Should Response to Preoperative Therapy Guide Local Management in Node-Positive Breast Cancer?

The last decade has seen a dramatic increase in the use of neoadjuvant systemic therapy in the management of breast cancer; over this period, our understanding of its potential benefits has shifted. The initial rationale for neoadjuvant therapy-to address micrometastatic disease early in the management course-has not proven fruitful, with randomized studies demonstrating no survival differences based on chemotherapy sequencing.[1,2] The neoadjuvant approach was typically reserved, therefore, for those with locally advanced disease, with the aim of converting inoperable disease to operable, or for patients who would otherwise be candidates for mastectomy but desired breast conservation. In addition, the preoperative approach serves as a platform for novel drug development, with pathologic complete response (pCR) serving as a surrogate for clinical outcomes. Moreover, because pCR has been observed to correlate with lower risk of locoregional recurrence (LRR),[3] pCR also has the potential to influence adjuvant radiation treatment, including decisions regarding omitting radiation or reducing the radiation target volume in selected cases.

The review article by Chapman and Jagsi expertly summarizes the evidence supporting use of postmastectomy radiotherapy (PMRT) in patients with node-positive breast cancer.[4] It describes the data, albeit limited, regarding the impact of neoadjuvant therapy on outcomes and patient selection for PMRT, including data supporting the omission of PMRT in selected patients with pCR.[4] Several issues raised in this review merit special attention.

The large National Surgical Adjuvant Breast and Bowel Project (NSABP) studies B-18 and B-27, designed to evaluate the impact of chemotherapy sequencing on survival outcomes, have also demonstrated that response to neoadjuvant chemotherapy is predictive of LRR.[1] However, as discussed in Chapman and Jagsi’s review, this relationship differs with breast cancer subtype. There is considerable variation in the response to chemotherapy, with rates of pCR lower than 10% in patients with estrogen receptor (ER)/progesterone receptor(PR)-positive, human epidermal growth factor 2 (HER2)-negative disease and as high as 60% in those with triple-negative or HER2-positive disease.[5-7] In those subtypes with a high rate of pCR, achieving this endpoint is highly correlated with locoregional outcomes. The Collaborative Trials in Neoadjuvant Breast Cancer (CTNeoBC) analysis described in the review demonstrates this well, with an LRR rate after mastectomy of 6.2% for patients with triple-negative disease and pCR, compared with 22.1% in patients with triple-negative disease without pCR.[8] However, those subtypes that generally have a lower rate of response to neoadjuvant therapy-the ER/PR-positive and HER2-negative tumors-also have lower rates of LRR with or without pCR. Recent data from the Memorial Sloan Kettering Cancer Center similarly showed a risk of LRR of 26% in patients with triple-negative disease without a pCR but a rate of only 4% in those with hormone receptor–positive disease without pCR.[7] In addition, disease-free survival after LRR is higher in patients with ER-positive disease than in those with triple-negative disease.[9] Thus, lack of response to therapy may not be an equally strong predictor of outcomes in all patients. Moreover, the use of pCR to tailor PMRT decisions in ER/PR-positive disease may lead to its overuse in these lower-risk patients.

Another important issue is how the timing and extent of nodal surgery should impact treatment decisions. The practice of upfront sentinel lymph node biopsy (SLNB) prior to neoadjuvant treatment has the advantage of providing accurate pathologic nodal assessment for staging at diagnosis but precludes the ability to assess nodal response to treatment and subsequent tailoring of treatment on this basis. Ultrasound-guided biopsy of abnormal axillary nodes has a lower sensitivity than SLNB but still detects involved lymph nodes in over 50% of cases; this is an alternative approach to axillary staging before neoadjuvant chemotherapy.[10] This approach allows SLNB after chemotherapy, with the benefit of assessing response to treatment and avoiding axillary dissection in those who become node-negative.[11] Increasing evidence suggests that when both dye and radiotracer are used and two or more sentinel nodes are identified, the false-negative rate of SLNB after neoadjuvant chemotherapy for patients who initially had node-positive disease is similar to that of upfront SLNB.[12] It is likely that accurate staging postchemotherapy is a more meaningful predictor of LRR than accurate staging prechemotherapy. Ideally, a limited axillary assessment postchemotherapy will provide accurate information and at the same time minimize treatment morbidity and allow for tailoring of adjuvant radiation decisions.

In light of the increased use of both neoadjuvant therapy and mastectomy in breast cancer patients, the ability to appropriately select patients for PMRT after neoadjuvant treatment is increasingly important and poses one of the greatest challenges in breast radiation oncology at this time. The ongoing studies described in the review article, NSABP B-51/Radiation Therapy Oncology Group 1304 and Alliance 011202, are well designed to answer many of the important questions, but, as Chapman and Jagsi point out, questions will remain unanswered regarding the optimal extent of nodal radiation. There may also be insufficient power to fully understand the impact of subtype on outcomes. Future study is needed to determine whether molecular markers or other measures of response, beyond pCR, can be used to tailor treatment decisions, especially for patients with subtypes less likely to develop pCR. In addition, trials evaluating escalation of therapy in patients with residual triple-negative disease are needed.

Current data challenge the statement that recommendations for PMRT should be based on the highest clinical or pathologic stage. Instead, data suggest that in a majority of patients, the pathologic stage after neoadjuvant chemotherapy carries more prognostic value. Over-radiation remains a substantial problem in management of patients after mastectomy. Although a meta-analysis demonstrated a survival advantage with PMRT even in patients with one positive lymph node,[13] more recent studies demonstrate substantially lower rates of LRR,[12] probably related to the beneficial impact of modern systemic therapy. Response to systemic therapy may prove to be a powerful tool for selecting patients with node-positive disease at diagnosis who can ultimately avoid radiotherapy. The ongoing cooperative group studies are poised to provide further support for the tailoring of adjuvant radiation decisions based on response to treatment rather than solely on the upfront clinical stage. Ultimately, the ability to limit local therapy in node-positive patients may be one of the greatest advantages of preoperative treatment.

Financial Disclosure: The authors have no significant financial interest in or other relationship with the manufacturer of any product or provider of any service mentioned in this article.

References:

1. Rastogi P, Anderson SJ, Bear HD, et al. Preoperative chemotherapy: updates of National Surgical Adjuvant Breast and Bowel Project protocols B-18 and B-27. J Clin Oncol. 2008;26:778-85.

2. Wolmark N, Wang J, Mamounas E, et al. Preoperative chemotherapy in patients with operable breast cancer: nine-year results from National Surgical Adjuvant Breast and Bowel Project B-18. J Natl Cancer Inst Monogr. 2001;30:96-102.

3. Mamounas EP, Anderson SJ, Dignam JJ, et al. Predictors of locoregional recurrence after neoadjuvant chemotherapy: results from combined analysis of National Surgical Adjuvant Breast and Bowel Project B-18 and B-27. J Clin Oncol. 2012;30:3960-6.

4. Chapman CH, Jagsi R. Postmastectomy radiotherapy after neoadjuvant chemotherapy: a review of the evidence. Oncology (Williston Park). 2015;29:657-66.

5. Gianni L, Pienkowski T, Im YH, et al. Efficacy and safety of neoadjuvant pertuzumab and trastuzumab in women with locally advanced, inflammatory, or early HER2-positive breast cancer (NeoSphere): a randomised multicentre, open-label, phase 2 trial. Lancet Oncol. 2012;13:25-32.

6. von Minckwitz G, Untch M, Blohmer JU, et al. Definition and impact of pathologic complete response on prognosis after neoadjuvant chemotherapy in various intrinsic breast cancer subtypes. J Clin Oncol. 2012;30:1796-804.

7. Yang TJ, Morrow M, Modi S, et al. The effect of molecular subtype and residual disease on locoregional recurrence in breast cancer patients treated with neoadjuvant chemotherapy and postmastectomy radiation. Ann Surg Oncol. 2015 July 1. [Epub ahead of print]

8. Mamounas EP, Cortazar P, Zhang L, et al. Locoregional recurrence (LRR) after neoadjuvant chemotherapy (NAC): pooled-analysis results from the Collaborative Trials in Neoadjuvant Breast Cancer (CTNeoBC). J Clin Oncol. 2014;32(suppl 26):abstr 61.

9. Braunstein LZ, Niemierko A, Shenouda MN, et al. Outcome following local-regional recurrence in women with early-stage breast cancer: impact of biologic subtype. Breast J. 2015;21:161-7.

10. Feng Y, Huang R, He Y, et al. Efficacy of physical examination, ultrasound, and ultrasound combined with fine-needle aspiration for axilla staging of primary breast cancer. Breast Cancer Res Treat. 2015;149:761-5.

11. Mamounas EP. Impact of neoadjuvant chemotherapy on locoregional surgical treatment of breast cancer. Ann Surg Oncol. 2015;22:1425-33.

12. Boughey JC, Suman VJ, Mittendorf EA, et al. Factors affecting sentinel lymph node identification rate after neoadjuvant chemotherapy for breast cancer patients enrolled in ACOSOG Z1071 (Alliance). Ann Surg. 2015;261:547-52.

13. McGale P, Taylor C, Correa C, et al. Effect of radiotherapy after mastectomy and axillary surgery on 10-year recurrence and 20-year breast cancer mortality: meta-analysis of individual patient data for 8135 women in 22 randomised trials. Lancet. 2014;383:2127-35.