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Carefully selected patients with triple-negative or HER2-positive breast cancer who demonstrated pathologic complete responses to neoadjuvant systemic therapy as predicted by image-guided vacuum-assisted core biopsy avoided breast surgery and went on to standard radiotherapy.
Carefully selected patients with triple-negative or HER2-positive breast cancer who demonstrated pathologic complete responses (pCRs) to neoadjuvant systemic therapy as predicted by image-guided vacuum-assisted core biopsy (VACB) avoided breast surgery and continued to standard radiotherapy, according to findings from the 2-year planned prospective outcome analysis of a phase 2 trial (NCT02945579) that were published in Lancet Oncology.
A total of 62% (n = 31; 95% CI, 47.2%-75.4%) of patients enrolled in the study had achieved pCR by VACB with neoadjuvant systemic therapy and proceeded to radiotherapy without breast surgery. At a median follow-up of 26.4 months (interquartile range, 15.2-39.6), none of the 31 patients had ipsilateral breast tumor recurrences. The investigators observed no other recurrence events.
“Targeted systemic therapies are greatly improving, from about a 12% [pCR] 20 years ago to 70% in triple-negative breast cancer [TNBC] today. Drugs for HER2-positive breast cancer are getting better and better. As surgeons, we had a responsibility to figure out a way to eliminate surgery for patients in whom it would provide no conceivable benefit,” lead study author Henry M. Kuerer, MD, PhD, FACS, CMQ, of The University of Texas MD Anderson Cancer Center in Houston, said.
In previous studies, VACB has accurately determined the patients with TNBC or HER2-positive breast cancer who have a pCR to neoadjuvant systemic therapy. This multicenter, single-arm, phase 2 study evaluated the efficacy of radiotherapy without breast surgery in patients with early-stage TNBC or HER2-positive breast cancer who achieved pCR by VACB.
Between March 6, 2017, and November 9, 2021, 50 women from 7 centers in the United States were enrolled. July 28, 2022 was the date of the last patient follow-up.
Eligible patients included those aged at least 40 years who were not pregnant and had pathologically confirmed, non-recurrent, unicentric, invasive clinical T1 or T2, N0 or N1 disease, with 4 or fewer abnormally-appearing axillary lymph nodes and no clinical or pathologically determined distant disease. Patients needed to have TNBC or HER2-positive breast cancer and a residual breast lesion of less than 2 cm after clinically standard neoadjuvant systemic therapy.
Patients were ineligible if they were participating in a clinical trial of neoadjuvant systemic therapy that required surgical resection of the primary tumor and lymph nodes; if they had pathological or clinical evidence of distant metastases or skin involvement; if they had a prior diagnosis of either ductal carcinoma in situ in the ipsilateral breast or invasive breast cancer; if they had clinical evidence of progressive disease in over 20% of the breast or new evidence of nodal metastases while on neoadjuvant standard therapy; or if their final breast imaging after finishing neoadjuvant standard therapy showed density, a residual mass legion, enhancement of over 2 cm, or suspicious microcalcifications.
The median age of the patients was 62 years (interquartile range, 55-77). Of these patients, 42% (n = 21) had TNBC and 58% (n = 29) had HER2-positive breast cancer. A total of 18% (n = 9) of patients had biopsy-driven nodal metastases at baseline.
Patients who consented to participation received clinically standard neoadjuvant therapy as recommended by their medical oncologists. They then underwent 1 biopsy of the tumor bed to obtain a minimum of 12 VACB cores with a 9G needle. Patients with no histologically identifiable invasive or in situ disease did not have breast surgery and received standard whole-breast and nodal radiotherapy at 40 Gy in 15 fractions or 50 Gy in 25 fractions, as well as a mandatory boost at 14 Gy in 7 fractions, beginning the day after completion of whole-breast irradiation. Patients with initial documented nodal disease and a breast pCR were eligible for radiotherapy if they had no residual nodal disease upon targeted axillary dissection after completing neoadjuvant systemic therapy.
Patients received a physical and history examination every 6 months after completing radiotherapy. Surveillance mammograms were required at the 6-month follow-up visit and every 6 months thereafter for 5 years.
Suspicious findings that remained so after additional imaging were biopsied to determine the presence or absence of ipsilateral breast tumor recurrence. Biopsy was also required in patients whose calcifications morphology changed to a more aggressive morphology; in those who had an increase in the size of calcifications, a residual mass, or asymmetry; and in those who developed a new mass or asymmetry.
The primary end point of this analysis was biopsy-confirmed ipsilateral breast tumor recurrence rate, assessed in the per-protocol population, defined as the proportion of patients who did not receive breast surgery at 6 months and 1, 2, 3, and 5 years.
Planned secondary end points included the number of patients with residual disease at final biopsy, residual disease quantification in the surgery specimens, and the number of patients who were recommended to receive ipsilateral breast or axillary node image-guided biopsy during follow-up. The safety assessment included all patients who received VACB.
The mean initial largest tumor size was 2.28 cm. The mean final tumor size following neoadjuvant standard therapy was 0.90 cm (standard deviation, 0.81).
A total of 34% (n = 17; 95% CI, 21.2%-48.8%) of patients had a complete radiological response. Additionally, a mean of 15.24 VACB specimens that were obtained (standard deviation, 5.05) showed that 38% (n = 19) of patients had residual disease.
The ipsilateral breast tumor recurrence-free survival and overall survival rates were both 100%.
In a prespecified secondary end point analysis, 37% (n = 7) of the patients with VACB-identified residual disease (n = 19) had no residual disease at the time of breast surgery. Of the 63% (n = 12) of the patients with residual disease, the mean size was 9.00 mm (standard deviation, 5.03) for invasive cancer and 2.33 mm (standard deviation, 2.09) for ductal carcinoma in situ. None of the patients with residual disease had nodal metastases.
Additionally, in the prespecified secondary end point analysis of ipsilateral breast and nodal biopsy recommendation and performance, 29% (n = 9) of the 31 patients with no VACB-identified residual disease were recommended to have image-guided breast or nodal biopsy. Six of these patients had biopsy recommended once, 2 had it recommended twice, and 1 had it recommended 3 times. Patients were recommended for biopsy at 6 months (n = 3), 12 months (n = 4), 24 months (n = 3), 36 months (n = 1), and 48 months (n = 1). Two patients were recommended contralateral breast biopsies.
The indications for these biopsies included new or increasing architectural distortion (n = 7), enhancement (n = 3), new calcifications (n = 1), and a suspicious axillary lymph node (n = 1). All biopsy findings were benign and matched imaging findings. The biopsy findings included benign lymphoid tissue (n = 1); fibrosis, necrosis, or scar (n = 8); fibroadenoma (n = 2); and a papilloma (n = 1).
The post-hoc analysis of outcomes by hormone receptor (HR) status detected no difference in the rate of breast pCR by tumor HR status. A pCR was reported in 71% (n = 15) of the patients with TNBC and 55% (n = 16) of patients with HER2-positive disease (P = .24). Additionally, 39% (n = 7) of the patients with HER2-positive and HR-positive disease (n = 18) had a pCR compared with 81% (n = 9) of the patients with HER2-positive, HR-negative disease (n = 11; P = .052).
Furthermore, 18% (n = 9) of the total study population had N1 disease by image-guided biopsy. All 9 of these patients had a nodal conversion from positive by percutaneous biopsy to histologically node negative after neoadjuvant standard treatment. Of these patients, 1 did not have a breast pCR; VACB determined them to have residual ductal carcinoma in situ, and they received standard lumpectomy. All 8 patients who had nodal metastases and a breast pCR by VACB also had a nodal pCR confirmed on targeted axillary dissection.
In total, 82% (n = 14) of patients with complete radiological response (n = 17) had a pCR; 18% (n = 3) had a complete radiological response but no breast pCR. In comparison, 52% (n = 17) of patients with incomplete radiological response (n = 33) had a pCR.
No patients experienced serious biopsy-related adverse effects (AEs) or treatment-related deaths. During the biopsy procedure, 2 patients had grade 1 complications. One patient experienced nausea during the biopsy that resolved without intervention. The other patient experienced a VACB device malfunction that was rectified, allowing for successful procedure completion.
“This is the very beginning of a new field that is rapidly advancing. This approach will need to be tested in several larger studies before it becomes a standard treatment option, and we are committed to studying this further,” Kuerer concluded.
Kuerer HM, Smith BD, Krishnamurthy S, et al. Eliminating breast surgery for invasive breast cancer in exceptional responders to neoadjuvant systemic therapy: a multicentre, single-arm, phase 2 trial. Lancet Oncol. Published online October 25, 2022. doi:10.1016/S1470-2045(22)00613-1