Historically, neoadjuvant systemic therapy (NST) has been mainly used to convert breast cancer from inoperable to operable; however, today NST also is incorporated into the treatment of patients who initially present with operable disease. NST can allow some patients with stage II-III breast cancer who initially present with disease extent necessitating mastectomy to possibly undergo breast-conserving therapy (BCT) by down-staging the volume of disease in the breast. This neoadjuvant approach is particularly useful in patients where systemic therapy is clearly indicated, such as triple-negative breast cancer (TNBC) and Human Epidermal Growth Factor Receptor (HER) 2-positive disease.1-4
Study on effect of NST
Although NST has been studied extensively, comprehensive data on the impact of NST on converting BCT-ineligible patients to BCT-eligible is lacking. To quantify this conversion rate, a prospective surgical study was incorporated into Cancer and Leukemia Group B 40603 (CALGB, now a part of the Alliance for Clinical Trials in Oncology), a randomized phase II-III trial that tested the addition of carboplatin and bevacizumab to a standard neoadjuvant regimen (paclitaxel followed by doxorubicin and cyclophosphamide) in TNBC. The primary clinical endpoint was pathological complete response (pCR), defined as the absence of residual invasive disease in the breast, and the primary surgical endpoint was breast preservation rates.5,6
Specifically, this study required that the treating breast surgeon assess and document the patients’ eligibility for BCT based on physical exam, native breast size, and breast imaging studies both at initial presentation before the start of NST and after the completion of drug therapy. The surgeon also was asked to document the reason for non-candidacy for breast conservation at both time points.
A total of 404 TNBC patients, treated from 2009 to 2012, had pre- and post-NST surgical assessments and surgical procedure outcomes. Before NST, 219 (54 percent) patients were considered eligible for BCT; of these patients, 197 (90 percent) remained eligible, with BCT attempted in 138 (70 percent) and successful in 130 (94 percent). Of the 185 (46 percent) patients who were considered ineligible for BCT pre-NST, 78 (42 percent) were considered eligible for BCT after treatment. Of these, BCT was attempted in 53 (68 percent) and was successful in 48 (91 percent).
Overall, there was a significant increase in the incidence of surgeon-determined BCT eligibility from 54 percent before NST to 68 percent after NST (p < 0.001). BCT was attempted in 69 percent of eligible patients and was successful in 93 percent. Final surgical management was BCT in 191 (47 percent) patients and mastectomy in 213 (53 percent) patients, including 13 patients in whom BCT was unsuccessful. The rate of pCR did not differ significantly according to breast conservation candidacy.
By including this prospective surgical sub-study in this large, randomized NST trial, we identified that a substantial number of patients with TNBC deemed ineligible for BCT at presentation by the treating surgeon could be successfully converted to BCT-eligible (42 percent) with NST. For those patients who attempted BCT, the likelihood of success was 93 percent. Before NST, the breast surgeon and/or radiologic factors most commonly cited as the reasons a patient was BCT-ineligible were a tumor being deemed too large and/or concern of a probable poor cosmetic outcome. However, because most TNBC downsize with NST, multi-centricity became the predominant factor for non-candidacy after NST.
Our 47 percent BCT rate needs to be viewed in the context of three other large trials on NST: Neo-ALTTO, women with HER2-positive disease, 44 percent BCT rate; CALGB 40601, women with HER2-positive disease, 48 percent BCT rate; and GeparSixto, women with HER2-positive disease and TNBC, nearly 75 percent BCT rate.7-10
Despite the high rate of BCT in the GeparSixto trial, the addition of carboplatin, which increased the pCR, did not lead to an increase in BCT in that arm of the trial. Intuitively, higher pCR rates should lead to higher BCT rates, but, interestingly, this outcome has not always been observed in modern trials. In an era when drug therapies have produced remarkably high pCR rates for TNBC, it is surprising that BCT rates are lower than in the past when drug therapy was less robust and pCR rates were much lower.
In CALGB 40603, many BCT-eligible patients, regardless of whether they were always candidates for BCT or converted to BCT candidates with NST, ultimately did not seek breast conservation. Instead, they opted for mastectomy regardless of the clinicoradiographic response to NST. Patient and surgeon perceptions (whether accurate or not) about an in-breast recurrence or development of a secondary primary breast cancer or concern regarding radiation, with or without identification of a deleterious germline BRCA mutation, likely played some role in these decisions.11-13
Suggestions for the future
Breast surgical oncologists need to appropriately convey to patients the risks of locoregional recurrence or second primary cancers and discuss likely cosmetic outcomes so patients can make informed decisions regarding local therapy. In addition, breast imaging needs to improve to accurately determine treatment response to NST so that interested patients can be offered BCT, if appropriate.
Despite NST successfully converting 42 percent of patients from BCT-ineligible to BCT-eligible and overall high rates of pCR, most NST patients still underwent mastectomy—many without even attempting BCT. Future NST trials should be prospectively designed to address patient, surgeon, and radiologic-specific factors that may influence offering and/or successful completion of BCT.14
If the main proven benefit of NST is to increase BCT rates, our results are disappointing and warrant an effort among surgical oncologists and medical oncologists to encourage decision making based on modern-day response to therapy.
- Barry PA, Schiavon G. Primary systemic treatment in the management of operable breast cancer: Best surgical approach for diagnosis, biological evaluation, and research. J Natl Cancer Inst Monogr. 2015;51:4-8.
- Mauri D, Pavlidis N, Ioannidis JP. Neoadjuvant versus adjuvant systemic treatment in breast cancer: A meta-analysis. J Natl Cancer Inst. 2005;97(3):188-194.
- 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(5):778-785.
- van der Hage JA, van de Velde CJ, Julien JP, et al. Preoperative chemotherapy in primary operable breast cancer: Results from the European Organization for Research and Treatment of Cancer trial 10902. J Clin Oncol. 2001;19(22):4224-4237.
- Sikov WM, Berry DA, Perou CM, et al. Impact of the addition of carboplatin and/or bevacizumab to neoadjuvant once-per-week paclitaxel followed by dose-dense doxorubicin and cyclophosphamide on pathologic complete response rates in stage II to III triple-negative breast cancer: CALGB 40603 (Alliance). J Clin Oncol. 2015;33(1):13-21.
- Golshan M, Cirrincione CT, Sikov WM, et al. Impact of neoadjuvant chemotherapy in stage II-III triple negative breast cancer on eligibility for breast-conserving surgery and breast conservation rates: Surgical results from CALGB 40603 (Alliance). Ann Surg. 2015;262(3):434-439; discussion 438-439.
- Criscitiello C, Azim HA, de Azambuja E, Rubio IT. Factors affecting surgical management following neoadjuvant therapy in patients with primary HER2-positive breast cancer: Results from the NeoALTTO phase III trial. Ann Oncol. 2014;25(4):910-911.
- Carey LA, Berry DA, Cirrincione CT, et al. Molecular heterogeneity and response to neoadjuvant human epidermal growth factor receptor 2 targeting in CALGB 40601, a randomized phase III trial of paclitaxel plus trastuzumab with or without lapatinib. J Clin Oncol. 2016;34(6):542-549.
- Ollila DW, Berry DA, Cirrincione CT, et al. Impact of neoadjuvant chemotherapy plus HER2-targeting on breast conservation rates: Surgical results from CALGB 40601 (Alliance). Paper presented at: 2013 American Society of Clinical Oncology Meeting, June 2, 2013, Chicago, IL.
- von Minckwitz G, Schneeweiss A, Loibl S, et al. Neoadjuvant carboplatin in patients with triple-negative and HER2-positive early breast cancer (GeparSixto; GBG 66): A randomised phase 2 trial. Lancet Oncol. 2014;15(7):747-756.
- Debled M, MacGrogan G, Breton-Callu C, et al. Surgery following neoadjuvant chemotherapy for HER2-positive locally advanced breast cancer. Time to reconsider the standard attitude. Eur J Cancer. 2015;51(6):697-704.
- Holmes D, Colfry A, Czerniecki B, et al. Performance and practice guideline for the use of neoadjuvant systemic therapy in the management of breast cancer. Ann Surg Oncol. 2015;22(10):3184-3190.
- McGuire KP, Hwang ES, Cantor A, et al. Surgical patterns of care in patients with invasive breast cancer treated with neoadjuvant systemic therapy and breast magnetic resonance imaging: Results of a secondary analysis of TBCRC 017. Ann Surg Oncol. 2015;22(1):75-81.
- Rippy EE, Ainsworth R, Sathananthan D, et al. Influences on decision for mastectomy in patients eligible for breast conserving surgery. Breast. 2014;23(3):273-278.