Assessing Other Options Aside from Surgery Shows “Promise” in Breast Cancer

“Not all patients would want to not have surgery...I think many would be interested [in not having surgery] if we prove someday that it is just as safe to not operate when there’s a [pCR]," according to Henry Kuerer, MD, PhD, FACS, CMQ.

The breast cancer field is evolving with new systemic therapy options, and practices should study the possibility of de-escalating surgery and radiation therapy for this population, said Henry Kuerer, MD, PhD, FACS, CMQ, in a presentation at the 41st Annual Miami Breast Cancer Conference® hosted by Physician Education Resource^® (PER) .¹

When considering the selective elimination of breast cancer surgery, Kuerer, a professor of surgery with tenure and the PH and Fay Etta Robinson Distinguished Professor in Cancer Research in the Department of Breast Surgical Oncology at The University of Texas, MD Anderson Cancer Center highlighted certain patients who might be suitable to receive treatment without surgery. For example, surgery may not be necessary for local control in some patients with a pathologic complete response (pCR) following neoadjuvant therapy.Additionally, he discussed some of the surgical and anesthetic morbidities that may affect cosmetic outcomes and have a psychological impact on patients, including infection, paresthesia, and lymphedema.

“Not all patients would want to not have surgery,” Kuerer said. “I think many would be interested [in not having surgery] if we prove someday that it is just as safe to not operate when there’s a [pCR].”

Kuerer highlighted a patient case to demonstrate the feasibility of using image-guided tissue sampling as a method for omitting surgery in patients following neoadjuvant therapy. A patient who had an “exceptional” response to chemotherapy and had no residual disease left in the breasts or nodes, however, the patient ultimately decided to proceed with a mastectomy. Following this case, Kuerer said he has been working for decades to develop a strategy that could safely and more accurately identify patients who could receive treatment without surgery, particularly those who have a response to neoadjuvant treatment.

According to findings from a study published in JAMA Surgery, theuse of an image-guided vacuum-assisted biopsy in patients with breast cancer who received and responded to neoadjuvant chemotherapy yielded a false-negative rate of 3.2% (95% CI, 0.1%-16.7%).²

Multi-Center Trial Design

Kuerer presented updated findings from a multi-center phase 2 trial (NCT02945579) evaluating the feasibility of eliminating breast cancer surgery in those who have a response to neoadjuvant systemic therapy.³ The study included patients 40 years and older with unicentric triple-negative or HER2-positive invasive breast cancer with 4 or fewer abnormal axillary nodes on initial ultrasound with biopsy following neoadjuvant systemic therapy and tumor shrinkage to 2 cm or less at the time of final breast imaging. Patients with prior ipsilateral breast cancer or pregnancy were excluded, as were those with stage T3/T4 disease, clinical progression in more than 20% of the breast, new evidence of nodal metastases, and distant metastases.

In cohort A1 of the trial, patients who had a “remarkable” CR or partial response (PR) to traditional neoadjuvant systemic therapy underwent an image-guided biopsy.⁴ Those who had no evidence of residual disease received no breast surgery, and those with residual disease were assigned to undergo standard surgery.

The trial’s primary end point was ipsilateral breast tumor recurrence (IBTR)–free survival, with secondary end points including quality of life (QOL), overall survival (OS), and disease-free survival (DFS). The incidence of recommending biopsy based on breast imaging at various follow-up periods was another secondary end point.

This study cohort included 50 patients who had a mean initial and final tumor size of 2.3 cm and 0.9 cm, respectively. Additionally, 34% of the patients had a radiologic CR, and 8 patients had a pCR in the breast and underwent a targeted dissection.

Updated Results from the Phase 2 Trial

With a median follow-up of 41.9 months (IQR, 31.8-57.9), the 42-month IBTR-free survival rate was 100%, and the OS and DFS rate was 100%. The pCR rate in the overall cohort was 62% (95% CI, 47.2%-75.4%), 71% in those with triple-negative breast cancer (TNBC), and 55% among those with HER2-positive disease.

Investigators of this study hypothesized that the elimination of breast surgery would make surveillance breast imaging easier and reduce the rate of biopsy compared with standard surgery. He cited findings from a study published in JAMA Surgery that included 121,879 patients with Surveillance, Epidemiology, and End Results (SEER) Medicare, and commercial insurance to support his hypothesis.⁵ After 10 years of follow-up, 14.9% to 23.4% of patients had ipsilateral breast biopsy, resulting in 20% to 30% of patients receiving additional anti-cancer therapy.

With respect to one of the secondary end points from the multi-center trial, investigators recommended breast biopsy for 29% of patients, including 2 who had contralateral cases.⁴

Investigators also reported longitudinal patient-reported outcomes (PROs) of interest from the trial in JAMA Network Open.⁶ Validated PRO measures included the Decision Regret Scale (DRS), which included 5 questions assessing a patient’s comfort with the treatment decision-making process; the Breast Cancer Treatment Outcome Scale (BCTOS), which featured 22 questions evaluating function, cosmesis, pain, and edema outcomes; and the FACT-B+4, which included 42 questions related to breast-specific, arm-specific, physical, social, and emotional QOL as well as functional well-being.

PROs highlighted that patients were highly comfortable with their decision to participate in the trial and forego surgery for breast cancer, which significantly increased over time. Additionally, there were minimal differences between breasts at baseline and slight differences in breasts over time, which was comparable with prior reports of patients who underwent breast conservation therapy. Patients also reported high QOL at baseline, which saw a further increase over time.

Investigators also assessed circulating tumor cells (CTCs) in 33 blood samples derived from 13 patients across 3 periods. Of these patients, 2 had CTC positivity at baseline, 2 were positive at 6 months, and 1 was positive at 12 months.

The study also included a circulating tumor DNA (ctDNA) assessment with 30 plasma samples collected from 12 patients at 3 different times. There were 2 patients who had positivity for TP53 at baseline, which included 1 with TNBC and another with HER2-positive or estrogen receptor (ER)–positive disease. TP53 cleared in the patient with TNBC after 6 months but persisted in the patient with HER2-positive disease at 6 and 12 months.

Overall, investigators reported no positive relationship between CTCs and ctDNA.

Future Research and Key Takeaways

As part of an alternative de-escalation strategy, Kuerer briefly discussed the design for cohort B of this multi-center trial, in which investigators are evaluating the possibility of eliminating radiotherapy in those who achieved an adequate response to neoadjuvant systemic therapy. Following neoadjuvant treatment and standard lumpectomy, patients with no residual disease will be eligible to omit radiotherapy, while those with residual disease will proceed with standard radiotherapy.

“The field is changing. We have better systemic therapies,” Kuerer said. “We have an obligation to test these alternatives…targeting imaging and biopsy is the way to go at this time.”

Concerning other future research, Kuerer also detailed the Korean OPTIMIST trial (NCT05505357), a single-arm, non-inferiority trial in which investigators will assess the omission of surgery for patients with a pCR diagnosed with MRI and biopsy following neoadjuvant chemotherapy. The study will include those with clinical stage II to III TNBC or HER2-positive, low-ER breast cancer. The study’s primary end point will be DFS at 5 years, with secondary end points including invasive DFS, IBTR-free survival, OS, and QOL.

References

1. Kuerer H. Eliminating breast surgery after neoadjuvant systemic therapy: clinical trials update. Presented at the 41st Annual Miami Breast Cancer Conference. March 7-10, 2024; Miami, FL.
2. Tasoulis MK, Lee HB, Yang W, et al. Accuracy of post-neoadjuvant chemotherapy image-guided breast biopsy to predict residual cancer. JAMA Surg. 2020;155(12):e204103. doi: 10.1001/jamasurg.2020.4103.
3. Eliminating surgery or radiotherapy after systemic therapy in treating patients with HER2 positive or triple negative breast cancer. ClinicalTrials.gov. Accessed March 11, 2024. https://tinyurl.com/44nmxkbx
4. 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. 2022;23(12):1517-1524. doi:10.1016/S1470-2045(22)00613-1.
5. van la Parra RFD, Liao K, Smith BD, et al. Incidence and outcome of breast biopsy procedures during follow-up after treatment for breast cancer. JAMA Surg. 2018;153(6):559-568. doi:10.1001/jamasurg.2017.5572.
6. Johnson HM, Lin H, Shen Y, et al. Patient-reported outcomes of omission of breast surgery following neoadjuvant systemic therapy: a nonrandomized clinical trial. JAMA Netw Open. 2023;6(9):e2333933. doi:10.1001/jamanetworkopen.