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Risk of Local Recurrence in Breast Cancer: Impact of Molecular Subtype and Surgical Approach


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Tari A. King MD, FACS

Tari A. King MD, FACS

THE RISK of local recurrence in breast cancer “does not differ substantially based on the operation we perform, but it does differ substantially by subtype,” Tari A. King MD, FACS, stated at the 2018 Lynn Sage Breast Cancer Symposium in Chicago.1 At 10-year follow-up, Dr. King reported, local recurrence rates following breast conservation surgery or mastectomy are 2% to 3% for patients with luminal A subtype, and 10% to 12% for patients with triple-negative cancers.2

Dr. King is the Anne E. Dyson Associate Professor of Surgery in the Field of Women’s Cancers at Harvard Medical School; Chief, Division of Breast Surgery, Brigham Health; and Associate Chair for Multidisciplinary Oncology at Brigham and Women’s Hospital, Boston. The symposium was hosted by the Robert H. Lurie Comprehensive Cancer Center at Northwestern University.

Age Is Not a Factor

“THIS RELATIONSHIP between local recurrence and molecular subtype holds true, even when we take age into account,” Dr. King stated. A study comparing 1,930 patients with stage I to III triple-negative breast cancer diagnosed before and after age 40 found no difference in overall local recurrence rates by age, operation performed, or regional recurrence rates,3 Dr. King stated.

Age should not be a factor in deciding which surgical procedure to use. A British Columbia Cancer Agency study of 965 patients, aged 20 to 39 years, with early-stage breast cancer found, at a median of 14.4 years, no difference in local recurrence–free, regional recurrence–free, disease-free, or overall survival based on the type of operation performed,4 Dr. King reported.

“A high-risk molecular subtype is not a reason to pursue contralateral prophylactic mastectomy.”
— Tari A. King, MD, FACS

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“The totality of the data demonstrates that bigger surgery does not beat bad biology.”

Bilateral Mastectomy

“A CLINICAL scenario that we all grapple with in our clinics is patients choosing bilateral mastectomy when they could be good candidates for breast conservation,” Dr. King noted. “Even in our highest risk cohorts—young women with estrogen receptor–negative breast cancer—there are no data that contralateral prophylactic mastectomy improves survival. A high-risk molecular subtype is not a reason to pursue contralateral prophylactic mastectomy.”

In a follow-up interview with The ASCO Post, Dr. King said that when women are asked why they choose contralateral prophylactic mastectomy, “the most common answer is for peace of mind. They feel like they will worry less, have less anxiety, and feel better going forward by eliminating what they perceive is a big risk. We try to inform them as to their actual risk of developing a breast cancer in that healthy breast over time and that the risk of their current breast cancer coming back is higher than the risk of developing a new breast cancer in the other breast.”

She also shares patient-reported outcomes data with her patients: 25% to 30% of women who chose bilateral mastectomy report they still worry as much as before; they have less self-confidence, less confidence in their appearance, and less sexual intimacy after bilateral mastectomy; and the procedure was more painful than expected. For a significant group of women, Dr. King noted, “the outcome of the procedure does not meet their expectations.”

Pathologic Complete Response

THE LIKELIHOOD of attaining a pathologic complete response varies by molecular subtype. A pooled analysis of data from 12 international trials, with close to 12,000 patients treated with neoadjuvant therapy and surgery, found the association between pathologic complete response and long-term outcomes was strongest in patients with triple-negative breast cancer and in those with HER2-positive, hormone receptor–negative tumors who received trastuzumab.5

“In the more modern era, where we are using dual anti-HER2 therapy, the rates of pathologic complete response in the HER2-positive subset are even higher,” Dr. King added. Patients with hormone receptor–positive disease are less likely to achieve a pathologic complete response but can still do well without one, she noted. “In the more aggressive subtypes, the HER2-positive and triple-negative subtypes, not achieving a pathologic complete response is associated with inferior outcomes, but the same would be true if these patients were treated with mastectomy,” Dr. King said. “So, there is no reason to think that bigger surgery is going to change outcomes after neoadjuvant therapy.”

Management of the Axilla

“IN PATIENTS who start with a clinically negative axilla, if there is an indication for neoadjuvant therapy, either driven by molecular subtype or the desire to downstage the tumor, we perform a sentinel node biopsy after neoadjuvant therapy,” Dr. King shared. Subsequent management of the axilla is based on pathology findings. For those going to primary surgery, “we are comfortable using the sentinel node biopsy procedure, and management of the axilla is based on disease burden.”

Dr. King continued: “In patients who start with a clinically positive axilla, we frequently now treat them with neoadjuvant therapy, to allow them the opportunity to have sentinel node biopsy and possibly to avoid axillary dissection; final management depends on the disease burden and clinical trial options.” Although proceeding to upfront surgery is less common today for patients with clinically positive axilla, “it still may be indicated in those for whom there is an uncertain need for chemotherapy, or the multidisciplinary team needs more information from the lymph node dissection to make this decision. That largely happens in the estrogen receptor–positive, HER2-negative subset,” she noted.

Applying the Algorithms

“HOW DO we apply these algorithms in the face of what we know about the presenting features of breast cancer and their molecular subtype?” To answer that question, Dr. King cited several studies.

To begin, she focused on a study of 6,072 consecutive patients treated at Memorial Sloan Kettering Cancer Center (MSK).6 “We learned that our HER2-positive patients had a higher probability of having any nodal disease. More than 50% had node-positive disease, but more important, this group had the highest probability of having a high burden of nodal disease, with more than 20% of patients having 4 or more positive lymph nodes,” Dr. King reported. These patients also presented with larger tumors. “We now know they have higher rates of pathologic complete response. So, in this group, we should be considering neoadjuvant therapy.”

Patients with estrogen receptor–positive, HER2-negative disease were “less likely to be node-positive (43%) and much less likely to have higher burdens of nodal disease,” Dr. King noted. For these patients, upfront surgery is more likely to be indicated, along with the opportunity to apply the results of the American College of Surgeons Oncology Group (ACOSOG) Z0011 and the European Organisation for Research and Treatment of Cancer 10981-22023 AMAROS trials.

Although triple-negative breast cancer is considered to be an aggressive subtype, “these patients are also less likely to have high-volume nodal disease,” Dr. King said. “We know they have respectable rates of pathologic complete response, so here we consider neoadjuvant chemotherapy, especially if there is a desire to downstage to obtain breast conservation.”

Avoiding Axillary Node Dissection

TO DETERMINE the likelihood of avoiding axillary node dissection by subtype and treatment, Dr. King cited another MSK trial,7 this one focusing on patients with clinical T1 to T2N0 breast cancer treated in the ACOSOG Z0011 era. The likelihood of requiring axillary node dissection was equal across molecular subtypes for patients who had initial breast conservation therapy, somewhat higher for patients who had initial mastectomy, but with no large variations based on subtype. Among patients who were treated with neoadjuvant chemotherapy, however, “those who had HER2-positive or triple-negative disease were substantially less likely to require axillary node dissection,” Dr. King said.

“Patients with estrogen receptor–positive, HER2-negative disease were actually three times more likely to require node dissection when neoadjuvant chemotherapy was used, compared with upfront breast conservation therapy,” she continued. “This is the group we continue to struggle with in our multidisciplinary teams. We would like to know which patients with estrogen receptor–positive breast cancer really need chemotherapy; and if they do need chemotherapy, should we give it to them upfront? If we do that, can—or should—we manage the axilla differently in patients who receive preoperative therapy and do not achieve a nodal pathologic complete response? This group still has their best treatment remaining—5 years of antiestrogen therapy—so is there an opportunity to manage the axilla differently in this population?”

Data to support different management strategies are lacking, but Dr. King was hopeful they would be forthcoming in the next several years. She and research colleagues are set to launch a trial using genomic assays in the preoperative setting to see how that might impact treatment strategies.

For patients presenting with clinically negative axilla and whose sentinel lymph node biopsy is negative, “there are robust data that no further surgery is needed,” Dr. King said. If the sentinel node biopsy does demonstrate disease within the axilla, treatment options vary by the number of positive nodes. “With more than three positive nodes, current data suggest axillary lymph node dissection should be performed. With one to two positive nodes, we manage the axilla differently, based on the results of several randomized trials.”

In three clinical trials, patients who had clinically node-negative disease but were found to have one to two positive nodes were randomly assigned to observation vs node dissection; and in two clinical trials, they were randomly assigned to axillary radiation therapy vs node dissection. All breast cancer subtypes were included. The results showed there were no differences in recurrence rates, disease-free survival, and overall survival among patients receiving axillary lymph node dissection vs observation or radiation therapy.

“We look forward to increasing opportunities to de-escalate therapy in patients with favorable subtypes.”
— Tari A. King, MD, FACS

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“The majority of patients in these trials were treated with breast conservation therapy, and as such, these data have been applied widely to this group of women,” Dr. King noted.

De-escalating Therapy

“THERE ARE multiple studies demonstrating how often node dissection can be spared when ACOSOG Z0011 criteria are applied,” Dr. King said.

“Looking to the future, I think we will see a lot more efforts to use molecular subtype to de-escalate local therapy,” Dr. King noted. There are several ongoing trials to identify low-risk patients for omission of radiotherapy. “We look forward to increasing opportunities to de-escalate therapy in patients with favorable subtypes.”

DISCLOSURE: Dr. King has received speakers honorarium from Genomic Health (although not in connection with this talk).

REFERENCES

1. King T: Selecting surgical approach by subtype. 2018 Lynn Sage Breast Cancer Symposium. Presented October 12, 2018.

2. Arvold ND, Taghian AG, Niemierko A, et al: Age, breast cancer subtype approximation, and local recurrence after breast-conserving therapy. J Clin Oncol 29:3885-3891, 2011.

3. Radosa JC, Eaton A, Stempel M, et al: Evaluation of local and distant recurrence patterns in patients with triple-negative breast cancer according to age. Ann Surg Oncol 24:698-704, 2017.

4. Cao JQ, Truong PT, Olivotto IA, et al: Should women younger than 40 years of age with invasive breast cancer have a mastectomy? 15-Year outcomes in a population-based cohort. Int J Radiat Oncol Biol Phys 90:509-517, 2014.

5. Cortazar P, Zhang L, Untch M, et al: Pathological complete response and long-term clinical benefit in breast cancer: The CTNeoBC pooled analysis. Lancet 384:164-172, 2014.

6. Wiechmann L, Sampson M, Stempel M, et al: Presenting features of breast cancer differ by molecular subtype. Ann Surg Oncol 16:2705-2710, 2009.

7. Pilewskie M, Zabor EC, Mamtani A, et al: The optimal treatment plan to avoid axillary lymph node dissection in early-stage breast cancer patients differs by surgical strategy and tumor subtype. Ann Surg Oncol 24:3527- 3533, 2017.


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