benefit are greatly needed.

By individualizing risk of LRR and radiosensitivity with molecular subtyping/ genomic classifiers, it is hoped that use and/ or extent of adjuvant XRT could be tailored. Studies such as MA.39 will provide information on whether these assays can guide decision making for PMRT in patients with 1 to 3 positive lymph nodes. Use of LRR and radiosensitivity assays in patients undergoing BCS may help to identify patients at sufficiently low risk of LRR to avoid breast XRT.

Tailoring of XRT dose or adding radiosensitizers could be considered to improve outcome in patients with high LRR risk and radioresistant tumors. Another provocative, yet unaddressed, question is whether the use of genomic assays could identify a population of patients with early-stage, hormonereceptor positive disease with primarily local recurrence risk rather than distant recurrence risk, who could be adequately treated with surgery plus XRT alone, without the need for 5 years of adjuvant endocrine therapy.

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In multivariate regression analysis, RS remained an independent predictor of LRR (HR, 2.61 for a 50-point difference in RS; P = .008) along with pathologic nodal status (HR, 1.91 for ≥4 vs 1 to 3 positive nodes; P = .007) and tumor size (HR, 1.28 for a 1-cm difference; P = .015). Solin et al evaluated RS for prediction of LRR risk in BCS plus XRT-treated patients with 1 to 3 positive nodes in the ECOG E2197 study comparing 2 chemotherapy regimens.²¹