EDITORIAL

Sometimes a Great Notion—An Assessment of Neoadjuvant Systemic Therapy for Breast Cancer

Nancy E. Davidson, Monica Morrow

Affiliations of authors: Johns Hopkins Kimmel Cancer Center, Baltimore, MD (NED); Fox Chase Cancer Center, Philadelphia, PA (MM)

Correspondence to: Nancy E. Davidson, MD, Johns Hopkins Kimmel Cancer Center, 1650 Orleans St., Rm. 409, Baltimore, MD 21231 (e-mail: davidna{at}jhmi.edu).

Sometimes I live in the country,

Sometimes I live in the town,

Sometimes I get a great notion...

From the song "Good Night, Irene"

By Huddie Ledbetter and John Lomax as adapted by Ken Kesey

The use of neoadjuvant (aka, preoperative or primary) systemic therapy for the management of operable breast cancer has been widely heralded as the future of breast cancer treatment. The underlying rationale consists of several important observations including the success of this strategy for locally advanced breast cancer, the utility of the approach to permit organ preservation in other tumor types, and a compelling preclinical literature suggesting that preoperative administration of chemotherapy is associated with improved survival in a rodent breast cancer model. Enthusiasm has also been engendered by the belief that preoperative therapy would improve clinical outcomes, enhance the likelihood of breast conservation, and facilitate prediction of treatment response, thereby leading to individualization of therapy (1,2).

A meta-analysis of neoadjuvant versus adjuvant systemic therapy for early-stage breast cancer in this issue of the Journal provides an opportunity for reflection about this approach (3). This meta-analysis appears to be carefully performed and methodologically sound. Its assumptions and limitations are meticulously delineated. In brief, a search of the medical literature yielded 12 potentially eligible trials of neoadjuvant versus adjuvant chemotherapy or endocrine therapy; three were excluded because the results have not yet been published in the peer-reviewed literature. Participants in the nine trials total a surprisingly meager 3946 patients; more than half are derived from the NSABP B18 (4) and EORTC 10902 (5) trials. The meta-analysis did not show any statistically or clinically significant difference between the adjuvant and neoadjuvant arms for death, disease progression, or distant recurrence. Paradoxically, neoadjuvant therapy was associated with a statistically significantly increased risk of loco-regional recurrence; this increased risk was largely attributed to trials where radiotherapy without surgery was used for patients who had a complete clinical response after neoadjuvant therapy. The rate of breast conservation was increased by neoadjuvant therapy in only six of the studies, and the rates of clinical and pathologic complete response were highly variable. The authors conclude that these results are not likely to change even with the inclusion of data from two studies of 1315 patients as yet unreported, a contention that is likely to be correct.

What can we conclude? First, this meta-analysis confirms that surgery remains an essential part of early breast cancer management, even when systemic therapy appears to have eradicated all grossly evident disease. The absence of any tumor (invasive or intraductal) on pathologic examination after neoadjuvant therapy was demonstrated in less than 10% of women in the larger studies in this overview (46). Although we might anticipate that radiation alone would give favorable local control rates in these women, the identification of patients with a pathologic complete response before surgery has proved to be a difficult task. Use of mammography, physical examination, or magnetic resonance imaging cannot reliably assess degree of response in this setting (7,8). Newer approaches using functional MRI show promise but they remain to be validated in large studies (9). Until complete pathologic responses to neoadjuvant therapy can be reliably identified and until clinical trials demonstrate that local control rates equivalent to those seen with surgery and radiation are obtained with radiotherapy alone, surgery must be considered a routine part of management.

Second, not only was the local failure rate increased by 22% in neoadjuvant recipients, but also the rate of conversion to breast conservation was not uniformly improved in these trials. This is in part because a large number of women were already candidates for breast conservation—66% and 24% of patients randomly assigned to neoadjuvant therapy on the NSABP B18 and EORTC trials, respectively (4,5). Also, higher rates of local recurrence are seen in those women who require chemotherapy to undergo breast preservation. For example, local recurrence rates were 15% in patients requiring chemotherapy to undergo breast conservation compared with 7% for those who were initially considered lumpectomy candidates in the NSABP B18 trial (4). Therapy-induced tumor regression is usually patchy not concentric. The increased rates of local recurrence after neoadjuvant therapy may reflect differences in the meaning of a negative excision margin in a situation where, by definition, the volume of tissue resected is smaller than the volume originally occupied by the cancer. In this setting, a negative margin may actually be associated with a clinically significant residual tumor burden that is unlikely to be controlled by radiation. Thus, an evaluation of surgical margins and the extent of viable tumor elsewhere in the specimen is essential and may dictate resection of additional breast tissue even when margins are apparently tumor free. From this analysis it follows that, for women who are candidates for breast conservation at presentation, neoadjuvant therapy offers no benefit for local control and may make determination of the appropriate extent of resection more difficult.

Finally, in addition to its practical implications for surgical and radiation oncologists, this meta-analysis affords the opportunity for medical oncologists to reassess expectations for neoadjuvant therapy. When compared with adjuvant therapy, neoadjuvant therapy did not improve overall or disease-free survival. In retrospect, it was perhaps naïve to expect that a shift in the timing of systemic therapy would have a meaningful impact. This analysis also exposes the modest effects of our current systemic therapy. Much importance has been attached to the pathologic complete response after neoadjuvant therapy because the women who attained a pathologic complete response in the NSABP B18 trial had better survival than any other group of women in the trial (4,10). Indeed, it has been suggested that achievement of a pathologic complete response could be considered as a surrogate marker to guide development of new therapies. Coincidentally, the meta-analysis of Mauri et al. (3) is reported in the wake of updated results from the NSABP B27 trial, a test in 2411 women with operable breast cancer of the combination of doxorubicin and cyclophosphamide before surgery, the combination of doxorubicin and cyclophosphamide followed by docetaxel before surgery, and the combination of doxorubicin and cyclophosphamide followed by surgery followed by docetaxel. The initial report of this trial documented a doubling in pathologic complete response from 14% to 26% with the addition of docetaxel to the combination of doxorubicin and cyclophosphamide chemotherapy, raising the hope that this would translate into a tangible effect on clinical outcome (11). Thus, the recent report that addition of docetaxel was not associated with a statistically significant increase in disease-free or overall survival after a median follow-up of approximately 5 years is a sobering one (12). It highlights the reality that new therapies will need to have a very substantial effect on end points, such as pathologic complete response, before they will alter survival. However, the power of the pathologic complete response to identify women with a relatively better outcome no matter which chemotherapy they received was validated, confirming yet again the medical oncology adage that responders fare better than non-responders.

Should we abandon neoadjuvant systemic therapy for women with operable breast cancer? Absolutely not. This meta-analysis demonstrates that survival and disease-free survival are similar with neoadjuvant and adjuvant approaches for operable breast cancer. Neoadjuvant therapy may enhance the rate of breast conservation but at the cost of increased local recurrence rates. The promise that in vivo assessment of tumor response will improve clinical decision making and outcome has been only partially fulfilled at this time. As a result, neoadjuvant therapy should not replace standard adjuvant therapy. Rather, it represents a reasonable alternative for women with palpable cancers who require mastectomy, and it is an excellent arena for clinical trials. Clinical experience has shown that women with large unicentric cancers that are high grade and steroid hormone receptor negative are the most likely to respond to preoperative chemotherapy (13,14), and the chance of successfully down-staging a woman who is not initially a candidate for breast conservation is approximately 25% (4,5). We should strive to move beyond this limited understanding by formulating a uniform definition of a pathologic complete response and delineation of its molecular and imaging predictors. Identification of non-responders early in the course of therapy has the potential to decrease toxicity and allow prompt conversion to a second potentially more effective therapy. This is a large assumption, and it remains to be shown that such a strategy will translate into meaningful clinical gains. However, early identification of those who are destined to have pathologic complete response could permit administration of a shorter course of therapy, thereby again minimizing toxicity. One of the frustrations of adjuvant therapy has been the inability to identify non-responders without a prolonged period of follow-up. The use of neoadjuvant therapy could potentially eliminate this limitation with pathologic, molecular, and/or imaging response serving as a predictive marker. In addition to improved predictive markers for therapy response, however, adoption of new treatment strategies will be a necessity if we are to improve patient outcomes.

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