Most of the newer systemic treatments for breast cancer can be safely and effectively paired with radiation therapy—although there are some exceptions, according to Mylin A. Torres, MD, the Louisa and Rand Glenn Family Chair in Breast Cancer Research and Associate Professor of Radiation Oncology at Emory University School of Medicine, Atlanta. Dr. Torres also co-leads the Cancer Prevention and Control Research Program at the Winship Cancer Institute.
“Concurrent hormone therapy and radiotherapy is safe and effective.”— Mylin A. Torres, MD
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At the 2020 Debates and Didactics in Hematology and Oncology Virtual Conference, sponsored by Emory, Dr. Torres shared what is known, and not known, about the concurrent use of radiotherapy and newer breast cancer drugs.1
“As a resident at MD Anderson, I worked in a lab looking at radiosensitizing agents…how systemic therapies can enhance radiation or how they can make radiation-related toxicities worse. With many new systemic treatments approved in breast cancer, this topic has become more relevant, yet we have very few data on whether the concomitant use of radiation is safe and effective,” she said.
The new agents pertuzumab, ado-trastuzumab emtansine (T-DM1), cyclin-dependent kinases 4 and 6 (CDK4/6) inhibitors, and the immunotherapies pembrolizumab and atezolizumab “all have the potential to be either radiosensitizing or radioinhibiting agents, yet there are few studies examining whether it is safe and effective for radiotherapy to accompany them for palliation or definitive treatment,” Dr. Torres said. She also discussed the older drugs trastuzumab and capecitabine.
Why the Concern?
Radiotherapy impacts the cancer cell cycle, and since systemic agents do as well, their combination could be either a good thing or a bad thing. Radiation causes DNA double-strand breaks, which lead to cell death. It preferentially kills rapidly proliferating cancer cells due to their poor DNA repair mechanism.
The most radiosensitive phases of the cell cycle are the G2 and M phases (where endothelial cells are rapidly proliferating). The most radioresistant phases are the G1, G0, and S phases. Depending on their mechanism of action, anticancer drugs exert their impact preferentially in the G1 and S phases and sometimes the G2 or M phase.
Thus, the relevant clinical questions are:
- Is concurrent treatment better than either modality alone?
- Are recurrence rates higher when treatments are combined than when they are given sequentially?
- Are toxicities of one treatment exacerbated by the other if they are administered concurrently?
- What is more convenient and practical: concurrent or sequential radiation and systemic therapy?
Endocrine Agents Safe to Combine With Radiotherapy
Tamoxifen inhibits cell proliferation by halting cells in the G1 phase. In theory, tamoxifen could actually inhibit the efficacy of radiation, which is most effective in the G2 and M phases. However, in multiple retrospective studies and large trials, the use of radiation with tamoxifen—given concurrently or sequentially—did not negatively impact tolerability or outcomes.2
“This indicates that while tamoxifen may halt cells in G1, a relatively radioresistant phase, clinically this has no implications. Concurrent hormone therapy and radiotherapy is safe and effective,” Dr. Torres concluded, saying she gives the green light to patients who want to start tamoxifen or an aromatase inhibitor without delay.
Limited Data on Anti-HER2 Agents Plus Radiotherapy
In the pivotal prospective trastuzumab trials, radiation was given before, after, or concurrently with the anti-HER2 agent; therefore, no conclusions could be drawn. Retrospective studies, however, have examined concurrent use and found no increase in serious toxicity.3 The standard of care, therefore, is that trastuzumab and radiotherapy can be given concurrently.
“My take-home is that we should avoid concurrent radiotherapy with capecitabine.”— Mylin A. Torres, MD
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The data are more limited on the newer anti-HER2 agents, pertuzumab and T-DM1. In the adjuvant APHINITY trial, where radiation was given concurrently with trastuzumab/pertuzumab or trastuzumab, grade ≥ 3 adverse events were similar between the arms, though the unique contribution of the radiation was not examined.4 In a study of 23 patients treated with dual HER2 blockade and concurrent radiation, global toxicity was deemed acceptable.5
From the data, she said, it is likely that concurrent pertuzumab/trastuzumab and breast-alone radiotherapy is safe and tolerable, though she advised using caution when treating abdominal lesions with the two anti-HER2 agents plus radiotherapy due to increased gastrointestinal toxicity seen in two case studies.6 Pertuzumab alone, plus radiotherapy, has not been studied.
T-DM1: Safe, With Caveats
In the seminal KATHERINE trial, patients with residual cancer after neoadjuvant trastuzumab plus a taxane generally received radiation within 60 days of surgery, given concurrently with trastuzumab or T-DM1.7 Radiation pneumonitis was slightly more common with T-DM1 (1.5%) than with trastuzumab (0.7%), but radiation skin injury was similar (27.6% vs 25.4%). In one reported series, however, 50% of patients developed radiation brain necrosis when T-DM1 and radiosurgery were given concurrently to treat brain metastases, vs 29% when the treatments were sequential.8
Given these findings, Dr. Torres believes that T-DM1 plus radiotherapy is “probably safe,” though there are caveats: “I generally avoid radiation to the brain with concurrent T-DM1. I also generally avoid concurrent T-DM1 with regional nodal radiation, due to the proximity of the radiation to the brachial plexus and the increased amount of the lung in the radiation field, which could increase the risk of pneumonitis.”
Capecitabine: Avoid Concurrent Radiotherapy
“CREATE X was a groundbreaking, practice-changing trial” in showing the benefit of capecitabine in treating residual disease after surgery,9 according to Dr. Torres. This landmark study did not, however, provide answers regarding the safety and efficacy of concurrent capecitabine and radiotherapy (which was not given in the trial).
Capecitabine inhibits thymidylate synthase, leading to DNA damage and cell death. For this reason, concurrent administration with DNA-damaging radiation may lead to increased toxicity. Indeed, a phase II study from The University of Texas MD Anderson Cancer Center evaluated concurrent postoperative radiotherapy and capecitabine in patients with residual nodal disease, unresectable chest wall disease, nodal recurrence after prior mastectomy, or oligometastases.10 Among 32 patients, 7 developed grade ≥ 3 toxicity, and the 5-year overall survival was less than 25%.
“This indicated the combination was not improving survival and there was an intolerable rate of toxicity,” she said. “My take-home is that we should avoid concurrent radiotherapy with capecitabine.”
CDK4/6 Inhibitors: Results With Radiation Unclear
The concurrent use of CDK4/6 inhibitors and radiotherapy raises concern for several reasons: Both are associated with neutropenia and fatigue, suggesting greater intolerability together, and murine models show palbociclib to be radiosensitizing, therefore potentially increasing the susceptibility to radiotherapy-related toxicity. However, other studies have suggested that CDK4/6 inhibitors actually promote radioresistance by arresting cells in G1/G0. It is also believed that holding palbociclib during radiotherapy may allow metastases to progress. The safety and efficacy of their concurrent use, therefore, remain unclear.
OF NOTE
On September 8, 2020, the U.S. Food and Drug Administration (FDA) alerted health-care professionals, oncology clinical investigators, and patients that a clinical trial studying the use of atezolizumab and paclitaxel in patients with previously untreated, inoperable, locally advanced or etastatic triple-negative breast cancer showed the drug combination did not work to treat the disease.
Emory is leading a phase II multicenter trial of 42 patients with bone metastasis receiving palbociclib and endocrine therapy plus radiotherapy for palliation. Patients will be followed for 3 months with a variety of laboratory and clinical parameters to determine whether combined treatment leads to excess toxicity or disease progression within the bone, due to the potential for radiation to be less effective in concert with palbociclib and endocrine therapy.
Immunotherapy: Possibly Boosted by Radiotherapy
Not much is known at this point about concurrent immunotherapy and radiation, although it is possible the two could work together. KEYNOTE-522 yielded promising data for pembrolizu-mab in locally advanced triple-negative breast cancer, regardless of PD-L1 status.11 Initially, pembrolizumab was given neoadjuvantly and then restarted at least 2 weeks after radiotherapy—it was not given concurrently. The protocol was amended to allow concurrent administration, as evidence emerged showing a synergistic effect without increased toxicity.
Actual benefit might be observed when they are combined, based on the potential for an abscopal response, ie, a systemic immune response that leads to tumor regression outside of the radiation field. “While this has mostly been shown in melanoma, it also has been seen in breast cancer,” Dr. Torres noted. “Additionally, radiation can actually enhance PD-L1–positive infiltrates in tumor.”
Emory will look for this in a phase II multicenter trial that pairs radiotherapy with talazoparib, an inhibitor of poly (ADP-ribose) polymerase, followed by atezolizumab plus radiotherapy. The study will enroll 23 patients with triple-negative PD-L1–positive germline BRCA1/2-negative tumors and at least three metastatic lesions.
Although talazoparib is approved for BRCA-positive metastatic breast cancer, it is of interest in BRCA wild-type tumors as a radiosensitizing agent. It is also possible that talazoparib and radiotherapy might boost the number of immune epitopes recognized by atezolizumab, Dr. Torres added, further improving outcomes over atezolizumab alone and without the excess toxicity that accompanies traditional systemic agents.
DISCLOSURE: Dr. Torres has served on the advisory board of the Centers for Disease Control and Prevention and has received research funding from Pfizer, Genentech, the National Cancer Institute, and the V Foundation.
REFERENCES
1. Torres M: Radiation and new systemic agents in breast cancer: Sensitizers or inhibitors? 2020 Debates and Didactics in Hematology and Oncology Virtual Conference. Presented July 17, 2020.
2. Li YF, Chang L, Li WH, et al: Radiotherapy concurrent versus sequential with endocrine therapy in breast cancer: A meta-analysis. Breast 27:93-98, 2016.
3. Mignot F, Ajgal Z, Xu H, et al: Concurrent administration of anti-HER2 therapy and radiotherapy: Systematic review. Radiother Oncol 124:190-199, 2017.
4. von Minckwitz G, Procter M, de Azambuja E, et al: Adjuvant pertuzumab and trastuzumab in early HER2-positive breast cancer [published errata in N Engl J Med 377:702, 2017; N Engl J Med 379:1585, 2018]. N Engl J Med 377:122-131, 2017.
5. Ajgal Z, de Percin S, Diéras V, et al: Combination of radiotherapy and double blockade HER2 with pertuzumab and trastuzumab for HER2-positive metastatic or locally recurrent unresectable and/or metastatic breast cancer: Assessment of early toxicity. Cancer Radiother 21:114-118, 2017.
6. Katz DA, Abrams RA, Sclamberg JS, et al: Radiosensitizing effect of anti-HER2/neu agents: Report of 2 cases and review of the literature. Pract Radiat Oncol 5:e61-e65, 2015.
7. von Minckwitz G, Huang CS, Mano MS, et al: Trastuzumab emtansine for residual invasive HER2-positive breast cancer. N Engl J Med 380:617-628, 2019.
8. Geraud A, Xu HP, Beuzeboc P, et al: Preliminary experience of the concurrent use of radiosurgery and T-DM1 for brain metastases in HER2-positive metastatic breast cancer. J Neurooncol 131:69-72, 2017.
9. Masuda N, Lee SJ, Ohtani S, et al: Adjuvant capecitabine for breast cancer after preoperative chemotherapy. N Engl J Med 376:2147-2159, 2017.
10. Woodward WA, Fang P, Arriaga L, et al: A phase 2 study of capecitabine and concomitant radiation in women with advanced breast cancer [published erratum in Int J Radiat Oncol Biol Phys 101:497, 2018]. Int J Radiat Oncol Biol Phys 99:777-783, 2017.
11. Schmid P, Cortes J, Pusztai L, et al: Pembrolizumab for early triple-negative breast cancer. N Engl J Med 382:810-821, 2020.
