The Effects of Omitting Radiation in Early Breast Cancer

Breast Cancer, Radiation: Breast Cancer, RadiationOmitting radiotherapy may increase the incidence of local recurrence of breast cancer. However, according to a recent study published in the New England Journal of Medicine, it bears no negative effect on the first event of distant recurrence or overall survival in women ages 65 and older who have low-risk, hormone receptor (HR)-positive early breast cancer (2023; doi: 10.1056/NEJMoa2207586). Breast cancer is increasing in prevalence among older adults in the U.S. About one in four (26%) people diagnosed with breast cancer are between 65 and 74 years of age. Historically, breast cancer in more mature individuals has been understudied in clinical trials. This has resulted in undertreatment and overtreatment. A meta-analysis conducted by the Early Breast Cancer Trialists Collaborative Group found that radiotherapy breast-conserving treatment only offers marginal survival benefits despite reducing the overall cumulative incidence that cancer would recur in node-negative patients. In the case of low-risk, older patients who have smaller HR-positive tumors, omitting radiotherapy following breast-conserving therapy is a controversial topic. To date, clinicians serving this population are forced to make this tough clinical decision with a paucity of level 1 evidence. Based on the 5-year results of the PRIME II trial, a lower percentage of women experienced local breast cancer recurrence without radiotherapy than those who received it (1.3% vs. 4.1%) in women ages 65 years of age or older with HR-positive T1 or T2 primary lymph node involvement and who received breast-conserving treatment. In this population, T1 tumors were defined as tumors equal to or greater than 3 cm in the largest dimension. New Evidence In a newer study, researchers conducted a Phase III, randomized trial following 1,326 enrollees from April 16, 2003, to December 22, 2009. Approximately half (n=658) were computer-randomized to receive whole-breast radiation, while the remaining 668 participants received no postoperative irradiation. The patients were from the U.K. (n=1,263), Greece (n=22), Australia (n=16), and Serbia (n-25). The criteria for entering the study included women 65 years of age and older who had T1 or T2 primary breast cancer defined as at least 3 cm in the largest dimension. They also must have previously received breast-conserving therapy in addition to axillary staging, defined by a four-node lower axillary sample, sentinel-node biopsy, or axillary-node clearance. In addition, they needed to be node-negative. Enrollees had to have estrogen receptor (ER)-positive, progesterone receptor (PR)-positive cancer, or both along with clear excision margins of at least 1 mm. Also, the patients must have had previous adjuvant or neoadjuvant endocrine therapy. The study included individuals who had either Grade 3 historical features or lymphovascular invasion but not both. All patients enrolled in the trial had to be healthy enough to receive treatment and engage in follow-up. Potential enrollees were excluded for any of the following reasons: being less than 65 years of age, having a history of in situ or invasive carcinoma found in either breast, or having a history of malignancy within the past 5 years. Exceptions to previous malignancy included non-melanomatous skin cancer or carcinoma in the site of the service. Participants receiving the object treatment received irradiation ranging 40-50 Gy in total, 2.66 to 2.00 Gy per fraction in 20-25 fractions during a period ranging from 3 to 5 weeks. The study design allowed for participants to receive boost irradiation either with electrons (10-15 Gy) or an iridium implant, such as 20 Gy to 85 percent of the reference isodose volume. Study researchers suggested participants receive tamoxifen at a dose of 20 mg per day for 5 years as standard adjuvant endocrine therapy. The primary endpoint was local breast cancer occurrence, while the secondary occurrences were regional recurrence, contralateral breast cancer, distance metastases, disease-free survival, and overall survival. In this study, investigators defined local recurrence as any cancer located in the scar tissue or found in the same breast. They defined regional recurrence as disease activity in the ipsilateral axillary or supraclavicular lymph nodes. Upon trial entry, patients had a median age of 70 years. The results of a decade of follow-up yielded the following results. Cumulative incidence of local recurrence in the non-irradiated group was 9.5 percent (95% CI: 6.8-12.3), while the radiotherapy group experienced a local recurrence of 0.9 percent (95% CI, 0.1-1.7%). Fifty-one patients assigned to the non-radiotherapy group and five patients assigned to the radiotherapy group had a local recurrence of breast cancer. In the non-radiotherapy arm, 48 of the 51 patients experienced local recurrences as a first event. This number includes 37 patients who had only local recurrence. Based on this study's findings of the 10-year cumulative incidence of first-event, distant recurrence was 1.6 (95% CI: 0.4-2.8) without radiotherapy and 3.0 percent (95% CI: 1.4-4.5) with radiotherapy. Researchers did not observe any substantial differences in cumulative incidence of regional recurrence, contralateral breast cancer, new cancers, or survival-free from new cancer at the 10-year mark. More than two-thirds (68.9%, 64.7-73) of the participants in the radiotherapy-free group had survived disease-free at the 10-year mark. The number of disease-free participants in the radiotherapy group was a little higher (76.3%; 95% CI: 72.5-80.2). Breast cancer survival at the 10-year mark was 97.4 percent (95% CI: 96.0-98.8). Both groups had similar mortality rates from breast cancer. Sixteen patients in the non-radiotherapy arm died from breast cancer and 15 patients in the radiotherapy arm succumbed to the disease. However, it is worth noting that breast cancer was not the leading cause of death in this clinical trial. Of the 231 patients who died during this study, 59 of them (25%) died from cancers other than breast cancer. In addition, both arms had similar overall survival outcomes at the decade mark, with 80.8 percent (95% CI: 77.2-84.3) in the non-radiotherapy group surviving after 10 years and 80.7 percent (95% CI: 76.9-84.3) in the radiotherapy group surviving. Ultimately, the study revealed that the 10-year incidence of local cancer recurrence after breast-conserving surgery was significantly lower in older women with HR-positive breast cancer treated with adjuvant endocrine therapy. In addition, the data showed women in both groups were more likely to die from other cancers than breast cancer, as well as other conditions. It is worth noting the impact of avoiding radiotherapy in women with Grade 3 cancers (n=36) or women with lymphovascular invasion is unclear in this study due to low enrollment numbers. Some limitations of the trial included investigators failing to collect data on comorbidities. They also did not monitor adherence to endocrine therapy prospectively. The study authors also revealed variability in the omission of postoperative irradiation following breast-conserving surgery and adjuvant endocrine therapy. Frieda Wiley is a contributing writer.

Topic: Breast Cancer Treatment Studies
Subfield: Cancer Research
Field: Biochemistry, Genetics and Molecular Biology
Domain: Life Sciences