Evaluating the Impact of Neoadjuvant Therapy in Localized Breast Cancer

The effect of neoadjuvant chemotherapy (NAC) on local disease management of breast cancer has a number of clinical implications. First, it can lead to tumor downsizing, reducing the size of the tumor to allow for breast-conserving surgery. Second, it boosts the potential for improved overall survival by achieving pathologic complete response (pCR), and third, it can guide future treatment decisions, such as the use of adjuvant therapy after surgery. These implications were explored by Anna Weiss, MD, during the 42nd Annual CFS, an event sponsored by Physicians’ Education Resource®, LLC (PER®).¹

Several landmark NAC trials were influential in establishing the role of neoadjuvant therapy in breast cancer.^2,3 The National Surgical Adjuvant Breast and Bowel Project (NSABP) Protocol B-18 was initiated in 1988 to determine whether 4 cycles of doxorubicin/cyclophosphamide given preoperatively improved survival and disease-free survival (DFS) compared with the same chemotherapy given postoperatively.² Perioperative chemotherapy was shown to be safe for patients with breast cancer in the phase 3 European Organization for Research and Treatment of Cancer (EORTC) 10994/ BIG1-00 trial.³

“These landmark neoadjuvant clinical trials helped us downsize breast tumors and achieve breast conservation,” Weiss, an associate pro- fessor of surgery and medicine, University of Rochester Medicine, and director of the breast cancer service line at Pluta Breast Center/Wilmot Cancer Institute in Rochester, New York, said during her presentation. “Where neoadjuvant [therapy] shines for these patients is in the larger tumors,” Weiss said (TABLE 1⁴). “It’s helpful when you have a big tumor that you need to get a little bit smaller in order to try for breast conservation,” Weiss added.

The benefit of NAC in locoregional recurrence (LRR) has also been demonstrated, according to Weiss. A meta-analysis by Mieog et al,⁵ evaluated 14 studies that randomly assigned 5500 women to receive neoadjuvant vs adjuvant chemotherapy for early breast cancer. The investigators reported that mastectomy rates had decreased by 16% (95% CI, 15.1%-18.1%) for patients who received NAC, with no differences observed in LRR in patients treated with NAC vs adjuvant chemotherapy; additionally, no differences in LRR were observed between those receiving planned breast-conserving therapy and those downstaged to breast-conserving therapy.⁵

Breast Conservation Eligibility

What tools are used to determine breast conservation eligibility? “I would say that my most useful tool is MRI,” Weiss said. “In this particular scenario, we know that MRI is 71% accurate when assessing neoadjuvant therapy response, the size of the tumor in the breast according to MRI, and the correlation of that with pathology is the most accurate for MRI.”

Yeh et al⁶ carried out a prospective comparison of mammography, sonography, and MRI in patients undergoing neoadjuvant chemotherapy. The investigators evaluated 41 patients with stage IIB to III palpable breast cancer; 31 patients completed the protocol of doxorubicin followed by paclitaxel or vice versa. All patients underwent physical examination, mammography, sonography, and MRI before and after receiving each neoadjuvant drug.

Agreement with the rate of response as measured by clinical examination, mammography, sonography, and MRI was 19%, 26%, 35%, and 71%, respectively, compared with pathology, the gold standard. MRI was determined to agree with the gold standard significantly more often (P < .002 for all 3 paired comparisons with MRI).⁶

Margin Concerns

Weiss noted that, ideally, tumor shrinkage occurs evenly in a unifocal fashion. However, that’s not always the case because the tumor often has a “buckshot pattern of response, as opposed to nice concentric shrinkage,” Weiss said. “This has caused some investigators to ask [whether] pathologic response patterns can explain this radiologic response that we see as surgeons.”

Pastorello et al gave a detailed review of histologic sections of the posttreatment surgical specimens for 665 patients with stage I to III breast cancer treated with NAC followed by surgery.⁷ Among 389 patients with residual invasive cancer in whom the pattern of residual disease could be assessed, 287 (73.8%) had a scattered pattern and 102 (26.2%) had a circumscribed pattern. There was a significant association between tumor subtype and pattern of response. Among patients with hormone receptor–positive, HER2-negative tumors, 89.4% had a scattered pattern and only 10.6% had a circumscribed pattern. In contrast, among those with triple-negative breast cancer, 52.8% had a circumscribed pattern and 47.2% had a scattered pattern (P < .001).⁷

What does this mean to the surgeon?
“If you resect this area and you have clear margins, you may think you've gotten all the cancer, and you actually have not,” Weiss said. “And this is something we worry about at tumor board.”

Investigators in a study that sought to determine the impact of margin width on local recurrence and survival after NAC and breast-conserving therapy evaluated 382 patients with stage I to III breast cancer.⁸

Choi J et al⁸ noted that breast pCR was achieved in 105 (27.5%) of patients. Final margin status was positive in 8 (2.1%) patients, 1 mm or less in 65 (17.0%), 1.1 to 2.0 mm in 30 (7.9%), and greater than 2.0 mm in 174 (45.5%). The 5-year locoregional recurrence-free survival (LRFS) rate was 96.3% (95% CI, 94.0-98.6), DFS was 85.5% (95% CI, 81.8-90.7), and OS was 90.8% (95% CI, 87.4-94.2). There was no difference in LRFS, disease-free survival (DFS), or OS for margins of 2 mm or less vs greater than 2 mm. In addition, no differences in DFS or OS for margins 1 mm or less vs greater than 1 mm were reported.

Another study found similar results. Of 582 patients, 88% of patients had margins greater than 2 mm, and 12% had margins of 2 mm or less.⁹ The majority of tumors were HER2-positive (38%) or triple negative (31%). Investigators reported that pCR was observed in 29% of patients.

NAC and Lymph Node Disease

The benefits of using NAC to eradicate nodal disease have been documented by a number of investigators.¹⁰

Mamtani A et al¹⁰ showed that of 288 node-positive patients, 70% were candidates for sentinel lymph node biopsy (SLNB) after receiving NAC. For 48%, axillary lymph node dissection was avoided, which sup- ports the role of NAC.

In the study, 534 patients with stage II and III cancer receiving NAC were identified.¹⁰

Among the patients with node-positive disease (n = 288), 132 (68%) were eligible for SLNB. Of those, 73 (55%) had estrogen receptor (ER)–positive disease; 21 (16%) had ER-negative, HER2-positive disease; and 38 (29%) had triple-negative disease. In 4 cases, SLNB was deferred intraoperatively.

“Patients who are ER-positive, HER2-negative have a lower pCR in the nodes, in a similar fashion as in the breast,” Weiss said (TABLE 2¹⁰).

What Effect Does NAC Have on SLNB?

Results of several studies have suggested identification rates that range from 80.1% to 92.9%, with a corresponding false negative rate that ranges from 9.6% to 15.0%.^11-13

“Even the study NSABP B-27,11 conducted in 2005, had a group of surgeons that each performed at least 1 sentinel node followed by axillary dissection in a patient, and they had an 85% sentinel node identification rate and a false-negative rate of 10.7%,” Weiss said.

Further prospective studies evaluated patients who had received NAC followed by SLNB and axillary dissection. In those studies, false-negative rates were higher than 10%. “At that point, we asked, ‘Could a surgeon reduce the false-negative rate?’” Weiss said. There were a number of technical factors, including the mapping agent, number of lymph nodes obtained, pathologic evaluation, and localization/ identification of the clipped node. “All of these are technical factors that could reduce the false-negative rate,” Weiss said.

Notably, the trials looking at clipping the lymph node garnered further attention. Clipping and ensuring the lymph node is removed with SLNB provides the lowest false-negative rate, results showed.^14-16

Future for Patients With cN0 and cN1 Disease

Nodal pCR rates can be very high. One of the biggest predictors of nodal pCR rate, aside from clinical nodal status, is breast pathologic response. Weiss et al¹⁷ showed that 96% or more of patients with cN0 disease and who experienced breast pCR had nodal pCR as well.

Two studies explored this further. The EUBreast-01 study evaluated 267 patients who had a radiologic CR and underwent a lumpectomy.¹⁸

If the patient had a breast pCR, they were followed, but if residual disease was found, they underwent an SLNB.

The ASICS trial (NL-OMON48085) in the Netherlands evaluated 340 patients. If the patient has a breast MRI that shows radio- logic CR, they undergo a lumpectomy, and not doing SLNB.¹⁹

“That’s going a little bit further, but it’s interesting, nonetheless,” Weiss said.

In patients with cN1 disease, the challenges with NAC and residual disease are the volume of nodes that are positive and the patient’s response or lack of response to therapy. “I think the concern is that there is probably a high volume of disease present,” Weiss said. “These are higher-stage, aggressive tumors. Usually, we give patients NAC, and if there is residual disease, it means that the disease has not responded to therapy. It also indicates that there might be a lot more nodes that are positive. I think we need to do an axillary dissection for cN1 node-positive patients after NAC.”

Weiss concluded, “Surgical de-escalation is made possible by neoadjuvant therapy. Breast conservation does not rely on a breast pCR, but [you should] consider the pattern of response [when reviewing margins]. Axillary nodal PCR rates are high, and many patients can avoid an axillary dissection, and even more will be able to avoid it in the future, but for now, these [patients] should have a dissection.

REFERENCES

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