RESEARCHERS AT The University of Texas MD Anderson Cancer Center are testing the possibility of safely eliminating surgery in patients with breast cancer who are “exceptional responders” to neoadjuvant therapy, according to Henry M. Kuerer, MD, PhD, a breast cancer surgeon who described this approach at the 2018 Miami Breast Cancer Conference.1 “The field is changing,” Dr. Kuerer said. “We have better systemic therapies, and with this we have the obligation to study the possibility of not requiring surgery.”
Henry M. Kuerer, MD, PhD
“We’ve known for a while that some patients have dramatic responses,” he added. Dr. Kuerer described a patient who 20 years ago achieved a pathologic complete response after four cycles of chemotherapy. “We told the patient we were delighted to find nothing left in her lymph nodes or breast. Her response was, ‘Then why did you take off my breast?’”
“Essentially, over these past 2 decades, we’ve been performing less and less surgery after neoadjuvant chemotherapy. We now understand that neoadjuvant therapy can have a dramatic effect locally, eliminating both invasive and in situ carcinoma in up to 50% of patients, particularly those with HER2-positive or triple-negative disease,” he said.
Since HER2-negative and estrogen receptor–positive patients are far less likely to achieve a pathologic complete response, Dr. Kuerer would limit this approach to HER2-positive and triple-negative disease. He calculated that about 1 in 20 patients with early-stage breast cancer, therefore, might be able to forgo surgery.
In the past, the difficulty has been distinguishing patients with residual disease after systemic therapy from those without residual disease. Conventional imaging modalities have not been successful in identifying exceptional responders. Today, however, targeted imaging combined with contemporary biopsy techniques may accurately identify patients with residual disease, he revealed.
Surgery Is Safe: Why Consider Eliminating It?
“WHY EVEN CONSIDER eliminating surgery, since surgery is safe?” he asked. “This is similar to the discussions we had 30 years ago, when we asked, ‘Why just take out a lump when a mastectomy will get everything?’”
Aside from the potential for complications related to surgery as a reason to perform less surgery, Dr. Kuerer maintained that “we’re fooling ourselves that surgery will get everything, too.” He said the surgical resection of imaging-detected residual disease— the usual practice—could well be “leaving behind some disease after surgery in some of our patients.”
Feasibility Study
DR. KUERER and his colleagues conducted a feasibility study of 40 patients with HER2-positive or triple-negative T1–3 N0/N1 tumors.2 “This was not an easy study. We had to have close, meticulous collaborations with the radiologists, surgeons, medical oncologists, pathologists, radiologists, and radiation oncologists, and everyone in our research group had to work with the patients early on,” he noted.
“We are thinking about these cases differently now. We want to know who are the patients who really may have no residual disease.”— Henry M. Kuerer, MD, PhD
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The researchers reported that 48% of patients achieved a pathologic complete response in the breast, defined as no residual invasive and no in situ disease, which was the expected result. The median initial tumor size was 3 cm, with a final tumor size of 1.1 cm. The median number of vacuum-assisted biopsies was 12. Combined fine-needle aspiration and vacuum-assisted core biopsy provided an accuracy of 98%, a false-negative rate of 5%, and a negative predictive value of 95%. The radiologic response rate was 80%, with 20% complete responses. Adverse events were observed in 20% of patients, all grade 1, including bleeding and bruising.
For the two cases in which residual cancer was missed, “the disease was very limited (ie, 1 cm), with 1% to 3% cellularity,” he added. “Also, those two patients had only four or six biopsies, and we have learned from this study that we need a better sampling. In fact, for the clinical trial that is now open, we require a minimum of 12 cores of the residual region of prior carcinoma in and around the area of the marker clip.”
“This brings up the point again, that when we perform surgery in these exceptional responders—even if we removed the whole breast—we would also find a small amount of disease. I believe this approach is safe, and our IRB [internal review board] agreed that our patients could go on to radiotherapy, even with less than a 100% false-negative rate.”
Studies of Residual Disease
“WE ARE THINKING about these cases differently now. We want to know who are the patients who really may have no residual disease,” he said. In other words, are there identifiable patient or disease characteristics that might predict for the presence, or lack thereof, of residual disease?
A recent study found that the presence of ductal carcinoma in situ (DCIS) on the initial core biopsy and the presence of microcalcification on imaging were associated with residual disease.3 Neoadjuvant systemic therapy was able to eliminate 45% of these cases with invasive disease and DCIS on initial biopsy. HER2-positive patients with residual disease, however, were not more likely to present with microcalcifications and DCIS initially, according to Dr. Kuerer’s unpublished research, and 36% of HER2-positive patients had the DCIS component eradicated with neoadjuvant chemotherapy.
What about the axilla? Is it safe to forgo evaluation of the lymph nodes? An examination of the MD Anderson database has shown that when the initial ultrasound of the lymph nodes is negative, 100% of patients are also pathologically node-negative after neoadjuvant therapy. When positive nodes are revealed on ultrasound and confirmed by biopsy, 89.6% of patients converted to pathologically node-negative disease in the axilla after treatment.4 The 10% with residual disease are eligible for the study at MD Anderson if they undergo surgery and targeted axillary dissection.
Ongoing and Upcoming Trials
AN ONGOING STUDY at MD Anderson will evaluate 50 patients on the safety of eliminating surgery in exceptional responders. Patients must present with HER2-positive or triple-negative tumors that are ≤ 5 cm and reduced to < 2 cm after neoadjuvant therapy. Patients achieving at least a partial response undergo image-guided biopsy, with at least 12 cores sampled. Those with no residual disease (invasive and in situ) undergo radiotherapy alone, whereas those with residual disease receive standard surgery and radiotherapy. All patients are followed every 6 months, with the primary endpoint being local-regional tumor recurrence. Secondary endpoints are the need for further biopsy, cosmesis, quality of life, cost, and correlation of circulating tumor cells and circulating tumor DNA with pathologic complete response.
Other feasibility trials are ongoing or will be starting soon, including studies by the Netherlands Cancer Institute, the German Breast Group/University of Heidelberg, the University of Birmingham in the United Kingdom, and the NRG BR005 trial (https://clinicaltrials.gov/ct2/show/NCT03188393), which is currently accruing. This is a phase II trial to assess the accuracy of tumor-bed biopsies in predicting pathologic complete response among patients with clinical or radiologic complete response after neoadjuvant chemotherapy and to determine the feasibility of breast-conserving treatment without surgery.
Dr. Kuerer concluded by encouraging clinicians to “think differently about these patients” and to “support the trials where we can ensure the safety and efficacy” of eliminating surgery in exceptional responders. ■
DISCLOSURE: Dr. Kuerer has served on the speakers bureau for PER and has received funding from Genomic Health.
REFERENCES
1. Kuerer HM: Breast cancer management in exceptional responders to neoadjuvant therapy. Invited Lecture. 2018 Miami Breast Cancer Conference. Presented March 9, 2018.
2. Kuerer HM, Rauch GM, Krishnamurthy S, et al: A clinical feasibility trial for identification of exceptional responders in whom breast cancer surgery can be eliminated following neoadjuvant systemic therapy. Ann Surg 267:946-951, 2018.
3. van la Parra RFD, Tadros AB, Checka CM, et al: Baseline factors predicting a response to neoadjuvant chemotherapy with implications for non-surgical management of triple-negative breast cancer. Br J Surg 105:535-543, 108.
4. Tadros AB, Yang WT, Krishnamurthy S, et al: Identification of patients with documented pathologic complete response in the breast after neoadjuvant chemotherapy for omission of axillary surgery. JAMA Surg 152:665-670, 2017.
