Neoadjuvant Therapy for Early-Stage Breast Cancer: A Model for Individualizing Outcomes and Tailoring Locoregional and Systemic Therapy

November 15, 2015

The biologic rationale for the initial evaluation of preoperative chemotherapy or neoadjuvant chemotherapy in patients with early-stage breast cancer was based on experimental and clinical observations regarding primary tumor cell growth and dissemination.

The biologic rationale for the initial evaluation of preoperative chemotherapy or neoadjuvant chemotherapy in patients with early-stage breast cancer was based on experimental and clinical observations regarding primary tumor cell growth and dissemination.[1-3] Additional clinical justification was provided by the demonstration of equivalent survival among patients who underwent breast-conserving surgery (BCS) rather than mastectomy,[4,5] as well as the demonstration of benefit from adjuvant chemotherapy irrespective of pathologic nodal status.[6] As a result, neoadjuvant chemotherapy was compared against adjuvant chemotherapy in clinical trials, with the intent to convert patients requiring mastectomy into candidates for BCS.

Several large randomized trials, assessing neoadjuvant chemotherapy vs adjuvant chemotherapy in patients with operable breast cancer, showed no significant differences in long-term outcomes and confirmed that neoadjuvant chemotherapy significantly increased rates of BCS.[7-10] They also showed that achievement of pathologic complete response (pCR) in the breast and axillary nodes was significantly correlated with improved long-term outcomes. As a result, pCR can be used as a surrogate endpoint for efficacy of neoadjuvant chemotherapy, one which is currently accepted by the US Food and Drug Administration (FDA) as a pathway toward accelerated approval of new drugs for the treatment of early-stage breast cancer.[11]

Thus, neoadjuvant chemotherapy has become a reasonable alternative to adjuvant chemotherapy for patients with operable breast cancer, and it has several potential clinical advantages in addition to increasing the rates of BCS. By reducing the size of the primary tumor with neoadjuvant chemotherapy, there is potential for improving the cosmetic result of BCS, even for patients who were BCS candidates at presentation. This approach also downstages axillary lymph nodes in a significant proportion of patients-approximately 20% to 30% of those receiving anthracycline-containing regimens,[7,9] close to 40% when treatment includes an anthracycline plus a taxane,[10,12] and in more than 50% of patients with human epidermal growth factor receptor 2 (HER2)-positive breast cancer who receive chemotherapy plus anti-HER2 therapy. This observation has important clinical implications, since patients with involved axillary nodes at presentation can be downstaged with neoadjuvant chemotherapy and converted to candidates for sentinel lymph node biopsy (SLNB) alone, thereby avoiding axillary node dissection if the sentinel lymph nodes (SLNs) are negative.

Another potential advantage of neoadjuvant chemotherapy is that it enables clinicians to evaluate proven and putative biomarkers and correlate them with clinical and pathologic response-and, eventually, outcome.[13] Thus, one could rapidly gain biologic insight into the nature and function of such biomarkers relative to chemosensitivity or chemoresistance,[14,15] which, in turn, can facilitate the selection of appropriate candidates for particular neoadjuvant regimens while avoiding unnecessary toxicity in patients unlikely to benefit.

The article by Dr. Santa-Maria and colleagues in this issue of ONCOLOGY provides a comprehensive and yet extremely succinct review of the evolution and current state of the art of neoadjuvant chemotherapy.[16] It addresses many of the questions regarding locoregional and systemic therapy that are associated with neoadjuvant chemotherapy, and provides useful recommendations for how best to incorporate it into everyday clinical practice. First, as the authors note, the indications for neoadjuvant chemotherapy have expanded to consider not only the extent of the disease but also its biology. Thus, this approach is currently utilized not just for patients with locally advanced/large operable breast cancers who need downstaging, but is also used for those who, based on their tumor subtype, have chemoresponsive disease and an increased probability of pCR (by virtue of their inherent disease biology and the availability of effective therapy). The authors also correctly identify the limitations of neoadjuvant chemotherapy and discuss why it should be avoided in certain patient subgroups (ie, those with low probability of pCR and those for whom the use and appropriate type of chemotherapy are not clear until pathologic nodal status becomes known).

Regarding imaging assessment before neoadjuvant chemotherapy, Dr. Santa-Maria and colleagues emphasize the increased sensitivity of breast magnetic resonance imaging (MRI) in determining the extent of the primary breast tumor, but they also caution that MRI may overestimate tumor size. They recommend that the decision to use MRI be individualized, if BCS is desired. They also describe in detail the clinical and radiologic evaluation of the axilla before neoadjuvant chemotherapy is administered, and its implications for successful application of SLNB after neoadjuvant chemotherapy, particularly for patients with axillary nodal involvement at presentation who become pathologically node-negative after neoadjuvant chemotherapy. The authors appropriately point out the limitations of performing SLNB before treatment with neoadjuvant chemotherapy in patients with clinically negative axilla, correctly concluding that the ideal approach for such patients is to perform the SLNB after patients have received neoadjuvant chemotherapy.

The importance of a multidisciplinary approach for neoadjuvant chemotherapy candidates is discussed in detail. Such an approach is paramount for successful outcomes. Ideally, it should go beyond the initial involvement of surgical, medical, and radiation oncologists to include the multidisciplinary tumor board, pathologists, radiologists, plastic surgeons, genetic counselors, and clinical research personnel, since all of these specialists have important contributions to make to the patient’s plan of care from the beginning.

The article provides a thoughtful review of systemic therapy considerations for neoadjuvant chemotherapy. As the authors point out, this approach provides little benefit to patients with hormone-responsive breast cancer and favorable histology, who generally have very low pCR rates. On the opposite end of the spectrum, the authors discuss and critique both the evolving success of neoadjuvant chemotherapy plus anti-HER2 therapy in HER2-positive breast cancer, and the correlation between increases in pCR rates with more active neoadjuvant chemotherapy regimens and improvements in outcomes observed in adjuvant/neoadjuvant trials. Similarly, they review in depth several recent studies showing that increased pCR rates for patients with triple-negative breast cancer can be achieved when neoadjuvant chemotherapy is supplemented with bevacizumab, platinum salts, and poly (ADP-ribose) polymerase (PARP) inhibitors. In addition, Dr. Santa-Maria and colleagues emphasize the clinical research advantages of evaluating new agents in patients who have residual disease after neoadjuvant chemotherapy. This is a desirable setting, since treatment is targeted only to high-risk patients with tumors proven resistant to existing therapies; therefore, use of new experimental therapies is justified. Given the high event rate, smaller trials and shorter follow-up are required for success, and prognostic profiling data can be obtained from cells that are resistant to prior neoadjuvant chemotherapy.

Dr. Santa-Maria and colleagues provide a thoughtful discussion of surgical issues with respect to the breast and axilla following neoadjuvant chemotherapy, and the evolving integration of locoregional radiation therapy (RT) in the neoadjuvant setting. They review the performance of SLNB for patients who present with clinically negative axilla and those who present with documented axillary nodal involvement. They conclude that SLNB after neoadjuvant therapy is feasible for patients with initial node-positive disease, provided that: (1) more than two SLNs are removed, (2) dual-agent mapping is employed, and (3) SLNB is combined with localization and retrieval of biopsy-proven positive lymph nodes that were marked with a clip at initial core needle biopsy or fine-needle aspiration biopsy.

Lastly, regarding the use of post-mastectomy RT and regional nodal RT after neoadjuvant chemotherapy, the authors recognize the controversy, particularly for patients who present with axillary nodal involvement and achieve pCR in the nodes following such treatment. Studies evaluating risk of locoregional recurrence after neoadjuvant chemotherapy have consistently shown lower risk for patients who achieve pCR, compared with those who do not.[17,18] The authors describe the ongoing randomized phase III trial by the National Surgical Adjuvant Breast and Bowel Project (NSABP) and the Radiation Therapy Oncology Group (RTOG), NSABP B-51/RTOG 1304, which addresses the role of post-mastectomy and regional nodal RT in patients with positive axillary nodes before neoadjuvant chemotherapy who convert to pathologically negative axillary nodes afterwards. This study will help us to determine which patients can safely avoid post-mastectomy and/or regional nodal RT in the setting of nodal pCR.[19]

In summary, Dr. Santa-Maria and colleagues should be commended for their well-written and timely review of the current practice of neoadjuvant chemotherapy in early-stage breast cancer, as well as controversies and future directions in this setting. Although several such reviews exist, the authors’ approach is informative and comprehensive, and their article addresses all major issues on the topic, while being clear and concise.

Financial Disclosure:Dr. Mamounas has served on the advisory boards of Celgene, Genomic Health, Novartis, and Pfizer, and he currently serves on the speakers bureaus of Genentech/Roche and Genomic Health.

References:

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14. Pusztai L, Ayers M, Simman FW, et al. Emerging science: prospective validation of gene expression profiling-based prediction of complete pathologic response to neoadjuvant paclitaxel/FAC chemotherapy in breast cancer. Proc Am Soc Clin Oncol. 2003;22:abstr 1.

15. Paik S, Shak S, Tang G, et al. Multi-gene RT-PCR assay for predicting recurrence in node negative breast cancer patients - NSABP studies B-20 and B-14. Breast Cancer Res Treat. 2003;82(suppl 10):abstr 16.

16. Santa-Maria CA, Camp M, Cimino-Mathews A, et al. Neoadjuvant therapy for early-stage breast cancer: current practice, controversies, and future directions. Oncology (Williston Park). 2015;29:828-38.

17. Buchholz TA, Tucker SL, Masullo L, et al. Predictors of local-regional recurrence after neoadjuvant chemotherapy and mastectomy without radiation. J Clin Oncol. 2002;20:17-23.

18. 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.

19. Mamounas EP, White JR, Bandos H, et al. NSABP B-51/RTOG 1304: randomized phase III clinical trial evaluating the role of postmastectomy chest wall and regional nodal XRT (CWRNRT) and post-lumpectomy RNRT in patients (pts) with documented positive axillary (Ax) nodes before neoadjuvant chemotherapy (NC) who convert to pathologically negative Ax nodes after NC. J Clin Oncol. 2014;32(suppl 5s):abstr TPS1141.