Introduction: There are several accepted benefits to neoadjuvant therapy. Down-staging of axillary node disease can save 25-30% of selected patients from node dissection complications. Similarly, some patients are spared mastectomy due to primary tumor size reduction. Less commonly cited benefits include a decrease in lumpectomy volume and a more safely performed skin-sparing or nipple-sparing mastectomy. Finally, judging tumor response while still in vivo empowers oncologists to change the neoadjuvant cocktail or add additional post-surgical treatment. The glaring omission is a lack of survival benefit. Current surgical residents and practicing physicians are still taught that there is no survival advantage of neoadjuvant therapy. Is this about to change? Let us glimpse at the evidence.
The KEYNOTE-522 is a multicenter-multinational phase 3 clinical trial that evaluated the use of neoadjuvant chemotherapy (NAC) plus or minus the checkpoint inhibitor, pembrolizumab (Keytruda®). All patients were stage 2 or 3 triple-negative breast cancer (TNBC). Briefly, both the control and study groups received four paclitaxel cycles plus carboplatin and pembrolizumab or placebo. All groups received doxorubicin or epirubicin plus cyclophosphamide. After surgery, both groups received pembrolizumab or placebo q3 weeks for up to 9 cycles. In the first interim analysis, complete pathological response (pCR) was 64.8% in the pembrolizumab group and 51.2% in the group receiving placebo. Interestingly, the pembrolizumab cohort response was consistent across subgroups expressing and not expressing PD-L1. The Keynote-522 trial differs from the Impassion 130 trial, in which the checkpoint inhibitor atezolizumab was employed. This biologic interferes with PD-L1 as opposed to PD-1 and was only effective in PD-L1 expressing metastatic breast cancer.
In the phase 2 I-SPY2 trial patients with Her2 negative breast cancer were randomized to nonplatinum chemo plus or minus pembrolizumab. In this Her2 negative cohort, the pembrolizumab group had a pCR 27% higher than controls. In the Her2-/ hormone receptor-positive group, the pCR was 17% higher in those receiving pembrolizumab. Again, the triple-negative patients had the most significant benefit in which the pCR rate was 38% higher in the pembrolizumab group (see chart):
The most common adverse events of pembrolizumab were skin and infusion reactions. However, a small percentage of patients had adverse endocrine events, including hypothyroidism and adrenal insufficiency. Many of these endocrine events were permanent, requiring hormone replacement.
Addressing the question of a true survival advantage, the CREATE-X trial in Japan evaluated the additional treatment of patients with residual disease (no pCR) after completing neoadjuvant chemotherapy. Nine hundred two patients had residual disease after receiving neoadjuvant therapy with anthracycline, taxanes, or both. They were then randomized to receive capecitabine or no additional treatment. The trial terminated early when interim analysis met their primary endpoint, which was disease-free survival. Disease-free survival favored the treatment group by 6.5% (74.1% vs. 67.6%). As in the other trials mentioned above, the most significant differences were noted in TNBC (see graph). Hand-foot syndrome was the most common adverse effect.
More recently the Katherine trial (Von Minckwitz et al NEJM 2019) demonstrated the same phenomenon in HER2+ patients with residual disease (no pCR) after completing neoadjuvant treatment with chemotherapy and trastuzumab ± pertuzumab. Patients with residual disease were randomized to standard adjuvant trastuzumab or TDM-1. Those receiving TDM-1 had a significant improvement in distant recurrence-free survival (90% vs 83%) As seen in the CREATE-X study patients, standard neoadjuvant treatment revealed a group of patients with a treatment-specific survival advantage which could not have been identified in the conventional adjuvant setting.
Conclusions: To date, we still lack level I evidence that neoadjuvant chemotherapy compared to an identical adjuvant drug therapy results in a survival benefit. Yet, we now have evidence that there is a disease-free survival advantage in using postsurgical capecitabine (HER2-, especially TNBC) or TDM-1 (HER2+) in patients with less than a pCR following neoadjuvant treatment. These studies shows that neoadjuvant treatment reveals a group of poor responders that has a treatment-specific survival advantage not detectable with the conventional adjuvant approach. Even more exciting is the extraordinary increases in pCR seen in studies using neoadjuvant checkpoint inhibitors. While there has been a survival advantage seen in the neoadjuvant setting when compared to patients not receiving checkpoint inhibitors, no studies have compared these biologics to the same regimens given as adjuvant therapy. However, if the Goldie Coldman Hypothesis is indeed correct, then maybe, just maybe, we have developed biologic therapies that may show more benefit in the neoadjuvant setting when compared to the adjuvant setting.