PRIME II was a phase 3 randomized trial examining the omission of radiotherapy in women over 65 with hormone receptor–positive early breast cancer treated with adjuvant endocrine therapy after breast-conserving surgery.
It found that the omission of radiotherapy was associated with an increased risk of local recurrence. However, the omission of radiation wasn’t related to distant recurrence.
The study’s limitations are worth considering.
A new study published in the New England Journal of Medicine has found that in older women with hormone receptor–positive early breast cancer treated with adjuvant endocrine therapy, omitting radiotherapy after breast-conserving surgery was associated with an increased risk of local (but not distant) recurrence.
With the rate of breast cancer in older individuals rising, this research deepens the “limited” knowledge around the omission of radiotherapy in this specific patient group, according to the study’s authors. It’s also important to know that 26 percent of breast cancer diagnoses are in women between the ages of 65 and 74 even though there is an underrepresentation of older patients with breast cancer in clinical trials.
The study’s subjects
The study, called PRIME II, was designed by the Scottish Cancer Trials Breast Group and was a phase 3 randomized clinical trial conducted throughout 76 centers in the United Kingdom, Serbia, Greece, and Australia. The trial focused on women 65 and older with “hormone receptor–positive, node-negative, T1 or T2 primary breast cancer (with tumors under 3 cm in the largest dimension) treated with breast-conserving surgery with clear excision margins and adjuvant endocrine therapy,” according to the study report.
Excluded patients included anyone under the age of 65, a history of in situ or invasive carcinoma in either of their breasts, and malignant disease within the last five years (with only two exclusions). The study also did not record HER2 status or coexisting conditions. Lastly, the patients all were required to receive treatment and follow-up care.
658 patients were randomly chosen to get either whole-breast irradiation (at 40 to 50 Gy), while 668 were not treated with irradiation.
The results of the study
The results found that in the group without radiotherapy treatment, there was a 9.5 percent local cancer recurrence rate within 10 years. In the radiotherapy group, there was a 0.9 percent rate of recurrence within the same time frame.
It’s important to note that within those 10 years, the incidence of distant recurrence versus local recurrence was at 1.6 percent in the group without radiotherapy and 3.0 percent in the group with radiotherapy, leading researchers to believe that treatment with radiotherapy in this particular case did not have a bearing on distant recurrence.
Survival at 10 years was almost the same in both groups—at 80.8 percent for the group without radiotherapy and 80.7 percent with radiotherapy. The study also found that, “the incidence of regional recurrence and breast cancer–specific survival also did not differ substantially between the two groups.”
“These results are more evidence to support the clinical assertion that radiotherapy can be omitted in select women 65 years of age or older with ER- positive, early-stage breast cancer, with no significant impact on survival,” says Monique Gary, DO, MSc, FACS, a board-certified, fellowship-trained Breast Surgical Oncologist and Medical Director of the Grand View Health/Penn Cancer Network Cancer Program in Sellersville, PA.
What do these results mean for patients?
Constance M. Chen, MD, a board-certified plastic surgeon and breast reconstruction specialist, shares some thoughts. “While women have traditionally received radiation therapy after lumpectomy, it is an option to decline radiation therapy after lumpectomy—as long as women understand that they have a higher chance of having another breast cancer in their breast but they don’t have a higher chance of metastasis or dying.”
Some patients will be willing to accept the risk of local recurrence, Chen says. That’s if they don’t want to undergo the effects of radiation therapy. Also, she says, “If they do have a local recurrence of breast cancer, they can undergo another lumpectomy or mastectomy without worrying that they are at a higher risk of dying.”
Understanding which patients can skip radiotherapy is key. “There have been and continue to be studies to better define the ideal tumor characteristics and molecular markers that best represent those safe to forego treatment that is not without toxicities—including heart and lung complications as well as fatigue, pain, and skin changes like dermatitis,” Gary adds.
In fact, many patients don’t want to experience the many potential side effects of radiation therapy. According to a 2018 study in the Canadian Journal of Surgery, of 267 patients with breast cancer, 43 percent did not receive radiation. There were a few reasons, with one being fear of radiation toxicity.
The limitations of the study
According to Gary, physicians should be aware of some of the limitations of the study.
“It’s important to note that there was underrepresentation of tumors that were high grade, had lymphovascular invasion (an aggressive feature on breast pathology), and that the level of estrogen receptor expression impacted local recurrence in patients not receiving radiation,” Gary says.
She also noted that compliance with endocrine therapy—as the patients in the study were required to have—is challenging in reality, with many patients not taking adjuvant endocrine therapy as prescribed. “Higher local recurrence rates in the absence of AET should prompt future research that seeks ways to aid patients in management of their treatment-induced side effects to bolster adherence,” Gary adds.
She also says that the study’s lack of diversity is limiting. “A study of considerable homogeneity may not be extrapolatable to all populations, and genomic testing results vary in Black women, particularly….unfortunately, Black women comprise the greatest number of those with higher risk disease features, and it remains to be seen if fewer women of color may benefit from a de-escalation of adjuvant treatment. Further research is needed in this regard,” Gary adds.
In the end, PRIME II certainly helps to fill in some blanks—while leaving room for further research. “Studies like this can aid clinicians in having more robust conversations about the risks and benefits of each treatment we offer, allowing patients to make better and more informed choices,” Gary says.
“Future studies should focus not just on tumor type but the entire patient: diverse populations with comorbid conditions, and those who have difficulty in adhering to endocrine therapy. This is what we see in real life, and the treatments can and must be tailored to those individuals as well,” she adds. “Further, we should continue to evaluate the question of radiotherapy—whole and partial—over endocrine therapy in select low-risk patients, as is being studied in ongoing trials around the world.”