Progress in the search for more-targeted and more-personalized cancer care
The 45th Annual Meeting of the American Society of Clinical Oncology (ASCO), held May 29 to June 2, 2009, in Orlando, Florida, brought together an estimated 20,000 cancer specialists. The studies presented at the meeting addressed topics ranging from prevention and early detection through treatment and survivorship.
The theme of this year’s meeting was Personalizing Cancer Care. For many cancer types—including breast cancer—it’s becoming increasingly possible to tailor cancer treatment to the specific characteristics of the patient and the disease.
Positive News About Triple-negative Breast Cancer
For many women with breast cancer, medical advances have allowed for more-individualized and more-effective cancer treatment. Hormonal therapies such as tamoxifen (Nolvadex®) and aromatase inhibitors have reduced the risk of cancer recurrence and have improved survival among women with hormone receptor–positive breast cancer, and use of HER2-targeted therapies such as Herceptin® (trastuzumab) and Tykerb® (lapatinib) have dramatically improved the prognosis of patients with HER2-positive breast cancer.
But what about women who aren’t candidates for these therapies? An estimated 15 percent of women with breast cancer have what is called “triple-negative” breast cancer. Lee S. Schwartzberg, MD, FACP, medical director of the West Clinic in Memphis and clinical professor of medicine at the University of Tennessee College of Medicine, explains: “Triple-negative breast cancer refers to tumors that are estrogen receptor–negative, progesterone receptor–negative, and HER2-negative.” Because breast cancers with these characteristics do not respond to hormonal therapy or HER2-targeted therapy, treatment options are limited and prognosis tends to be worse than for other types of breast cancer. “For triple-negative tumors,” Dr. Schwartzberg continues, “we’re left with traditional chemotherapy; this has some benefit in triple-negative tumors, but over the past few years, as we’ve defined subgroups of breast cancer more clearly and looked at the response to both chemotherapy and targeted agents in each subgroup, we’ve found that in general the triple-negative patients do poorly even with standard chemotherapy. So there’s a very urgent need to understand triple-negative breast cancer and to develop drugs that in some way target that group of patients.”
Fortunately, research into novel targeted therapies is producing promising results. Targeted therapies are anticancer drugs that interfere with specific pathways involved in cancer cell growth or survival. Some targeted therapies block growth signals from reaching cancer cells, others reduce the blood supply to cancer cells, and still others stimulate the immune system to recognize and attack the cancer cell. Depending on the specific target, targeted therapies may slow cancer cell growth or increase cancer cell death.
Targeted drugs known as PARP inhibitors are showing promise in the treatment of triple-negative breast cancer. PARP stands for poly (ADP-ribose) polymerase. The PARP enzyme plays a role in DNA repair, including the repair of DNA damage from chemotherapy. Drugs that inhibit this enzyme may contribute to cancer cell death and increased sensitivity to chemotherapy.
“By two lines of reasoning,” Dr. Schwartzberg explains, “there is reason to believe that inhibiting the PARP enzyme might improve clinical outcome in triple-negative breast cancer.” The first is that a subset of women with triple-negative breast cancer has hereditary breast cancer resulting from a BRCA1 mutation. “The BRCA1 gene is a DNA repair gene, and when that is knocked out, as it is in breast cancers that develop in BRCA1 mutation carriers, PARP becomes even more important in those cells; so there was good reason to believe that inhibiting PARP in that group of patients would be a good strategy.” But even in women without BRCA1 mutations, PARP appears to play an important role in triple-negative breast cancer, providing the second line of reasoning in support of PARP inhibition: “It’s been realized that in triple-negative breast cancers in general,” notes Dr. Schwartzberg, “the levels of PARP go up as the cancer cells grow; so even in the non–BRCA mutation carriers, there was reason to believe that PARP inhibitors might be a good way to enhance chemotherapy effect.”
A Phase II clinical trial of an investigational PARP inhibitor known as BSI-201 was one of the highlights of this year’s ASCO meeting. The study compared treatment with chemotherapy alone to treatment with chemotherapy plus BSI-201 among 116 women with metastatic triple-negative breast cancer. Chemotherapy consisted of Gemzar® (gemcitabine) and Paraplatin® (carboplatin).
“The benefits of adding BSI-201 were dramatic,” says Dr. Schwartzberg. Sixty-two percent of women treated with chemotherapy plus BSI-201 experienced a clinical benefit compared with 21 percent of women treated with chemotherapy alone. Clinical benefit refers to either a reduction in detectable cancer or stable disease for at least six months. BSI-201 also improved both overall and progression-free survival. Median overall survival was 9.2 months among women treated with chemotherapy plus BSI-201 compared with 5.7 months among women treated with chemotherapy alone. Median survival without cancer progression was 6.9 months among women treated with chemotherapy plus BSI-201 compared with 3.3 months among women treated with chemotherapy alone.
“This was a very exciting proof-of-concept that inhibiting PARP in triple-negative breast cancer seems to be an important therapeutic advance,” says Dr. Schwartzberg. “It will be confirmed through a Phase III study that will be launching very shortly. This will be a larger study and will be designed to answer definitively whether or not BSI-201 helps patients with triple-negative breast cancer.”
In a separate Phase II clinical trial also presented at ASCO, the investigational PARP inhibitor olaparib was evaluated among 54 women with BRCA1 or BRCA2 mutations and advanced, previously treated breast cancer. All study participants were treated with olaparib alone, and more than one-third experienced tumor shrinkage.
Sentinel Node Micrometastases Indicate Need for Additional Treatment
Evaluation of the axillary (under the arm) lymph nodes for the presence of cancer is an important part of breast cancer staging. To assess the axillary lymph nodes, a surgeon performs either an axillary lymph node dissection, in which many lymph nodes are surgically removed and evaluated, or a less extensive procedure known as a sentinel lymph node biopsy.
The sentinel nodes are the first lymph nodes to which cancer is likely to spread. If a sentinel node biopsy determines that these nodes are free of cancer, a more extensive axillary lymph node dissection may not be required. But if the sentinel nodes are found to contain cancer, an axillary lymph node dissection is usually performed.
For some women the sentinel node biopsy will reveal very small areas of cancer. Areas of cancer that measure between 0.2 mm (millimeters) and 2.0 mm are referred to as micrometastases. Even smaller areas of cancer are referred to as isolated tumor cells. The clinical significance of sentinel node micrometastases and isolated tumor cells has been uncertain but was evaluated in a study conducted in the Netherlands.
The study evaluated the records of about 2,700 women who underwent surgery and sentinel lymph node biopsy for early-stage breast cancer and who had sentinel nodes that were free of cancer or that contained only micrometastases or isolated tumor cells. Some of the women underwent additional axillary lymph node treatment (either an axillary lymph node dissection or radiation therapy to the axillary nodes) and some did not.
- Among women with sentinel node micrometastases, the five-year risk of cancer recurrence was 4.5 times higher among women who did not receive any additional axillary lymph node treatment than among women who did receive additional axillary lymph node treatment.
- Additional axillary lymph node treatment did not significantly affect recurrence rates among women with sentinel nodes that were free of cancer or that contained only isolated tumor cells.
Based on these results, the researchers recommend additional axillary lymph node treatment (such as axillary lymph node dissection) for women who are found to have sentinel node micrometastases. This additional treatment is important to reducing the risk of breast cancer recurrence.
Antidepressants and Tamoxifen
Tamoxifen is a hormonal therapy used in the prevention and the treatment of breast cancer. Inside the body, tamoxifen is converted to its active form—endoxifen—by a liver enzyme known as CYP2D6.
Some people have inherited gene variants that are linked with lower levels of CYP2D6 activity. Studies suggest that people with these gene variants may derive less benefit from tamoxifen. Drugs that inhibit CYP2D6 may also reduce tamoxifen benefit. CYP2D6-inhibiting drugs include certain antidepressants, such Prozac® (fluoxetine) and Paxil® (paroxetine).
In two studies presented at ASCO, researchers explored how CYP2D6-inhibiting drugs influence tamoxifen effectiveness. The first study, conducted in the United States, involved 353 women who took both tamoxifen and a CYP2D6-inhibitor and 945 women who took tamoxifen alone. Among women who took a CYP2D6 inhibitor, the median duration of overlap with tamoxifen was 255 days.
Two-year risk of breast cancer recurrence was 13.9 percent among women taking both tamoxifen and a CYP2D6 inhibitor compared with 7.5 percent among women taking tamoxifen alone. This study suggests that CYP2D6-inhibiting drugs may reduce tamoxifen effectiveness.
In contrast, another study presented at ASCO did not find a relationship between CYP2D6 inhibitors and tamoxifen effectiveness. Conducted in the Netherlands, the study involved 1,990 breast cancer patients treated with tamoxifen. A total of 150 used a CYP2D6 inhibitor for 60 days or longer during their tamoxifen therapy. The risk of breast cancer recurrence in these women was similar to the risk in women who either did not use a CYP2D6 inhibitor or who used a CYP2D6 inhibitor for less than 60 days. The researchers note, however, that relatively few women in this study used both tamoxifen and a CYP2D6 inhibitor. This may have limited their ability to detect an effect.
Dr. Schwartzberg notes that although the jury is still out regarding CYP2D6 inhibitors and tamoxifen, he recommends that patients who are taking tamoxifen avoid strong inhibitors of CYP2D6. The good news for women who might benefit from antidepressant treatment, either for tamoxifen-associated hot flashes or for depression, is that not all antidepressants are CYP2D6 inhibitors. Women may wish to talk with their doctor about which drugs can be used safely in conjunction with tamoxifen.
Avastin and Metastatic Breast Cancer
Avastin® (bevacizumab) is a targeted therapy that slows or prevents the growth of new blood vessels by inhibiting a protein known as VEGF; this deprives the cancer of oxygen and nutrients. Through its effects on blood vessels, Avastin may also improve the delivery of chemotherapy to the cancer.
Avastin has been shown to improve treatment outcomes in selected patients with advanced colorectal, breast, and non–small cell lung cancer. Avastin is also being evaluated among patients with earlier-stage cancer and among patients with other types of cancer.
The RIBBON-1 study is a Phase III clinical trial of Avastin in combination with chemotherapy for the initial treatment of HER2-negative locally recurrent or metastatic breast cancer. The results of this study, presented at ASCO, provide additional evidence that the addition of Avastin to a variety of different chemotherapy regimens modestly delays cancer progression.
Taken together, these and other studies presented at ASCO highlight the gradual but very important progress that is being made in tailoring cancer therapy to the specific needs of each woman and the specific characteristics of each cancer. This progress offers hope for improved outcomes for all women with breast cancer, including those with cancers that previously have had relatively few effective treatment options.
. O’Shaughnessy J, Osborne C, Pippen J, et al. Efficacy of BSI-201, a poly (ADP-ribose) polymerase-1 (PARP1) inhibitor, in combination with gemcitabine/carboplatin (G/C) in patients with metastatic triple negative breast cancer (TNBC): Results of a randomized Phase II trial. Paper presented at: 45th Annual Meeting of the American Society of Clinical Oncology; May 29–June 2, 2009; Orlando, Florida. Abstract P3.
. Tutt A, Robson M, Garber JE, et al. Phase II trial of the oral PARP inhibitor olaparib in BRCA-deficient advanced breast cancer. Paper presented at: 45th Annual Meeting of the American Society of Clinical Oncology; May 29–June 2, 2009; Orlando, Florida. Abstract CRA501.
. Tjan-Heijnen VC, Pepels MJ, de Boer M, et al. Impact of omission of completion axillary lymph node dissection (cALND) or axillary radiotherapy (ax RT) in breast cancer patients with micrometastases (pN1mi) or isolated tumor cells (pN0[i+] in the sentinel lymph node (SN): Results from the MIRROR study. Paper presented at: 45th Annual Meeting of the American Society of Clinical Oncology; May 29–June 2, 2009; Orlando, Florida. Abstract CRA596.
. Aubert RE, Stanek EJ, Yao J, et al. Risk of breast cancer recurrence in women initiating tamoxifen with CYP2D6 inhibitors. Paper presented at: 45th Annual Meeting of the American Society of Clinical Oncology; May 29–June 2, 2009; Orlando, Florida. Abstract CRA508.
. Dezentje V, Van Blijderveen NJ, Gelderblom H, et al. Concomitant CYP2D6 inhibitor use and tamoxifen adherence in early-stage breast cancer: A pharmacoepidemiologic study. Paper presented at: 45th Annual Meeting of the American Society of Clinical Oncology; May 29–June 2, 2009; Orlando, Florida. Abstract CRA509.
. Robert NJ, Dieras V, Glaspy J, et al. RIBBON-1: Randomized, double-blind, placebo-controlled, Phase III trial of chemotherapy with or without bevacizumab (B) for first-line treatment of HER2-negative locally recurrent or metastatic breast cancer (MBC). Paper presented at: 45th Annual Meeting of the American Society of Clinical Oncology; May 29–June 2, 2009; Orlando, Florida. Abstract 1005.