Preventing Locoregional Recurrence of Breast Cancer Should Not Deter Efforts to Decelerate Therapy
Monica Morrow, MD, FASCO
“SURGEONS AND radiation oncologists are obsessed with locoregional recurrence of breast cancer,” Monica Morrow, MD, FASCO, remarked at the 2018 Lynn Sage Breast Cancer Symposium, Chicago. Working to prevent locoregional recurrence, “even if it may not be the major threat to mortality, is important,” she added, but this obsession “has held us back from appropriately decelerating therapy over time.”1
Dr. Morrow is Chief of the Breast Surgery Service and holds the Anne Burnett Windfohr Chair of Clinical Oncology, Memorial Sloan Kettering Cancer Center (MSK), New York. The Symposium was hosted by the Robert H. Lurie Comprehensive Cancer Center at Northwestern University.
“Locoregional recurrence is increasingly uncommon. That is a good thing for our patients, but it also means the evidence we have to guide treatment of locoregional recurrence is relatively limited,” Dr. Morrow noted. Much of the data available about treating locoregional recurrence comes from the eras when most patients were treated with modified radical mastectomy or later with breast conservation surgery and lymph node axillary dissection. “Now that we have been doing sentinel node biopsy alone in node-negative disease for a fairly prolonged period,” she explained, “what do we do when we see axillary recurrence after an initial sentinel node biopsy?”
“A GUIDING principle of the management of locoregional recurrence has always been that before you launch yourself into the operating room, the first thing you need to do is a metastatic workup,” Dr. Morrow said. This workup includes positron-emission tomography “to exclude the presence of coexisting distant metastatic disease,” she added. Historically, in nearly half of patients presenting with locoregional recurrence, distant metastases were diagnosed at the same time or within 3 months.
“Isolated axillary recurrence is uncommon,” Dr. Morrow noted, seen in less than 0.6% of women after negative and 1.1% after positive sentinel node biopsy not treated with axillary dissection. Axillary local recurrence may be due to the known false-negative rate of sentinel node biopsy and “may be prognostically different from recurrence after axillary lymph node dissection,” she added. “Axillary recurrence is an early event, and the overwhelming majority of cases occur in the first 5 years.”
“In the absence of distant metastases, axillary dissection is the appropriate approach” for the management of nodal recurrence after sentinel node biopsy, Dr. Morrow said.
Radiotherapy is determined based on new findings and the patient’s initial therapy.
“Isolated supraclavicular recurrence is so uncommon, it is difficult to be dogmatic about the most appropriate local therapy,” she noted. “A combination of local and systemic therapies is in line with how other local recurrences are treated,” she continued, “and therefore makes sense here.”
Reoperative Sentinel Node Biopsy
THE QUESTION of reoperative sentinel node biopsy arises in the setting of an in-breast or chest wall recurrence. A systematic review of 692 patients found that “the likelihood of successful mapping is much higher when the initial operation was a sentinel node biopsy, 81% vs 52% after an axillary dissection,”2 Dr. Morrow reported. “Patients were equally divided between those who underwent an initial sentinel node biopsy and those who had an axillary dissection, but almost all had breast-conserving surgery,” with or without radiation, which had no effect on mapping.
Among patients who were successfully mapped, 25% of those whose initial axillary surgery was a sentinel node biopsy had aberrant drainage, representing 14% of all the patients treated with a sentinel node biopsy. In contrast, 75% patients who had prior axillary dissection drained to basins outside the axilla or in addition to the axilla, representing about 33% of patients with axillary dissection.
“The most common site of aberrant drainage is the internal mammary nodes,” Dr. Morrow said. “About one-third of these patients have drainage across the midline to the contralateral axilla. These drainage pathways are relevant because of the 69 patients in this review who actually had metastases in their sentinel nodes, 19 occurring in aberrant drainage pathways,” she added.
“Given that nodal identification is less frequent in the reoperative rather than the primary mapping setting, it makes sense to use combined radioactive colloid and blue dye, because we know that increases nodal yield,” Dr. Morrow said. “We also know from the primary surgical setting that it is uncommon to see extra-axillary sentinel nodes if you inject the radioisotope intradermally or in the subareolar position. So, it makes sense to inject the isotope in the peritumoral region rather than under the skin or the subareolar region.”
Why Identify Nodal Metastases?
DR. MORROW listed several reasons why it might be useful to identify nodal metastases in locally recurrent breast cancer. “It might help to maintain local tumor control. It might change radiation therapy fields. Or maybe it will change systemic therapy.”
A study at MSK to address the utility of identifying nodal metastases examined 1,527 patients treated between 1997 and 2000 who had any size primary tumor and a negative sentinel node. Of the 83 patients who had a local recurrence, 79 had an in-breast recurrence and 4 had recurrences in the chest wall; 57% went on to receive axillary surgery.3 “There was no statistically significant difference in the use of surgical excision; the primary radiation that was delivered; or the use of chemotherapy, systemic therapy, or HER2 therapy,” Dr. Morrow explained.
The 5-year rate of nodal recurrence in patients receiving axillary surgery was 0% (although a single patient had a subsequent axillary failure at 6.6 years). “In contrast, in the patients who did not have axillary surgery, there was a 6% rate of nodal recurrence and what appears to be a somewhat higher rate of other locoregional recurrences. The bottom line is that the incidence of distant metastases and breast cancer death did not differ between these two groups,” Dr. Morrow reported.
“Two other small studies have attempted to address the question of whether lymph node staging in the setting of local regional recurrence changes management,” Dr. Morrow noted. A study among 12 patients with recurrences in the chest wall after mastectomy found sentinel nodes in 10 of them.4 The findings suggested not to radiate the supraclavicular field if the sentinel node was negative. “So, this indeed did change their management,” Dr. Morrow said.
In a study of 144 patients, 85% of whom had breast conservation therapy, 52% had a sentinel node identified.5 The authors reported that overall, this finding changed treatment in 17%, altering the recommendation for adjuvant therapy in 7 patients, for radiation therapy in 6 patients, and leading to contralateral axillary dissection in 4 patients.
Impact on Therapy Varies
“IN TODAY’S world, disease in the nodes is not the deciding factor for systemic therapy,” Dr. Morrow said. She cited the long-term results of the CALOR trial,6 which randomly assigned women with locoregional recurrences to receive chemotherapy or not. The results showed gains in disease-free survival, breast cancer–free interval, and overall survival among estrogen receptor–negative women receiving chemotherapy—but not estrogen receptor– positive patients.6 “Nodal status isn’t going to change that,” Dr. Morrow pointed out.
“The one caveat to my lack of enthusiasm for staging the lymph nodes is in patients who have what appears to be a second primary tumor in a conserved breast.”— Monica Morrow, MD
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“What we can say about lymph node staging after local recurrence is that it is technically feasible, that its impact on therapy (radiation therapy specifically) will vary with the circumstances of initial treatment—what radiation did the patients get as part of their primary cancer treatment and what exactly is the locoregional recurrence. Then, the outcome of locoregional recurrence is likely to be determined by biology, not by surgical staging and removal of the lymph nodes,” Dr. Morrow stated.
“The one caveat to my lack of enthusiasm for staging the lymph nodes is in patients who have what appears to be a second primary tumor in a conserved breast,” she added. “In that circumstance, finding that lymph node might change what you would do, just as finding lymph nodes in the primary treatment of breast cancer sometimes changes what we do.”
THE AMERICAN Joint Commission on Cancer TNM Staging System “classifies contralateral nodal disease as stage IV, whether you see that in the setting of untreated primary tumors and/or in the setting of local recurrence or a new primary and a previously treated axilla,” Dr. Morrow noted. “The limited literature precludes definitive recommendations, but good outcomes are seen with surgery for selected cases.”
For patients with contralateral nodal metastasis, a metastatic workup is necessary, Dr. Morrow advised. “You need to make sure to exclude a new primary tumor in that contralateral breast and that the mammogram is normal. Here, it makes sense to do magnetic resonance imaging.”
“Patients with nonlocally advanced recurrence on the other side may want to consider axillary dissection,” Dr. Morrow said. “However, these patients are particularly good candidates for initial systemic therapy,” which may avoid surgery in those who rapidly develop distant disease.
Ipsilateral Breast Tumor Recurrence After Breast-Conserving Therapy
IN STUDIES of lumpectomy alone for the management of ipsilateral breast tumor recurrence after breast-conserving therapy, the outcomes “do not look very good,” according to Dr. Morrow. “At median follow-ups from 6 to 244 months, the incidence of additional local recurrence is high—anywhere from 7% to 29%,” she reported.
“Repeat lumpectomy without radiation is not the standard of care,” Dr. Morrow said. “The only time I ever do it is when patients meet the criteria for no radiation therapy after primary surgery: namely they are older than age 70; have stage T1N0, estrogen receptor–positive, HER2-negative breast cancer; or have small-size, low-intermediate–grade ductal carcinoma in situ (≤ 1.5 cm). I am more enthusiastic about this approach if the disease is suspected of being a second primary tumor, namely there is a long disease-free interval and it is in a separate quadrant or if the patient has severe comorbidities and long-term local tumor control is not an issue.”
IN RESPONSE to a comment from the audience about seeing more local recurrences among young women who have nipple-sparing mastectomies without additional treatment, Dr. Morrow stated: “There is doubt in the mind of any surgeon who has ever done a nipple-sparing mastectomy; it is a technically more difficult operation to do properly than skin-sparing or conventional mastectomy. The increased risk of local recurrence is not just in the nipple-areola complex, where breast tissue may be left behind to keep a blood supply to that nipple-areola complex, but it is also all over the chest wall.”
In addition, higher recurrence rates may be related to inappropriate patient selection. Nipple-sparing surgery is for “patients who have smaller tumors in the periphery of the breast, but at least 1 or 2 cm away from the nipple-areola complex,” Dr. Morrow said. Patients who have cancer “right up into the subareolar space” are not appropriate patients for nipple-sparing mastectomy, she added. ■
DISCLOSURE: Dr. Morrow has received honoraria from Genomic Health and Merck, and has received travel/accommodations/expenses from Genomic Health.
1. Morrow M: Challenges in the surgical management of locoregional recurrence. 2018 Lynn Sage Breast Cancer Symposium. Presented October 12, 2018.
2. Maaskant-Braat AJ, Voogd AC, Roumen RM, et al: Repeat sentinel node biopsy in patients with locally recurrent breast cancer: A systematic review and meta-analysis of the literature. Breast Cancer Res Treat 138:13-20, 2013.
3. Ugras S, Matsen C, Eaton A, et al: Reoperative sentinel lymph node biopsy is feasible for locally recurrent breast cancer, but is it worthwhile? Ann Surg Oncol 23:744-748, 2016.
4. Johnson J, Esserman L, Ewing C, et al: Sentinel lymph node mapping in post-mastectomy chest wall recurrences: Influence on radiation treatment fields and outcome. Ann Surg Oncol 23:715-721, 2016.
5. Maaskant-Braat AJ, Roumen RM, Voogd AC, et al: Sentinel node and recurrent breast cancer (SNARB): Results of a nationwide registration study. Ann Surg Oncol 20:620-626, 2013.
6. Wapnir IL, Price KN, Anderson SJ, et al: Efficacy of chemotherapy for ER-negative and ER-positive isolated locoregional recurrence of breast cancer: Final analysis of the CALOR trial. J Clin Oncol 36:1073-1079, 2018.