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Impact of Neoadjuvant Endocrine Therapy and Neoadjuvant Chemotherapy on Rates of Breast‑Conserving Surgery


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“Studies that have compared neoadjuvant endocrine therapy with neoadjuvant chemotherapy have shown low pathologic complete response rates with both approaches. However, the rates of breast-conserving surgery have been shown to be slightly higher with neoadjuvant endocrine therapy,” Kelly Hunt, MD, said in the breast cancer forum during the virtual edition of the 2020 Society of Surgical Oncology (SSO) International Conference on Surgical Cancer Care.1

Kelly Hunt, MD

Kelly Hunt, MD

Data from the ACOSOG Z1031 (Alliance) trial showed that among postmenopausal women with clinical stage II to III strongly estrogen receptor–positive breast cancer randomly assigned to one of three aromatase inhibitors, “67% were able to have breast-conserving surgery and over 50% of these women were thought to require mastectomy at initial presentation,” Dr. Hunt reported. “There were five patients who had no residual disease in the breast at surgery. Of patients who had nodal surgery, 47% had no nodal metastases at surgery.” Dr. Hunt is Chair of the Department of Breast Surgical Oncology at The University of Texas MD Anderson Cancer Center, Houston.

Most of the patients had T2 tumors and “were clinically node-negative at presentation,” Dr. Hunt said. “Cohort A included 377 patients who received 16 weeks of an aromatase inhibitor followed by surgery. Cohort B included 245 patients who had an on-treatment biopsy at 2 to 4 weeks. If the Ki67 index was found to be greater than 10%, patients were recommended to undergo neoadjuvant chemotherapy or surgery.”

“Local or regional recurrences were the first event in 12 patients, for an estimated 5-year cumulative incidence of 1.6%. Of these patients, nine had partial mastectomy and three had total mastectomy,” Dr. Hunt reported.

“The rate of conversion from mastectomy to breast-conserving surgery is clinically meaningful and underscores the value of this approach for patients with estrogen receptor–rich tumors,” Dr. Hunt concluded. “Local-regional recurrence events after surgery are uncommon and support the use of breast-conserving surgery after neoadjuvant aromatase inhibitor therapy.” Asked if one of the aromatase inhibitors used in the study was more successful than the others in downstaging, Dr. Hunt replied: “All three were essentially equivalent and clinically effective.”

Patients With Large Tumors

Giacomo Montagna, MD, MPH, of Memorial Sloan Kettering Cancer Center, New York, reported on a study evaluating whether modern neoadjuvant chemotherapy can be used for conversion to breast-conserving surgery among women with large tumors relative to breast size.2 Using a prospective database, the investigators identified consecutive patients with stage I to III breast cancer treated from November 2013 to March 2019 with neoadjuvant chemotherapy. A total of 93% had received dose-dense doxorubicin and cyclophosphamide plus paclitaxel, and 99% of patients with HER2-positive disease had received dual blockade.

Giacomo Montagna, MD, MPH

Giacomo Montagna, MD, MPH

“Patients with a large tumor size compared with breast size comprise our cohort,” Dr Montagna explained. Among 600 patients, “61% were deemed not to be candidates for breast-conserving surgery by the treating surgeon, and 39% were considered borderline candidates.” Overall, 450, or 75%, became eligible for breast-conserving surgery with neoadjuvant chemotherapy. “Of these patients, 68% chose breast-conserving surgery, which was successful in 93% of cases,” and “48% of patients with a large tumor size avoided mastectomy with neoadjuvant chemotherapy.” The rates of conversion to breast-conserving surgery eligibility were higher among patients considered to be borderline breast-conservation candidates than among those considered to be non–breast-conservation candidates (87% vs 69%). Additionally, triple-negative and HER2-positive tumors were more likely to become eligible for conserving surgery (84% and 79%, respectively) compared to hormone receptor–positive tumors (62%).

“In borderline candidates for breast-conserving surgery, there is little rationale to consider upfront surgery in those for whom chemotherapy is indicated,” Dr. Montagna concluded. In patients with large tumors considered ineligible for breast-conserving surgery, “neoadjuvant chemotherapy offers a substantial clinical benefit and allows for surgical de-escalation in the breast with avoidance of mastectomy.”

Time to Surgery

“Since the advent of cytotoxic chemotherapy in the 20th century, surgical dogma has been to operate no sooner than 4 to 6 weeks after neoadjuvant chemotherapy, primarily due to the perceived risk of wound-healing complications,” Thomas Sutton, MD, reminded forum participants. “Recently, that dogma has been questioned in light of the oncologic implications of longer times to surgery, which has been particularly well characterized in rectal cancer. In breast cancer, contradictory evidence exists in the two relevant studies. We sought to break the tie.”

Thomas Sutton, MD

Thomas Sutton, MD

To do so, Dr. Sutton and colleagues at the Oregon Health and Science University, Portland, conducted a retrospective review of the health system’s tumor registry from 2011 to 2017 to identify women with nonmetastatic breast cancer who had undergone neoadjuvant chemotherapy and surgery.3 The 463 patients identified were sorted into three groups: 220 whose last administration of neoadjuvant chemotherapy was within 4 weeks of surgery; 175 with the time to surgery between 4 and 6 weeks; and 68 the time to surgery being more than 6 weeks.

There were no differences in most patient factors, noted Dr. Sutton. However, he added, those with a time to surgery of more than 6 weeks were more likely to be older than age 50 and to have a higher clinical and postneoadjuvant stage.

Oncologic Outcomes

“A statistically significant difference in recurrence-free survival was seen between all time-to-surgery groups on Kaplan-Meier analysis, with shorter time to surgery intervals associated with improved recurrence-free survival. Similar findings were seen for disease-specific survival,” Dr. Sutton reported.

“Time to surgery of more than 6 weeks was strongly and independently associated with worse recurrence-free survival, whereas time to surgery of between 4 and 6 weeks has been shown to be independent associated with recurrence-free survival that just missed the significance cutoff. Similarly, time to surgery of more than 6 weeks had an independent association with worse disease-specific survival, with a hazard ratio of 2.8.”

Residual Cancer Burden

Among the 70% of patients with residual cancer burden scores calculable from pathologic data, “an apparent linear increase in the score with successive time to surgery in 2-week groups was seen,” Dr. Sutton reported. “On multivariate analysis, hormone receptor–positive disease, HER2-positive disease, lymphovascular invasion, and higher clinical burden of cancer all had the intuitive association with residual cancer burden score one would expect. Independent of this, however, we found that a time to surgery of more than 6 weeks had an independent association with higher residual cancer burden score, with an effect size rivaling that in patients who had stage III disease at diagnosis.”

The study findings “may be mediated by tumor regrowth and metastatic seeding during the time to surgery interval,” continued Dr. Sutton. “We recommend surgery be performed within 6 weeks following neoadjuvant chemotherapy in the absence of contraindications. Additional consideration should be given to operation within 4 weeks, given that a time to surgery of 4 to 6 weeks had a reduction in recurrence-free survival that approached independent significance.”

In closing, Dr. Sutton called for additional studies “to clarify the optimal time to surgery that balances surgical complication rates with oncologic outcomes.” 

DISCLOSURE: Drs. Hunt, Montagna, and Sutton reported no conflicts of interest.

REFERENCES

1. Hunt K, Suman VJ, Leitch M, et al: Local-regional recurrence following neoadjuvant endocrine therapy: Data from ACOSOG Z1031 (Alliance). 2020 SSO International Conference on Surgical Cancer Care. Abstract 5.

2. Petruolo O, Gonen M, Morrow M, et al: How often does modern neoadjuvant chemotherapy downstage patients to breast-conserving surgery? 2020 SSO International Conference on Surgical Cancer Care. Abstract 13.

3. Sutton TL, Schlitt A, Gardiner SK, et al: Time to surgery following neoadjuvant chemotherapy for breast cancer impacts residual cancer burden, recurrence, and survival. 2020 SSO International Conference on Surgical Cancer Care. Abstract 12.


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