Preoperative S-PBI Plus Endocrine Therapy is Safe, Produces Responses in Early-Stage ER+ Breast Cancer

Ablative preoperative stereotactic partial breast irradiation (S-PBI) plus endocrine therapy was safe at a single fraction of 34 Gy and generated pathological complete responses (pCRs) and near CRs (nCRs) in patients with early-stage, estrogen receptor (ER)–positive breast cancer, according to interim data from the phase 1 trial (NCT04040569).

Findings presented at the 2023 American Society for Radiation Oncology (ASTRO) Annual Meeting showed that at a median follow-up of 21.5 months, patients treated in the 34 Gy cohort (n = 15) experienced a pCR/nCR rate of 93.3% vs 37.5% in patients treated in the 30 Gy cohort (n = 11; P = .002). The pCR rates were 46.6% vs 0%, respectively (P = .019), and the nCR rates were 46.6% vs 37.5%, respectively (P = .689). The median time to surgery for those in the 34 Gy cohort was 7.4 months vs 4.3 months for those in the 30 Gy cohort (P < .001). Of note, out of the patients in the 34 Gy cohort, 57% had 1 to 3 mm of residual disease.

The maximum tolerated dose (MTD) was not reached in the 30 Gy or 34 Gy cohorts. Thirty-three acute grade 1 adverse effects (AEs) involving breast pain and skin changes were reported, and 2 instances of acute grade 2 AEs of breast pain and dermatitis were observed. Regarding late toxicities, 10 instances of grade 1 AEs, including breast pain, skin changes, and edema, were reported. One patient had late grade 2 breast pain, and 1 patient with uncontrolled diabetes experienced a late grade 3 slow-healing wound.

“Escalating the dose and postponing time to surgery with endocrine therapy achieved dramatic CR/nCR rates and significant reduction in Ki67 in those with residual disease,” Asal Rahimi, MD, MS, lead study author, chief of the Breast Radiation Oncology Service, medical director of the Clinical Research Office at Harold C. Simmons Comprehensive Cancer Center, associate vice chair of Diversity, Equity, and Inclusion, and associated professor at the University of Texas Southwestern Medical Center in Dallas, said in a presentation of the data. “[S-PBI plus endocrine therapy] could be a promising technique for non-surgical management in highly selected patients in the future.”

Although the role of surgery and radiation for the treatment of patients with early-stage breast cancer has evolved over recent decades, Rahimi noted that few data are available for the use of preoperative S-PBI and endocrine therapy. She said a goal of the phase 1 study was to help identify an appropriate dose of S-PBI used in this setting.

The phase 1 dose-escalation study enrolled female patients at least 18 years of age with unifocal invasive ductal, medullary, lobular, papillary, or mucinous carcinoma of the breast that was cT1 to T2N0 (<3 cm) based on ultrasound or MRI prior to biopsy. Patients needed to have ER-positive, HER2-negative disease that did not require chemotherapy, and if oncotype testing was performed, only patients with low-risk scores were eligible. Patients could not have tumor involvement with overlying skin (≥5 mm from the skin) or the chest wall.

The tumor needed to be visible on CT scan and/or marked with clips, and patients underwent an MRI to aid in tumor delineation and rule out additional foci of disease.

After undergoing mammogram, MRI, ultrasound, and clip placement, and prior to receiving S-PBI, patients had the option of submitting a blood sample within 30 days before treatment and receiving a tumor biopsy. Patients then received a single fraction of S-PBI at 30 Gy, 34 Gy, or 38 Gy before having the option to undergo a biopsy within 14 days of radiation and submitting a blood sample within 30 days of radiation. Endocrine therapy was started within 21 days following biopsy. Patients also had the option to receive an MRI prior to surgery.

To administer S-PBI, 1 to 6 clips were placed to outline the tumor for treatment planning. The gross tumor volume (GTV) was defined as the clinical target volume (CTV), and the planning target volume (PTV) was the CTV plus 5 mm (excluded from the skin and chest wall). The PTV received a minimum of 27 Gy to 95% volume while maintaining skin constraints, and 99% of the GTV received a minimum 93% of the dose of radiation.

Lumpectomy plus sentinel lymph node biopsy was performed between 8 and 52 weeks following S-PBI at the discretion of the surgeon and radiation oncologist. An optional blood sample could be taken 4 weeks after surgery. Adjuvant hormonal therapy was given if indicated, and patients were then followed for toxicity, cosmesis, and local control.

The primary end point of the study is to escalate the dose of ablative S-PBI to the primary tumor without exceeding the MTD. Secondary end points included pCR rate, acute and late toxicities, local and regional control, patient and physician cosmesis outcomes, and patient quality-of-life assessments. Radiomics on MRI to predict pCR and translational correlates through blood and tissue sample following S-PBI served as exploratory end points.

Dose-limiting toxicities (DLTs) were defined as one that is grade 3 or higher and is attributed to S-PBI. Dose escalation was allowed in each arm if 0 of 7 patients, 2 of 9 patients, no more than 3 of 12 patients, or no more than 4 of 15 patients experienced a DLT within 90 days of undergoing S-PBI. The MTD was exceeded if more DLTs occurred in any cohort.

Among all patients (n = 26), which included the 30 Gy (n = 11) and 34 Gy (n = 15) cohorts, the median age was 66 years (range, 44-77). Twenty-four patients had cT1N0 disease and 2 patients had cT2N0 disease. Thirteen patients had grade 1 disease at diagnosis, and 12 had grade 2 disease. Additionally, 65.3% of all patients underwent oncotyping. The median GTV/CTV volume was 3.1 cc (range, 1.2-13.9), and the median PTV volume was 19.76 cc (range, 4.9-62.0). Radiation methods included MRI LINAC unit (n = 6), breast cobalt stereotactic (n = 17), and robotic radiosurgery unit (n = 3).

Additional data showed that all patients experienced a significant reduction in Ki-67 following preoperative S-PBI and endocrine therapy. In 8 evaluable patients with evaluable residual disease, 7 patients (87.5%) had Ki-67 of less than 3% after surgery, S-PBI, and endocrine therapy. Among all patients, the mean Ki-67 at diagnosis was 12.2% (standard deviation [SD], ± 6.7%), and the mean Ki-67 on evaluable residual disease on surgical specimens was 1.9% (SD, ± 2.3%; P < .001). In the 34 Gy cohort, the mean Ki-67 was 11.9% (SD, ± 6.5%) at diagnosis and 2.4% (SD, ± 3.2%) on residual disease surgical specimens (P < .001). For the 30 Gy cohort, those rates were 12.6% (SD, ± 7.2%) and 1.4% (SD, ± 0.5%; P < .001).

Analysis is ongoing for patients treated in the 38 Gy cohort.

Editor’s note: Dr. Rahimi reported serving as a consultant for Hologic; serving on a scientific advisory board for GE Health; receiving a research grant, educational speaking honorarium, and travel assistance from Accuray, and serving on an advisory board for Accuray.

Reference

Rahimi A, Leitch M, Dogan B, et al. Early results of a phase I pre-operative single fraction ablative trial for early stage breast cancer. Presented at: 2023 American Society for Radiation Oncology Annual Meeting; September 30-October 4, 2023; San Diego, CA; Abstract LBA11.