May 2007

There is growing and compelling evidence that anthracycline chemotherapy has limited value in the adjuvant treatment of breast cancer and may offer preferential benefit to only the small percentage of patients whose breast cancers co-amplify the Her2 and TopoII genes,¹ which is less than ten percent of all breast cancers. This is based on a review of multiple published studies and recently announced (unpublished) findings from the BCIRG 006 clinical trial. Anthracyclines have well known and serious side effects such as cardiac dysfunction and leukemia. There are non-anthracycline treatment regimens with at least the same efficacy and fewer toxicities, yet the vast majority of chemotherapy regimens for breast cancer in the adjuvant setting include an anthracycline and in many cancer centers they are considered the standard of care.²

NBCCF believes it is time for the oncology community to incorporate the evidence that has accumulated on this issue. It may very well be time to do away with anthracycline drugs in all but the very small percentage of women whose breast cancers co-amplify the Her2 and TopoII genes. NBCCF urges the oncology community - regulators, researchers, providers, and advocates - to come together to look carefully at these data and revise adjuvant treatment guidelines accordingly.

Background

Since their introduction in the 1980s, combination chemotherapy regimens containing anthracyclines³ have largely replaced CMF (cyclophosphamide, methotrexate and 5-FU) as adjuvant therapy for non-metastatic breast cancer (CMF was first introduced in the mid-1970s). While the evidence from individual trials that compare anthracycline-containing regimens versus CMF chemotherapy has been inconclusive, a meta-analysis of 11 trials by the Early Breast Cancer Trialists' Collaborative Group (EBCTCG)⁴ found that, at five years of follow up, treatments that contained anthracycline slightly improved disease free and overall survival.⁵ As a result, anthracycline therapy has been widely adopted as standard of care in the adjuvant treatment of breast cancer.

Breast cancers aren't all the same

Over the last decade and a half we have made significant progress toward understanding the complexity of breast cancer. We have known for half a century that the estrogen receptor plays an important role in a large percentage of breast cancers, enabling the development of effective treatments to block it such as tamoxifen and other hormonal treatments for estrogen receptor-positive (ER+) breast cancer. More recent investment in basic and clinical research has identified other distinct types of breast cancer for which newer targeted therapies are now available. One such type of breast cancer is Her2-positive, and now there are two approved targeted therapies: trastuzumab and lapatinib.⁶

Research on Her2-positive breast cancer has also helped us learn more about who benefits from commonly used chemotherapy regimens. Data published as far back as 1994 suggested that the benefit of anthracyclines in the adjuvant setting was limited to Her2-positive breast cancer.^7-9 Studies published starting in 2002 have helped clarify this connection implicating another gene, topoisomerase II alpha (TopoII).^10-15 Most recently, data presented at the 2006 San Antonio Breast Cancer Symposium from BCIRG 006, confirmed that only tumors that amplify both the Her2 AND TopoII genes, are specifically sensitive to anthracycline therapy.¹⁶

BCIRG 006 studied the effect of treating Her2-positive breast cancer with chemotherapy, with and without the targeted therapy trastuzumab.¹⁷ One of the study arms in this trial looked at treating Her2-positive breast cancer without an anthracycline in the chemotherapy mix. The researchers were interested in this because of evidence that the well-known cardiac risks of anthracycline therapy are elevated when it is combined with trastuzumab. Data from the second planned interim analysis¹⁸ of this trial demonstrated a comparable decrease in breast cancer relapse and improved survival in the treatment arms that used trastuzumab, regardless of whether the chemotherapy included an anthracycline. Looking at genetic characteristics, the investigators found that patients with tumors that co-amplified the Her2 and TopoII genes (about one-third of the Her2-positive population that was the focus of this trial) responded similarly well regardless of treatment arm. This was because these tumors are preferentially sensitive to anthracycline therapy as well as to trastuzumab (and all treatment arms had one or the other). However, the remaining two-thirds of patients (non-coamplifiers of Her2 and TopoII) were not particularly sensitive to anthracycline-based chemotherapy alone, but as a group did well in either of the trastuzumab treatment arms. In terms of toxicities, BCIRG 006 revealed that the incidence of cardiac dysfunction was five times higher when trastuzumab was used in combination with an anthracycline-based chemotherapy regimen as opposed to when it was combined with chemotherapy that did not contain an anthracycline.¹⁹ In addition, there were no reported cases of leukemia in the non-anthracycline arm compared to a combined total of four cases reported from the two anthracycline-containing arms.²⁰

In summary, for the vast majority of women with breast cancer, anthracycline-based chemotherapy is no more effective and has the potential for more serious toxicities than other known regimens. This includes all women with Her2-normal breast cancer as well as those with Her2-positive breast cancer who do not co-amplify TopoII.

What does this mean for women?

Anthracyclines preferentially benefit only those patients whose breast cancers co-amplify the Her2 and TopoII genes. These patients constitute less than 10% of all patients with breast cancer since about 25-30% of all breast cancers are Her2-positive, and of these, only about a third are TopoII-positive (TopoII amplification only occurs when Her2 is amplified.²¹) In light of the known and serious toxicities of anthracycline therapy, it will be necessary to determine the balance between potential benefit and harms in this population of patients.

We know that all therapies have side effects: some are minor, others serious; some are common and others are rare; and some occur just during therapy while others are long-term. Some therapies are significantly more expensive than others, yet may not confer more benefit or less risk. It is, therefore, necessary to weigh carefully the benefits, risks, and financial implications of all therapies.

We believe there is now ample evidence to change the way we treat breast cancer in the adjuvant setting and incorporate what we have learned from research. One potential obstacle is that while the medical oncology community is quick to embrace additional treatments, it is extremely cautious toward change in the other direction even when the evidence warrants it. Meanwhile, women with breast cancer are subject to complex regimens of toxic and expensive treatments that they simply may not need. We must change this culture and make treatment guidelines and decisions truly patient-centered.

About NBCCF

The National Breast Cancer Coalition Fund is a grassroots organization dedicated to ending breast cancer through the power of action and advocacy. The Coalition's main goals are to increase federal funding for breast cancer research and collaborate with the scientific community to implement new models of research; improve access to high quality health care and breast cancer clinical trials for all women; and expand the influence of breast cancer advocates in all aspects of the breast cancer decision making process.

NBCCF is proud of its collaboration with the Breast Cancer International Research Group on the BCIRG 006 clinical trial. This trial met our expectation of answering an important question in breast cancer by advancing the community's understanding of Her2-positive breast cancer, and guiding the appropriate selection of treatment for this form of the disease. It took courage on the part of investigators and mostly on the part of patients to agree to participate in a trial with a treatment arm that didn't include an anthracycline as part of the chemotherapy regimen. While there was ample biological evidence to support this design, it dared to challenge the oncology community on the need for anthracycline in breast cancer.

Notes

¹ Her2 is also known as HER2/neu and ErbB-2. TopoII is short for topoisomerase II alpha.

² Of the sixteen chemotherapy regimens listed in the National Comprehensive Cancer Network's Breast Cancer Clinical Practice Guidelines, only two do not include an anthracycline.

³ Anthracyclines commonly used for the treatment of breast cancer include doxorubicin, epirubicin, and mitoxantrone.

⁴ Polychemotherapy for early breast cancer: an overview of the randomised trials. Early Breast Cancer Trialists' Collaborative Group. Lancet 1998; 352(9132): 930-42. Click here to view abstract.

⁵ Five-year survival among women taking CMF alone was 69%, compared to 72% among women taking an anthracycline-containing regimen (log-rank 2-sided p-value=0.02).

⁶ Trastuzumab has been approved for both the treatment of metastatic and early breast cancer, while lapatinib has only been approved for the treatment of Her2-positive breast cancers previously treated with trastuzumab.

⁷ Muss HB, Thor AD, Berry DA, et al. c-erbB-2 expression and response to adjuvant therapy in women with node-positive early breast cancer. N Engl J Med 1994 May 5; 330(18): 1260-6. Click here for full text article (available with free registration.)

⁸ Paik S, Bryant J, Park C, et al. erbB-2 and response to doxorubicin in patients with axillary lymph node-positive, hormone receptor-negative breast cancer. J Natl Cancer Inst 1998 Sep 16; 90(18): 1361-70. Click here for full text article in PDF format.

⁹ Pritchard KI, Shepherd LE, O'Malley FP, et al. HER2 and responsiveness of breast cancer to adjuvant chemotherapy. N Engl J Med 2006; 354(20): 2103-11. Click here for full text article (available with free registration.)

¹⁰ Park K, Han S, Gwak GH, et al. Topoisomerase II-alpha gene deletion is not frequent as its amplification in breast cancer. Breast Cancer Res Treat 2006 Aug; 98(3): 337-42. Click here to view abstract.

¹¹ Scandinavian Breast Group Trial 9401; Tanner M, Isola J, Wiklund T, et al. Topoisomerase IIalpha gene amplification predicts favorable treatment response to tailored and dose-escalated anthracycline-based adjuvant chemotherapy in HER-2/neu-amplified breast cancer: Scandinavian Breast Group Trial 9401. J Clin Oncol 2006 Jun 1; 24(16): 2428-36. Click here for full text article.

¹² Knoop AS, Knudsen H, Balslev E, et al. A retrospective analysis of topoisomerase IIa amplifications and deletions as predictive markers in primary breast cancer patients randomly assigned to cyclophosphamide, methotrexate, and fluorouracil or cyclophosphamide, epirubicin, and fluorouracil: Danish Breast Cancer Cooperative Group. J Clin Oncol 2005 Oct 20; 23(30): 7483-90. Click here for full text article.

¹³ Park K, Kim J, Lim S, Han S. Topoisomerase II-alpha (topoII) and HER2 amplification in breast cancers and response to preoperative doxorubicin chemotherapy. Eur J Cancer 2003 Mar; 39(5): 631-4. Click here to view abstract.

¹⁴ Coon JS, Marcus E, Gupta-Burt S, et al. Amplification and overexpression of topoisomerase IIalpha predict response to anthracycline-based therapy in locally advanced breast cancer. Clin Cancer Res 2002 Apr; 8(4): 1061-7. Click here for full text article.

¹⁵ Di Leo A, Gancberg D, Larsimont D, et al. HER-2 amplification and topoisomerase IIalpha gene aberrations as predictive markers in node-positive breast cancer patients randomly treated either with an anthracycline-based therapy or with cyclophosphamide, methotrexate, and 5-fluorouracil. Clin Cancer Res 2002 May; 8(5): 1107-16. Click here for full text article.

¹⁶ Slamon D, Eiermann W, Robert N, et al. Phase III trial comparing AC-T with AC-TH and with TCH in the adjuvant treatment of HER2 positive early breast cancer patients: second interim efficacy analysis. San Antonio Breast Cancer Symposium, December 14, 2006. Breast Cancer International Research Group (BCIRG) presentation available here.

¹⁷ Study participants had Her2-positive, and node-positive or high-risk node-negative, early breast cancer. The commercial name of trastuzumab is Herceptin®.

¹⁸ Study participants had been followed for an average period of 36 months at the time of the second planned interim analysis.

¹⁹ There were 20 cases of cardiac left ventricular function (CHF), grade 3/4, in the AC-TH arm, and 4 in the TCH arm (p=0.0015). Slamon D, Eiermann W, Robert N, et al. Phase III trial comparing AC-T with AC-TH and with TCH in the adjuvant treatment of HER2 positive early breast cancer patients: second interim efficacy analysis. San Antonio Breast Cancer Symposium, December 14, 2006.

²⁰ No p-value is available for this comparison.

²¹ Eiermann W, Pienkowski T, Crown J, et al. Phase III randomized trial comparing docetaxel in combination with doxorubicin and cyclophosphamide (TAC) versus doxorubicin and cyclophosphamide followed by docetaxel (AC®T) in Her-2/neu negative early breast cancer patients with positive axillary lymph nodes: Interim analysis of the BCIRG 005 study. Proceedings of the 28th Annual San Antonio Breast Cancer Symposium. San Antonio, Texas. 2005. Abstract 1069. Click here to view abstract.

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