IN CERTAIN CANCERS, GIVING CHEMOTHERAPY PREOPERATIVELY MAY RESULT IN A SURVIVAL ADVANTAGE

Giving chemotherapy before surgery is called neoadjuvant therapy. Until recently, it had precise indications. Patients with a small number of cancerous axillary lymph nodes could have cancer irradicated in about 25-30%, sparing the patient a complete node dissection and reduce the risk of lymphedema. Similarly, some patients whose cancers are too large for lumpectomy will undergo neoadjuvant chemotherapy, which can reduce cancer size, allowing for more limited surgery.. Furthermore, in many instances, neoadjuvant therapy can result in a more safely performed skin-sparing or nipple-sparing mastectomy. Finally, giving chemotherapy before its surgical removal empowers oncologists to change what drugs are given or add postsurgical therapy. The glaring omission is that preoperative or neoadjuvant therapy has not resulted in a survival advantage until recently!

There are four clinical trials worth mentioning. The first is the KEYNOTE-522 trial (most trials are given fancy names, though some are known by a number). This trial used neoadjuvant chemotherapy plus a biologic immune therapy called a checkpoint inhibitor. You can get an idea of how checkpoint inhibitors work by looking at this short YouTube video.

Patients received either standard chemotherapy or chemotherapy plus the biologic therapy called pembrolizumab (Keytruda®). Thus far, the results have shown that approximately 14% more patients in the group receiving the biologic therapy had complete disappearance of their cancer than those not receiving it.

Another trial, called ISPY2, using the same drug had similar results, showing a 27% improvement in complete tumor eradication. Researchers observed that In both KEYNOTE-522 and ISPY2, the biologic therapies’ best responses occurred in patients with the most aggressive cancers.

The CREATE-X clinical trial in Japan studied a large group of patients who had received preoperative chemotherapy. After surgery, patients whose cancer had not wholly disappeared were then randomized to receive another chemotherapy drug (capecitabine) or no further treatment. For one of the first times since we began using preoperative therapy, researchers noted a survival advantage of 6.5% in the group receiving the additional treatment.

Finally, the KATHERINE trial tested patients whose cancers carried to Her2 gene with standard therapy, which employs biologic agents targeting these genes. In those patients not having all visible cancer obliterated, half of the patients received the same biological agents with a molecule of chemotherapy attached to it (ado-trastuzumab, also called TDM-1 or Kadcyla®). The researchers found that patients receiving TDM-1 had a 7% survival advantage over those who did not.

Conclusion: These studies show that we can identify and potentially improve the cure rate of patients who do not respond well to initial therapy with drugs such as capecitabine and TDM-1. Even more exciting is the extraordinary increase in tumor response rates when we added immune therapy using checkpoint inhibitors. Though no studies compare giving these same checkpoint inhibitors pre and postoperatively, there is hope that these immune therapies may offer the possibility of an improved cure rate for breast cancer, particularly when given before surgery.

Alan Stolier