MIAMI BEACH—Historically, patients with breast cancer found to have metastatic disease identified in their lymph nodes routinely underwent axillary lymph node dissection (ALND), but recent studies suggest that patients with low-volume nodal disease may not require that. Speaking here at the Miami Breast Cancer Conference, Elizabeth A. Mittendorf, MD, PhD, Associate Professor and Deputy Chair for Research in the Department of Surgical Oncology at the University of Texas MD Anderson Cancer Center, reviewed the current research.
“Patients may benefit from axillary radiation, or perhaps do well without specific axillary therapy,” she said in her presentation, “Management Strategies in Clinical N1 Disease.” She focused her talk only on hormone receptor-positive patients, and purposely did not include patients who present with bulky or significantly palpable adenopathy.
Case: T2N1 HER2+ Breast Cancer
Mittendorf said patients with breast cancer at MD Anderson routinely undergo ultrasound examination, and a suspicious-appearing lymph node suggests the need for either a fine needle aspiration biopsy (FNAB) or core biopsy. A positive biopsy then leads to a clinical N1 designation.
She presented the case of a 61-year-old postmenopausal woman with a palpable mass of just over two centimeters, also seen on mammogram and ultrasound. Ultrasound also demonstrated two suspicious lymph nodes, subjected to an FNA biopsy, which confirmed grade 2 invasive ductile carcinoma, richly ER-positive, HER2-neu-negative, classified as clinical T2N1 breast cancer.
“This patient was desirous of breast preservation, and as her surgical oncologist, I thought she was a marginal candidate due to her fairly small breast size. So we had a lengthy conversation and discussed these options: a total mastectomy with an axillary resection; lumpectomy with neoplastic considerations; neoadjuvant chemotherapy; and perhaps neo-adjuvant endocrine therapy.
Mittendorf said some surgeons might have suggested a lumpectomy with sentinel lymph node biopsy—“because if the ultrasound hadn't been done this patient would have been Z0011 criteria.”
Mittendorf cited a study last year on predicting the extent of nodal disease from her institution (Caudle et al: Ann Surg Oncol 2014;11:3440-3447) that looked at patients with clinical T1-T2 tumors. There were 190 patients who had metastases detected by ultrasound and FNA, and 518 who had it detected by sentinel lymph node biopsy.
“I would point out that those who had ultrasound-detected disease were more likely to have a greater number of positive nodes, larger metastases, and extranodal extensions, suggesting that ultrasound-detected metastases may in fact be slightly worse than the sentinel node detected metastases.”
Back to the case, Mittendorf said the first two options proposed, a total mastectomy with an axillary lymph node dissection or lumpectomy with oncoplastic tissue rearrangement and ALND, each have pros and cons. The cons for upfront surgery include the likelihood of mastectomy—and this patient wanted breast reconstruction—as well as the likelihood of ALND.
On the pro side, upfront surgery would allow the surgeon to determine the true extent pathologically of the disease, which would have potential implications for radiation oncologists. Also, with upfront surgery the patient could participate in the RxPONDER (Rx for Positive-Node, Endocrine-Responsive Breast Cancer) trial.
“Most guidelines would tell you that the node-positive patient requires chemotherapy, but I think a lot of us would question whether chemotherapy really is needed in a patient who's postmenopausal, with a richly ER-positive tumor, with low-volume nodal disease. And that is what the RxPONDER trial is designed to answer.”
Mittendorf said the rationale for RxPONDER is from a paper that looked at the SWOG 8814 trial of postmenopausal, ER-positive, lymph node-positive patients (Albain et al: Lancet Oncol 2010;1:55-65). One arm of the trial had tamoxifen alone, the others had chemotherapy—cyclophosphamide, doxorubicin, and fluorouracil (CAF)—or chemotherapy plus tamoxifen.
The study showed that a 21-gene recurrence score could stratify patients receiving tamoxifen alone with respect to disease-free and overall survival.
This suggested that the recurrence score may have utility in patients with node-positive disease, Mittendorf said.
The RxPONDER trial is designed to answer that question, she said. It is enrolling node-positive, hormone receptor-positive patients who have a recurrence score of 25 or less, randomizing them to chemotherapy plus endocrine therapy, or to endocrine therapy alone.
What about neoadjuvant chemotherapy for her patient, Mittendorf posed. The con here is whether this ER-positive patient even needs chemotherapy. The pro is that it may decrease the size of the tumor, facilitating breast preservation, which the patient wants.
There are some data questioning the benefit of chemotherapy in addition to endocrine therapy in women over age 60, Mittendorf said, citing a 2004 paper by Bernard Fisher et al (Lancet 2004;364:858-868). “We know that neoadjuvant chemotherapy does not offer any benefit with respect to overall and disease-free survival,” she said. “It does, of course, facilitate breast preservation, which is important to this patient.”
But the response to therapy is not the same across subtypes, she added, and in fact hormone receptor-positive tumors may be less responsive than some of the other subtypes.
“My patient asked me, if she were to get the neoadjuvant chemotherapy, could we limit the extent of her axillary surgery?” Mittendorf said.
That question has been addressed in three recent studies. These were similar in that patients with clinically node-positive disease received neoadjuvant therapy and then underwent sentinel lymph node dissection, followed by axillary dissection, which allowed the researchers to determine the false-negative rate.
The first, ACOSOG Z1071 (JAMA 2013;14:1455-1461) reported a false-negative rate of 12.6 percent. That was quite similar to the 14.2 percent from the comparable population in the SENTINA trial (Lancet Oncol 2013; 7:609-618), and the 13.3 percent in the SN-FNAC trial (JCO 2015;3:258-63).
All of these false-negative rates were determined from sentinel nodes that were evaluated by hematoxylin and eosin stain, she said.
Reduce False Negatives
“If you look a little deeper at the data from these three studies, there are methods that could be employed to decrease that false-negative rate,” Mittendorf said. “One is to use dual tracers, both technetium and blue dye, and another is to ensure removal of an adequate number of sentinel nodes. A third is to ensure removal of the clipped biopsy-proven positive node, and a fourth is to use immunohistochemistry (IHC) for pathologic analysis.”
The ACOSOG Z1071 study had an overall false-negative rate of 12.6 percent, but a follow-up to that study reported at last year's San Antonio Breast Cancer Symposium (Boughey et al: Abstract P2-01-02) showed that:
- Using dual tracers reduced the false-negative rate to 10.8 percent;
- If three or more sentinel lymph nodes were identified and removed, the false-negative rate was 9.1 percent;
- Removing the clipped node reduced the rate to 6.8 percent; and
- Analysis by IHC reduced the rate to 8.7 percent.
‘Targeted Axillary Dissection’
“When we talked about incorporating the Z1071 data into our practice at MD Anderson, we decided on a concept we're referring to as targeted axillary dissection,” Mittendorf said. “We routinely perform a regional nodal ultrasound evaluation on our newly diagnosed patients, and we have the ability to do immediate pathologic evaluation.
“When that suggests a positive disease, a clip is placed into that lymph node. Once the patient completes their neoadjuvant chemotherapy we will perform a sentinel lymph node dissection. And we plant a radioactive seed into that lymph node so we can ensure its removal.”
Early data (presented by Abigail Caudel in March at the Society of Surgical Oncology Annual Cancer Symposium) looking at the first 103 patients showed a very interesting concordance rate. “In about 76 percent of cases the clipped node is a sentinel node—which means, of course, that in the remaining cases it was not a sentinel node,” Mittendorf said.
The practice at MD Anderson has largely been to do an axillary dissection in these patients to determine the false-negative rate of this targeted axillary dissection approach, she said. Following this protocol, data from 90 patients show that 55 (60%) had residual disease.
Looking just at the sentinel lymph node, the false-negative rate is 9.6 percent. But looking at the biology of the sentinel node as well as the clipped node, the false-negative rate is less than two percent. “We're very excited about further exploring targeted axillary dissection for these patients,” she said.
With respect to Mittendorf's patient, she advised her that the standard of practice is to do an axillary dissection—“but if she were to receive the adjuvant chemotherapy, I encouraged her to go on the Alliance A11202 trial.” That trial is being conducted to determine whether axillary radiation alone is not inferior to lymph node dissection plus radiation for patients who remain node-positive pathologically after their neoadjuvant chemotherapy.
“I advised my patient that we could enroll her on the study and that then at the time of surgery I would do a sentinel lymph node biopsy. If that sentinel lymph node on intra-operative evaluation was positive, she would remain on the study and we would perform an intra-operative randomization.”
If the patient is randomly assigned to study Arm 1 she would undergo lymph node dissection followed by nodal radiation. On Arm 2 she would have no further axillary surgery, but would get axillary and nodal radiation.
If the patient has a complete pathological response she might be eligible for the NSABP B-51/RTOG 1304 trial, which compares hormonal therapy and radiation therapy versus radiation alone. The trial is designed to evaluate whether the addition of regional nodal radiation will improve disease-free survival rates in patients who convert to being pathologically node-negative.
Neoadjuvant Endocrine Therapy
Addressing the possibility of neoadjuvant endocrine therapy for this patient, Mittendorf reviewed the Z1031 trial, which enrolled 374 postmenopausal patients with clinical stages T2 -T4, N0-N3, ER-positive breast cancer, comparing the use of three different aromatase inhibitors.
“While the primary endpoint was clinical response, the endpoint that was of interest to me as a surgeon was the ability to perform breast-conserving surgery in these patients,” she said.
Breast-conserving surgery was successfully performed in 83 percent of patients considered marginal candidates for breast preservation—Interestingly, for those who were thought to require mastectomy at presentation, we actually were successful at breast preservation in 51 percent.”
This is consistent with data from other studies, mostly in the U.K., she said.
Mittendorf concluded with a recommendation for the ALTERNATE trial of postmenopausal patients with tumors that are two centimeters or larger and palpable. Patients are randomized to receive anastrozole or fulvestrant, or the combination.
“The thing I like about this study, and that my patients have been enthusiastic about, is that it requires a biopsy after four weeks of treatment. At the time of that biopsy, the specimen is assessed for the Ki67 level. If that is greater than 10 percent, I advise the patient that this may be a tumor that is a little more aggressive and they may benefit from chemotherapy. Then they can go into having chemotherapy or directly to surgery. But if the Ki67 is less than 10 percent they then continue on endocrine therapy.
“At the time of surgery, the final pathologic specimen is evaluated with a PEPI score. If the score is zero, then no adjuvant systemic therapy is recommended. If the score is greater than zero, then the adjuvant chemotherapy can be given at the discretion of the treating medical oncologist. I like the ALTERNATE trial, and how it gets to that same question of whether the patient with richly hormone receptor-positive disease even needs chemotherapy.”
Mittendorf said that after careful consideration, her 61-year-old postmenopausal female patient with clinically T2N1 ER-positive cancer did enroll in the ALTERNATE trial. Her four-week biopsy showed that her Ki67 level dropped to four percent, and on physical examination she has had a good response with decrease of her tumor size.
“And in about two weeks I'll be taking her to the operating room for a lumpectomy with an axillary lymph node dissection,” Mittendorf said.