Adjuvant Anthracyclines: Time for a Change of Heart?

As our knowledge of the molecular profiles of breast cancer has increased as a result of moving closer to our goal of individualized therapy, it is clear that we need to re-think our approach to the adjuvant treatment of early-stage breast cancer. Anthracyclines have undoubtedly improved outcomes for patients with early-stage breast cancer,[1] and these agents have been widely used for several decades. We have, however, begun to question this widespread use of anthracyclines for two principal reasons. First, their overall efficacy is less clear when we take into account the increasing knowledge of breast cancer subsets that has come with the movement away from a one-size-fits-all treatment approach. Second, the toxicity profile of anthracyclines, especially the risk of long-term complications in patients whose breast cancer has been cured, is well established. Although such complications are thankfully rare, they are potentially very serious. The recent focus on the use of anthracyclines in early-stage breast cancer has been sparked by the availability of newer non–anthracyline-containing regimens that appear to be equally effective but that do not have the potential for serious long-term toxicities associated with anthracyclines.[2, 3]

The widespread use of anthracyclines began when these agents were shown to be superior to CMF (cyclophosphamide, methotrexate, and 5-fluorouracil).[1] However, do we really have definitive evidence that anthracycline-based regimens are superior to CMF in patients with early-stage breast cancer? Of the trials that have addressed this question, only one[4] demonstrated that an anthracycline-containing regimen was significantly superior to CMF, and a meta-analysis of all these trials was required to confirm a modest benefit for anthracyclines.[1] A key issue with these older trials is that they accrued patients with breast cancers unselected for subtype, so it is not possible to discern which patients truly benefited more from an anthracycline than from CMF. Given our increasing molecular-level knowledge of diverse breast cancer subtypes,[5] more recent trials should be able to address the question of which patients really need anthracyclines, thereby enabling us to avoid these potentially toxic agents in patients who will not benefit from them.

In patients with unselected breast cancers, the combination of docetaxel and cyclophosphamide (TC) was shown to be superior to doxorubicin and cyclophosphamide (AC) in both disease-free survival and overall survival.[2] As Dr. Henderson states, this was a small trial that was somewhat underpowered overall and that clearly was underpowered with regard to addressing the issue of which patients really do not require an anthracycline-based regimen. TC does appear to have a more favorable long-term toxicity profile than AC, with no apparent potential for cardiac issues; however, our experience with this regimen is considerably shorter than our experience with anthracycline-based regimens. TC appears to be a reasonable alternative to AC in patients with lower-risk disease, although these could also be the patients who do not truly benefit from any chemotherapy in the adjuvant setting.[6, 7]

In contrast to trials of patients with unselected breast cancers, Breast Cancer International Research Group (BCIRG) trial 006[3] randomly assigned patients with HER2 gene-amplified breast cancers to treatment with either AC followed by docetaxel plus trastuzumab, or a non–anthracycline-containing regimen comprised of docetaxel, carboplatin, and trastuzumab (TCH). After 5 years of follow-up, there was no significant difference in outcome in the two groups, although there were fewer events in the AC-docetaxel-trastuzumab group. Topoisomerase IIα (TOP2A) has been previously shown to be a possible predictive marker of benefit from anthracyclines.[8] Intriguingly, patients in BCIRG 006 whose tumors co-expressed both HER2 and TOP2A not only derived more benefit from AC followed by docetaxel and trastuzumab than they did from TCH, but they also did not appear to benefit from the addition of trastuzumab, when compared with patients treated with AC followed by docetaxel alone. This finding underscores the importance of further molecular profiling to the individualization of therapy. TCH has a more favorable toxicity profile with fewer cardiac events compared with AC followed by docetaxel and trastuzumab, and it can be considered a reasonable alternative for patients with early-stage HER2-positive breast cancer, regardless of prognostic markers, such as lymph node status.[3]

Clearly, it is essential that we define which subtypes of breast cancer will benefit from the use of an anthracycline. To date, this information is lacking, and existing and ongoing adjuvant trials may not definitively answer the question. Cancer and Leukemia Group B (CALGB) trial 40101[9]-which randomly assigned patients to treatment with either AC or single-agent paclitaxel, each given for 4 or 6 cycles-recently closed. Results to date demonstrate equivalence between the two durations of therapy,[9] but there are, as yet, no data available on AC vs paclitaxel. The molecular profiling of breast cancers in this trial may help shed light on which cancers benefit from an anthracycline and which from a taxane.

In summary, the evidence to date has left us with an unclear picture of which subtypes of breast cancers are likely to benefit from anthracyclines. The use of an anthracycline prior to or in combination with a taxane appears to be a reasonable approach for triple-negative breast cancers, given the fact that better outcomes for triple negative breast cancers have been noted with this approach in the adjuvant setting.[10] Based on data from the BCIRG 006 trial,[3] anthracyclines can probably be avoided in the majority of HER2-positive breast cancers, with the caveat that there is likely a yet-to-be-defined group of HER2-positive cancers that are exquisitely sensitive to anthracyclines. It is now clear that many estrogen receptor (ER)-positive breast cancers derive little, if any, benefit from adjuvant chemotherapy.[6, 7] The optimal therapeutic regimen for ER-positive cancers with a high recurrence score has not been defined, and whether an anthracycline is needed in this setting remains unclear. Given the available data, it seems reasonable to limit the use of anthracyclines to higher-risk cancers, such as triple-negative breast cancers, while avoiding their use in lower-risk cancers. The use of a neo-adjuvant approach in future studies should allow a direct correlation between molecular profiling and response to anthracyclines, and it could obviate the need for large adjuvant trials that often leave us with more questions than answers.

Financial Disclosure:The author has no significant financial interest or other relationship with the manufacturers of any products or providers of any service mentioned in this article.

References:

References:

1. Effects of chemotherapy and hormonal therapy for early breast cancer on recurrence and 15-year survival: an overview of the randomised trials. Lancet. 2005;365:1687-717.

2. Jones S, Holmes FA, O’Shaughnessy J, et al. Docetaxel with cyclophosphamide is associated with an overall survival benefit compared with doxorubicin and cyclophosphamide: 7-year follow-up of US Oncology Research Trial 9735. J Clin Oncol. 2009;27:1177-83.

3. Slamon D, Eiermann W, Robert N, et al, on behalf of the BCIRG006 investigators. Phase III randomized trial comparing doxorubicin and cyclophosphamide followed by docetaxel with doxorubicin and cyclophosphamide followed by docetaxel and trastuzumab with docetaxel, carboplatin and trastuzumab in HER2neu-positive early stage breast cancer patients: BCIRG006 Study. SABCS. 2009.

4. Levine MN, Pritchard KI, Bramwell VH, et al. Randomized trial comparing cyclophosphamide, epirubicin, and fluorouracil with cyclophosphamide, methotrexate, and fluorouracil in premenopausal women with node-positive breast cancer: update of National Cancer Institute of Canada Clinical Trials Group Trial MA5. J Clin Oncol. 2005;23:5166-70.

5. Sorlie T, Perou CM, Tibshirani R, et al. Gene expression patterns of breast carcinomas distinguish tumor subclasses with clinical implications. Proc Natl Acad Sci U S A. 2001;98:10869-74.

6. Albain KS, Barlow WE, Shak S, et al. Prognostic and predictive value of the 21-gene recurrence score assay in postmenopausal women with node-positive, oestrogen-receptor-positive breast cancer on chemotherapy: a retrospective analysis of a randomised trial. Lancet Oncol.11:55-65.

7. Paik S, Tang G, Shak S, et al. Gene expression and benefit of chemotherapy in women with node-negative, estrogen receptor-positive breast cancer. J Clin Oncol. 2006;24:3726-34.

8. O’Malley FP, Chia S, Tu D, et al. Topoisomerase II alpha and responsiveness of breast cancer to adjuvant chemotherapy. J Natl Cancer Inst. 2009;101:644-50.

9. Shulman LN, Cirrincione C, Berry DA, et al. Four versus six cycles of doxorubicin and cyclophosphamide or paclitaxel as adjuvant therapy for breast cancer in women with 0 to3 positive axillary lymph nodes: CALGB 40101 - a 2 X 2 factorial phase III trial: First results comparing 4 versus 6 cycles. SABCS. 2010;Abstract S6-3.

10. Citron ML, Berry DA, Cirrincione C, et al. Randomized trial of dose-dense versus conventionally scheduled and sequential versus concurrent combination chemotherapy as postoperative adjuvant treatment of node-positive primary breast cancer: first report of Intergroup Trial C9741/Cancer and Leukemia Group B Trial 9741. J Clin Oncol. 2003;21:1431-9.