Locoregional Treatment of Breast Cancer: Where to Next?

Personalized cancer care is generally thought of as using molecular information from tumors in order to identify which therapeutic agents will be most effective in a given patient. For breast cancer patients, estrogen receptor (ER) status is used to determine who will benefit from hormonal therapy; HER2 overexpression is required to predict benefit from trastuzumab (Herceptin); and Oncotype DX, a multigene assay, helps to clarify which patients with ER-positive, lymph node–negative tumors will benefit from the addition of chemotherapy. The article by Dr. Rizzo and Dr. Wood in this issue of ONCOLOGY reviews advances made in surgical and radiation oncology that allow us to also personalize locoregional treatment for breast cancer patients.

Sentinel Lymph Node Biopsy and the Need for Completion Axillary Lymph Node Dissection

From the late 1800s until the mid-1970s, women diagnosed with breast cancer underwent a Halsted radical mastectomy, in which surgeons removed the breast, pectoralis muscle, and axillary lymph nodes. Today, a significant number of patients undergo breast-conserving therapy (BCT), which involves a segmental resection with clear margins, evaluation of the axillary lymph nodes, and radiation. As Rizzo and Wood describe in detail, patients diagnosed with early stage, clinically node-negative breast cancer undergo sentinel lymph node (SLN) biopsy. SLN biopsy accurately stages the axilla and spares women much of the morbidity associated with a complete axillary lymph node dissection (ALND). If this commentary were written 18 months ago, we would suggest that all women with metastasis identified in their SLN require completion ALND. However, results of the recently published American College of Surgeons Oncology Group (ACOSOG) Z0011 trial demonstrated that appropriately selected patients may be treated without ALND. The trial enrolled patients with clinical T1-T2, N0 invasive breast cancer treated with breast-conserving surgery and one or two positive SLNs identified by hematoxylin-and-eosin staining. Patients were randomized to undergo ALND or no further surgery; all patients were to receive whole-breast irradiation (WBI). The primary endpoint of the trial was overall survival (OS), and at a median follow-up of 6.3 years, 5-year OS was 91.8% with ALND and 92.5% with SLND alone. Locoregional recurrences (LRR) were reported in 3.6% of patients in the ALND group vs 1.8% in the SLND-alone group.[1,2] At The University of Texas MD Anderson Cancer Center, we discussed these data in a multidisciplinary forum, and we now advise the majority of women with clinical T1-T2, N0 tumors with a positive SLN who are undergoing breast-conserving surgery and WBI that they may omit completion ALND with no significant impact on local-regional control or OS.[3]

Neoadjuvant Chemotherapy: Implications for Surgical Management of the Axilla

Use of neoadjuvant chemotherapy has made BCT an option for more patients. As reviewed by Rizzo and Wood, neoadjuvant chemotherapy results in a decrease in tumor size, thereby allowing breast preservation. Although not discussed in the present review, a study published by Hunt et al demonstrated that SLN biopsy was appropriate in patients receiving neoadjuvant chemotherapy who presented with clinically node-negative disease.[4] The study evaluated 575 patients undergoing SLN biopsy after chemotherapy, compared with 3,171 patients who underwent surgery first. SLN identification rates were excellent (97.4% in the neoadjuvant group and 98.7% in the surgery-first group) and false-negative rates were low (5.9% in the neoadjuvant group vs 4.1% in the surgery-first group). When patients were evaluated based on their presenting T stage, there were fewer positive SLNs in the group undergoing neoadjuvant chemotherapy, suggesting that patients with clinical T2 and T3 tumors were more likely to be spared a completion ALND if they received neoadjuvant chemotherapy. Importantly, performing the SLN biopsy after neoadjuvant chemotherapy did not lead to higher LRR rates. Currently SLN biopsy is contraindicated in patients receiving neoadjuvant chemotherapy who present with clinically node-positive disease. The question of whether SLN biopsy may be appropriate in this population is being investigated in the ACOSOG Z1071 trial, a phase II study evaluating the role of SLN biopsy following neoadjuvant chemotherapy in women who present with clinical N1-2 disease. The trial accrued well and was closed to new patient entry in June 2011.

Advances in Radiation Therapy for Patients Undergoing Breast-Conserving Therapy

In addition to performing less surgery, we are also administering less radiation to select breast cancer patients undergoing BCT. As discussed by Rizzo and Wood, there is increasing interest in using accelerated partial breast irradiation (APBI) as an alternative to WBI. APBI can be administered via several modalities, including interstitial brachytherapy, catheter-based intracavitary brachytherapy, or external beam 3-D conformal radiotherapy. Purported benefits of APBI include a decrease in overall treatment time as well as a decrease in the dose of radiation delivered to uninvolved portions of the breast.[5] An important trial investigating APBI is the RTOG 0413/NSABP B-39 study. This is a randomized, phase III study of conventional WBI vs APBI for women with stage 0, I, or II breast cancer, and the primary objective is to determine if APBI provides equivalent local tumor control compared with WBI. The trial began enrolling patients in 2005 and after rapid accrual of the lowest-risk patients (those ≥ 50 years of age with ductal carcinoma in situ and patients with invasive cancer who are ≥ 50 years of age, node-negative, and hormone receptor–positive) the study closed accrual to that population and encouraged enrollment of younger patients with node-positive, hormone receptor–negative disease. It is anticipated that enrollment will be completed in the next 1 to 2 years. Until the data from the RTOG 0413/NSABP B-39 study are available, clinicians are advised to refer to the consensus statement published by the American Society for Radiation Oncology to identify patients considered "suitable," "cautionary," or "unsuitable" for APBI.[5]

The theme of the article by Rizzo and Wood is that "less is more." But is it? Data from the National Cancer Institute of Canada Clinical TGrials Group (NCIC-CTG) MA.20 trial presented at the 2011 meeting of the American Society of Clinical Oncology suggest that this is not true in all cases. The MA.20 trial evaluated the addition of regional nodal irradiation (RNI) to WBI following breast-conserving surgery. Patients with node-positive or high-risk node-negative disease treated with breast-conserving surgery and adjuvant chemotherapy and/or endocrine therapy were randomized to WBI or WBI plus RNI to the internal mammary, supraclavicular, and high axillary lymph nodes. All node-positive patients underwent an ALND. The study enrolled more than 1,800 patients, and after a median follow-up of 62 months, investigators reported that the addition of RNI was associated with an improvement in local-regional disease-free survival (DFS) (HR = 0.59, P = .02, 5-year risk: 96.8% for WBI plus RNI vs 94.5% for WBI alone) as well as distant DFS (HR = 0.64, P = .002, 5-year risk: 92.4% for WBI plus RNI vs 87.0% for WBI alone). They also demonstrated a trend towards improvement in OS for those receiving RNI (HR = 0.76, P = .07, 5-year risk: 92.3% for WBI plus RNI vs 90.7% for WBI alone).[6] The study was randomized and there does not appear to be an imbalance between the two arms that could explain the findings. Perhaps the most striking finding in the MA.20 study was that addition of RNI lowered the absolute risk of a distant metastatic event within 5 years of diagnosis, from 13% down to 7.7%, indicating that 41% of all distant metastatic events in this patient population can be prevented by RNI. Unexpectedly, the 5.4% absolute improvement in risk of distant metastases associated with RNI actually exceeded the improvement in risk of local-regional recurrence. We would suggest that this difference may speak to the importance of tumor biology.

Future Directions for the Locoregional Management of Breast Cancer

So where do we go from here? Some may be frustrated with these emerging data suggesting that the results of the Z0011 and MA.20 are in conflict. We would point out that the patient populations enrolled in the two trials are different, with patients in the Z0011 trial having more favorable tumor characteristics and likely lower volumes of axillary disease. Both trials suggest, however, that patients benefit-sometimes less, sometimes more-from appropriately selected local-regional treatment strategies. The challenge that remains is to identify what each patient needs, in order to personalize the local-regional care received. Arriving at the answer is likely to be more complicated than knowing routine clinicopathologic data that are currently collected, including ER status, the number of involved nodes, or the size of the metastatic tumor. To improve local-regional treatments, we need to identify molecular markers in both the primary tumor and any metastatic nodes that predict for aggressive biology translating into distant recurrences and, ultimately, death from disease. This was evaluated to some degree by Mamounas et al, who identified an association between Oncotype DX recurrence scores and the risk of local-regional recurrence in node-negative, ER-positive patients who had enrolled in the NSABP B-14 and B-20 trials.[7] As an example, they identified a high-risk subgroup (< 50 years of age with high recurrence score) who may benefit from RNI after segmental mastectomy or chest wall irradiation/RNI after mastectomy. While the study was limited in that it did not account for more current adjuvant systemic therapy regimens, it was hypothesis-generating. The hypothesis would be that determination of molecular characteristics of the primary tumor and metastatic foci can be used to guide local-regional therapy decisions. The time has come for this hypothesis to be tested in a well-conducted clinical trial.

Financial Disclosure:The authors have no significant financial interest or other relationship with the manufacturers of any products or providers of any service mentioned in this article.

References:

References

1. Giuliano AE, Hunt KK, Ballman KV, et al. Axillary dissection vs no axillary dissection in women with invasive breast cancer and sentinel node metastasis: a randomized clinical trial. JAMA. 2011;305:569-75.

2. Giuliano AE, McCall L, Beitsch P, et al. Locoregional recurrence after sentinel lymph node dissection with or without axillary dissection in patients with sentinel lymph node metastases: the American College of Surgeons Oncology Group Z0011 randomized trial. Ann Surg. 2010;252:426-32.

3. Caudle AS, Hunt KK, Kuerer HM, et al. Multidisciplinary considerations in the implementation of the findings from the American College of Surgeons Oncology Group (ACOSOG) Z0011 study: a practice-changing trial. Ann Surg Oncol. 2011 Feb 15 (Epub ahead of print).

4. Hunt KK, Yi M, Mittendorf EA, et al. Sentinel lymph node surgery after neoadjuvant chemotherapy is accurate and reduces the need for axillary dissection in breast cancer patients. Ann Surg. 2009;250:558-66.

5. Smith BD, Arthur DW, Buchholz TA, et al. Accelerated partial breast irradiation consensus statement from the American Society for Radiation Oncology (ASTRO). Int J Radiat Oncol Biol Phys. 2009;74:987-1001.

6. Whelan TJ, Olivotto IA, Ackerman I, et al. NCIC-CTG MA.20: an intergroup trial of regional nodal irradiation in early breast cancer (abstract). J Clin Oncol. 2011;29(suppl):LBA1003.

7. Mamounas EP, Tang G, Fisher B, et al. Association between the 21-gene recurrence score assay and risk of locoregional recurrence in node-negative estrogen receptor-positive breast cancer: results from NSABP B-14 and NSABP B-20. J Clin Oncol. 2010;28:1677-83.