Between 1-2 women out of every 10 who developed breast cancer, have what is considered locally advanced disease. Locally advanced disease is generally considered tumors greater than 2 cm in diameter, involved axillary lymph nodes, and or tumors that invade the skin or cause inflammation in the skin (inflammatory breast cancer). Many of these tumors do not require estrogen or progesterone for growth (ER and PR negative). When locally advanced, these cancers are ideally suited to preoperative (neoadjuvant) chemotherapy. However, a majority (70%) of cancers are considered ER-positive and or PR-positive (ER+, PR+) in that they are at least partially dependent upon estrogen or progesterone for growth. Although these cancers may respond to chemotherapy given in the preoperative setting, many do not. There is an abundance of data to suggest that these ER+/PR+ cancers do not respond as well to chemotherapy given in the neoadjuvant setting as those cancers that are ER/PR negative.

Because most cancer cells (70%) are sensitive to estrogen (ER+), they lend themselves to hormonal therapy. There are three classes of hormonal treatment. The first class is called estrogen receptor modulators. These drugs block the receptor for estrogen located on the cancer cell wall preventing estrogen from attaching to the cancer cell and activating that cell. The most used drug in this category is tamoxifen. The second class of drugs is called an estrogen receptor degrader. These drugs block the estrogen receptor on the cancer cell wall and have destructive action on the receptor as well. Fulvestrant is the most commonly used drug in this category. Finally, there are the aromatase inhibitors. These drugs inhibit the production of estrogen in body fat and other internal organs. Because aromatase inhibitors do not affect estrogen produced by the ovaries, they are only effective in postmenopausal women. There are three drugs in this category, including anastrozole, letrozole, and exemestane.

Preoperative hormonal therapy has received a fair amount of traction in Europe while failing to do so in the US. One reason for this is that hormonal treatment does not result in the same number of complete pathologic responses as preoperative chemotherapy. A complete pathologic response is defined as no invasive cancer remaining in the breast or lymph nodes after a course of preoperative treatment. Another reason is that the length of time required for preoperative hormonal therapy to achieve a visible response is much longer than that for chemotherapy. Nonetheless, in recent years several tests have been discovered that, when used appropriately, may make a reaction to preoperative hormonal therapy more likely.

Ki67

The Ki67 level is now routinely tested on invasive cancers. Ki67 is a test that measures how aggressive cancer behaves. It was initially thought that a low Ki67 level, which is associated with less aggressive disease, would be most suitable for preoperative hormonal therapy. This is indeed the case. But it was also thought that higher Ki67 levels in patients with ER+ tumors would be unlikely to respond to preoperative hormonal therapy. In recent studies, however, it was found that in patients whose Ki67 dropped within just a few weeks of treatment would be very likely to have an excellent response to hormonal therapy. The scenario would look like this. A patient with an aggressive ER+ tumor with a high Ki67 would begin preoperative hormonal treatment. Approximately 2 to 3 weeks into treatment, a needle biopsy would again be performed. If the Ki67 dropped into the low range, the hormonal therapy would have a good chance of response. If the Ki67 stayed in the high range after the initial treatment, the patient would be switched to chemotherapy.

PEPI

Researchers have come up with every unique way to score cancers based on the likelihood that they will respond to hormonal therapy. PEPI stands for “preoperative endocrine prognostic index.” After breast cancer surgery is completed, the surgical tissue is analyzed for tumor size, lymph node status (positive or negative), Ki67, and the estrogen receptor’s intensity. For instance, a score of zero is associated with only a 10% risk of recurrence. In contrast, a score of four is associated with a 48% risk of recurrence. Interestingly, when the PEPI score is combined with the progesterone receptor value, it becomes an even more reliable predictor of outcome than the PEPI score alone. This is called PEPI-P.

Duration of Therapy

Two studies investigated the optimal length of preoperative hormonal therapy using the drug, exemestane. One study found no difference in cancer response rates at four and six months. On the other hand, the second study found a significant increase in response rates from 3 to 6 months of treatment. Consequently, current recommendations range from four to six months. However, it is interesting to note that there is good evidence to suggest that preoperative hormonal therapy given for up to 12 months is safe if the tumor is monitored closely.

Emerging Therapies

In recent years a new class of drugs called CDK4/6 inhibitors was discovered. The first of these drugs was called Ibrance® (generic name is palbociclib). When combined with hormonal therapy, the effects of hormonal treatment are enhanced significantly. Researchers examined the rate of breast-conserving surgery and clinical response in a clinical trial that combined letrozole and palbociclib in the preoperative setting compared to chemotherapy. They found that a combination of the CDK4/6 inhibitor and hormonal therapy resulted in almost identical responses and breast-conserving surgery compared to chemotherapy. One clinical trial was carried out in patients that had more aggressive ER+ tumors. These are some of the more worrisome and difficult tumors for oncologists to treat. They are not overly responsive to chemotherapy and do not respond as well to hormonal therapy as less aggressive tumors do. In this trial, however, the cancers were more responsive to the hormonal combination than chemotherapy. This clinical trial was particularly important. It demonstrated that hormonal therapy plus a CDK4/6 inhibitor could be used in the preoperative setting and can obtain high rates of response even in more aggressive tumors. That contrasts significantly with prior thinking that preoperative hormonal therapy should only be used in patients with less aggressive cancers.

Conclusions

Although oncologists in the US have been slow to utilize preoperative hormonal therapy, newer methods to evaluate patients such as PEPI will help us assess which patients might be more appropriate for this form of treatment. Furthermore, adding CDK4/6 inhibitors to hormonal therapy, particularly aromatase inhibitors, may allow us to obtain better and more sustained responses.