Patients diagnosed with invasive breast cancer who had low scores on an investigational gene molecular signature had similar rates of local recurrence whether or not they received adjuvant radiotherapy after breast-conserving surgery.

This is the conclusion according to results of a meta-analysis presented at the San Antonio Breast Cancer Symposium (SABCS), held December 6-10, 2022 in San Antonio, Tx. [1]

Patients with breast cancer who undergo breast-conserving surgery are recommended to receive adjuvant radiotherapy to reduce the risk of local recurrence.

“However, many patients will not experience a local recurrence even without radiotherapy,” said Per Karlsson, MD, a professor of oncology at the Sahlgrenska Comprehensive Cancer Center and the University of Gothenburg in Sweden.

“Currently, we do not have any reliable predictive classifiers to identify patients who might be able to skip radiotherapy,” he added.

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“Since radiation therapy can be associated with problematic side effects in some patients, it is of clinical importance to identify those patients for whom radiotherapy can be safely omitted.”

In their study, Karlsson and colleagues evaluated the predictive potential of POLAR (Profile for the Omission of Local Adjuvant Radiotherapy; Exact Sciences), an investigational 16-gene molecular signature that was developed based on gene expression differences between patients with and without local recurrence after breast-conserving surgery.

POLAR is both prognostic for the risk of local regional recurrence and predictive of radiotherapy benefit. Genes included in the signature have known roles in cellular proliferation and the immune response.

“POLAR signature addresses a significant clinical need for those with early-stage, hormone receptor positive breast cancer, identifying which patients may benefit from radiotherapy and which may not,” said Rick Baehner, MD, chief medical officer of Precision Oncology at Exact Sciences.

“Like chemotherapy, radiotherapy has significant physical, mental, and monetary costs associated with it. These data are a critical step toward providing patients with a new tool to help ensure better breast cancer treatment decisions,” Baehner added.

Per Karlsson, MD, PhD – Institute of Clinical Sciences, Sahlgrenska Academy, University of Gothenburg

The researchers performed a meta-analysis of 623 patients with lymph node-negative, estrogen receptor-positive, HER2-negative breast cancer who were enrolled in one of three randomized clinical trials examining the efficacy of breast-conserving surgery with and without local breast radiation therapy.

The clinical trials included in the meta-analysis from the Swedish Breast Cancer Group 91 Radiotherapy trial (SweBCG91RT), [2] the Scottish Conservation Trial (SCT) [3], and a trial from the Princess Margaret Hospital (PMH), Toronto, Ontario, Canada, which is affiliated with the University of Toronto Faculty of Medicine as part of the University Health Network. [4]

Among the 623 patients in the meta-analysis, 354 (57%) were from the Swedish Breast Cancer Group 91 Radiotherapy trial (SweBCG91RT), 137 (22%) from SCT, and 132 (21%) from the PMH trial.

In the study, the numbers of locoregional recurrence events in each cohort included 72 (20%) from the SweBCG91RT, 28 (20%) from the SCT study and 16 (125) from the PMH trial. There was a mix of systemic therapy used (no systemic therapy for SweBCG91RT, chemotherapy or adjuvant endocrine therapy, but not both, in SCT, and tamoxifen (Nolvadex®; AstraZeneca) but no chemotherapy for PMH).

To evaluate the predictive capability of POLAR, the researchers analyzed gene expression in patient breast tumor samples to assign each patient a POLAR score.  In the next step, the researchers examined the impact of radiotherapy for patients with high and low POLAR scores.

In the study, the median follow-up time for the patients who did not have locoregional recurrence was 13.3 years for SweBCG91RT, 21.1 years for SCT, and 8.6 years for PMH. A multivariable Cox proportional hazards model on time to locoregional recurrence, including the continuous standardized POLAR score, radiotherapy, and interaction, stratified by cohort, was used to test the interaction between the continuous POLAR score and radiotherapy. Additional Cox models tested the association between treatment arms separately for patients with a low and high POLAR score using a pre-specified cut point. Cumulative incidences were computed, with distant metastasis and death without recurrence considered as competing events.

No significant difference
The study for interaction between radiotherapy treatment and POLAR was statistically significant (p = 0.022). Among the 429 (69%) patients with high POLAR scores, those who received adjuvant radiotherapy after breast-conserving surgery had a 63% reduction of local recurrence compared with those who did not receive adjuvant radiotherapy, suggesting that adjuvant radiotherapy was beneficial for these patients (The 10-year cumulative incidence of local recurrence rate was 20% [15%-26%] for those not treated with RT vs 7% [4%-11%] for those treated with RT; hazard ratio for RT vs no RT: 0.37 [0.23-0.60], p < 0.001),

In contrast, for the 194 (31%) patients with low POLAR scores, there was no significant difference in local recurrence rate between those who received adjuvant radiation therapy and those who did not. After 10 years, 5% (2% – 11%) of patients who received radiotherapy experienced a local recurrence, compared with 7% (3% – 14%) of those who did not receive radiotherapy (hazard ratio for RT vs no RT: 0.92 [0.42-2.02], p = 0.832).

“In a patient-level meta-analysis of three independent randomized clinical trials, the POLAR gene profile successfully predicted which patients would and would not benefit from local radiation therapy, thereby identifying a group of breast cancer patients where radiation therapy may be safely omitted after breast-conserving surgery,” Karlsson summarized.

“Although only a minority of patients experience severe side effects to breast radiation, this adds up to a fair number of patients once you consider how prevalent breast cancer is,” he added.

Based on the outcome of the study, the researchers believe that patients with a high POLAR score should be recommended radiotherapy while patients with a low score may be candidates for omission of radiotherapy after breast conserving surgery.

“The POLAR gene profile may, therefore, help mitigate toxicities and improve quality of life for many patients.”

Further validation required
Karlsson noted that the POLAR gene profile will need further validation and additional streamlining before it could be used in the clinic. Future research from Karlsson and colleagues will examine whether the POLAR gene profile can also identify patients who could safely avoid regional radiotherapy, which is associated with more severe
toxicities than local radiotherapy.

A limitation of the study is its retrospective design. Additionally, the POLAR gene profile was developed using samples from patients who did not receive currently available endocrine therapies; however, validation trials included patients who received such therapies.

The study was supported by funds from the Swedish Cancer Society, the Swedish Research Council, the King Gustaf V Jubilee Clinic Foundation, the ALF Agreement of the Swedish government, PFS Genomics, and Exact Sciences.

[1] Karlsson P. Validation of Profile for the Omission of Local Adjuvant Radiotherapy (POLAR) in a meta-analysis of three randomized controlled trials of breast conserving surgery +/- radiotherapy. Abstract GS4-03. Presented during the San Antonio Breast Cancer Symposium (SABCS), held December 6 – 10, 2022.
[2] Kovács A, Stenmark Tullberg A, Werner Rönnerman E, Holmberg E, Hartman L, Sjöström M, Lundstedt D, Malmström P, Fernö M, Karlsson P. Effect of Radiotherapy After Breast-Conserving Surgery Depending on the Presence of Tumor-Infiltrating Lymphocytes: A Long-Term Follow-Up of the SweBCG91RT Randomized Trial. J Clin Oncol. 2019 May 10;37(14):1179-1187. doi: 10.1200/JCO.18.02157. Epub 2019 Apr 2. PMID: 30939091.
[3] Forrest AP, Stewart HJ, Everington D, Prescott RJ, McArdle CS, Harnett AN, Smith DC, George WD. Randomised controlled trial of conservation therapy for breast cancer: 6-year analysis of the Scottish trial. Scottish Cancer Trials Breast Group. Lancet. 1996 Sep 14;348(9029):708-13. doi: 10.1016/s0140-6736(96)02133-2. PMID: 8806289.
[4] Clark RM, McCulloch PB, Levine MN, Lipa M, Wilkinson RH, Mahoney LJ, Basrur VR, Nair BD, McDermot RS, Wong CS, et al. Randomized clinical trial to assess the effectiveness of breast irradiation following lumpectomy and axillary dissection for node-negative breast cancer. J Natl Cancer Inst. 1992 May 6;84(9):683-9. doi: 10.1093/jnci/84.9.683. PMID: 1314910.

Featured image: San Antonio Breast Cancer Symposium (SABCS) held at the Henry B. Gonzalez Convention Center in San Antonio, Tx., December 6 – 10, 2022. Photo courtesy: © 2022 AACR/SABCS MedMeetingImages/Todd Buchanan. Used with permission.

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