Update on Treatments for HER2-Positive Cancer

Herceptin Plus Chemotherapy Improves Survival

D. Slamon and others

San Antonio Breast Cancer Symposium, December 8, 2005, General Session I

Is this for me? If you have early-stage, HER2-positive breast cancer, you might want to read this article.

Background and importance of the study: HER2-positive cancers make too much of the HER2 gene or HER2 protein. HER2-positive cancers tend to grow faster and are more likely to come back than breast cancers that are HER2-negative. About one out of every four breast cancers is HER2-positive.

Herceptin (chemical name: trastuzumab) is approved by the U.S. Food and Drug Administration for women with metastatic, HER2-positive breast cancer. Metastatic cancer is advanced cancer that's spread beyond the breast and nearby lymph nodes. Herceptin slows down or even stops the cancer's growth.

Since Herceptin does such a good job of treating metastatic breast cancer, researchers want to know if Herceptin could also benefit women with HER2-positive disease that's at an early stage. The Breast Cancer International Research Group (BCIRG) 006 trial is studying this question.

Early results from the BCIRG 006 trial released in September 2005 suggest that Herceptin improves disease-free survival (the length of time until the cancer comes back) compared to chemotherapy alone. Herceptin works well when given after chemotherapy, but works even better when combined with chemotherapy. In one of the treatment plans in this study, women received Herceptin after getting anthracycline-based chemotherapy. But Herceptin given with or after anthracylines can cause heart problems.

The study reviewed here reported on updated results from the BCIRG 006 trial.

Study design: More than 3,200 women with early-stage, HER2-positive cancer were randomly assigned to one of three treatment plans (called "arms"):

• AC-T arm: Adriamycin (chemical name: doxorubicin), an anthracycline, and Cytoxan (chemical name: cyclophosphamide), followed by Taxotere (chemical name: docetaxel). No Herceptin was given in this arm.
• AC-TH arm: AC-T, with Herceptin given at the same time as Taxotere.
• TCH arm: Taxotere, Paraplatin (chemical name: carboplatin), and Herceptin, all at the same time.

Results: Compared to women in the AC-T arm (no Herceptin given), women who received chemotherapy AND Herceptin had better disease-free survival. The TCH arm had a 39% relative increase in disease-free survival and the AC-TH arm had a 51% increase. These differences are statistically significant, meaning that the difference was likely due to Herceptin and not just to chance. These results are the same as the early results reported in September 2005.

Link to heart problems confirmed:

The study also showed more heart problems when Herceptin was taken along with Adriamycin. In women who took both (the AC-TH arm), the risk for a significant heart problem was 2.3%, double the risk (1.2%) of women who didn't take Herceptin (the AC-T arm). In the women who took Taxotere, Paraplatin, and Herceptin (the TCH arm), the risk of significant heart problems was 1.2%. But these differences were not statistically significant, which means that the researchers can't be sure whether they were just due to chance.

Heart problems from Adriamycin were not short term. Seventeen percent of women who took Adriamycin and Herceptin and 9% of women who took Adriamycin and no Herceptin developed heart problems. None of these women had normal heart function a year and a half after treatment. In women who took Herceptin but not Adriamycin, 8% developed heart problems. All of these women had return of normal heart function during the 18-month follow-up period.

Cancer that is HER2-positive and topo II-positive:

The study also looked at a subset of women who had cancer that was both HER2-positive AND topoisomerase II alpha (or topo II)–positive. Topo II–positive cancers make too much of the topo II protein. About 35% of HER2-positive cancers are also topo II–positive.

Topo II–positive cancers are more likely to respond to Adriamycin than cancers that are topo II–negative. Adriamycin targets the topo II protein much like Herceptin targets the HER-2 protein.

In the BCIRG 006 trial, women with cancer that was both HER2-positive and topo II–positive responded better to treatment with the Adriamycin/Herceptin combination, AC-TH. Women with topo II–negative cancers did just as well with TCH therapy (containing Taxotere, but no Adriamycin) as with Adriamycin-containing therapy.

Conclusions: The study suggests that taking Herceptin with a chemotherapy regimen without an anthracycline in it (the TCH arm) is nearly as effective as taking Herceptin with an anthracycline (the AC-TH arm). But the TCH regimen has less risk of heart problems.

The study also suggests that women with HER2-positive and topo II–positive breast cancer may get more benefits from a treatment plan that includes Adriamycin than one that includes Taxotere.

Take-home message: This is another large clinical trial showing that Herceptin plus chemotherapy significantly reduces the risk of recurrence in early-stage, HER2-positive breast cancer. Women who received Herceptin after having anthracycline-based chemotherapy significantly lowered their risk of recurrence, by 51%. Women who took Herceptin along with chemotherapy that contained a taxane instead of an anthracycline reduced their risk of recurrence by 39%.

Still, getting Herceptin after Adriamycin can cause heart damage in some women. This study showed that heart problems were significant and could still be detected more than 18 months after treatment. With longer follow-up and careful monitoring, we'll learn more about how long the heart problems will last and what can be done to lessen them.

If risk of heart damage is a significant issue for you, you still have a good option. Herceptin given with taxane-based chemotherapy (without Adriamycin) still offers more benefit than the best available chemotherapy alone. Adding Herceptin to a taxane-based chemotherapy reduced the risk of recurrence by 39%. If you have cancer that is HER2-positive and topo II–negative—in this study, about 65% of women did—the Taxotere, Paraplatin, and Herceptin (TCH) regimen is just as effective as a plan containing Adriamycin. And it has a lower risk of heart problems.

If you have cancer that is both HER2-positive AND topo II-positive, you may want to consider Adriamycin chemotherapy followed by Herceptin and a taxane. Topo II–positive cancers seemed to have a better response to Adriamycin-based chemotherapy.

Right now, testing for topo II is not routinely done. With these study results, it's likely that more hospitals and cancer centers will start doing this test. As more women are tested for topo II, we'll see if these results hold up over time. Knowing whether you are topo II–positive might help you and your doctor decide which regimen is right for you.

Making treatment decisions is like a balancing act. You want to do everything you can to get rid of the cancer with the fewest side effects. If you have early-stage, HER2-positive breast cancer, you need to seriously consider adding Herceptin to your plan of chemotherapy. Your discussion with your doctor should include an in-depth look at any cardiac risk factors you may have. Your heart's health needs to be checked before and during any treatment plan that includes Adriamycin or Herceptin.

Remember that every woman reacts differently to treatment. It's very important to find the right combination that you're comfortable with and that works best for YOU.

Stay tuned to breastcancer.org for the very latest information on Herceptin and other treatments.