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Certain biomarkers predict anthracycline chemotherapy benefit in breast cancer
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Patients with early-stage breast cancer whose tumors expressed CEP17 duplication or TOP2A aberrations but not HER-2 amplification were likely to benefit from adjuvant anthracycline chemotherapy, according to the results of a pooled analysis.
“Chemotherapy comes with benefits for a group of patients who respond and whose disease is controlled by the treatment, but it also carries with it a number of specific side effects,” John M.S. Bartlett, PhD, of the department of transformative pathology at the Ontario Institute for Cancer Research, told HemOnc Today. “Anthracycline chemotherapy — the main chemotherapy our study targeted — carries with it increased risks for heart damage, some forms of leukemia and neutropenia. We wanted to identify patients who were most likely to benefit from the therapy.”
Previous studies have failed to suggest a link between predictive biomarkers and benefit from anthracycline chemotherapy with strong evidence, according to study background.
Bartlett and colleagues evaluated data from 3,846 patients with early breast cancer from five trials that compared anthracycline chemotherapy with cyclophosphamide, methotrexate and fluorouracil (CMF).
The majority of patients had fluorescent in situ hybridization data available for HER-2 status (89.3%), CEP17 duplication (80.6%) and TOP2A status (80.6%).
Researchers observed that 41% (n = 1,581) experienced relapse and 34% (n = 1,329) died during follow-up.
The benefits conferred by anthracycline-containing chemotherapy in these patients with regard to OS (HR = 0.84; 95% CI, 0.76-0.94) and RFS (HR = 0.82; 95% CI, 0.74-0.91) were comparable to those observed in the overall population of the five represented trials.
In analyses stratified by trial and adjusted for confounding factors, the treatment-by-marker interaction was significant for RFS and OS for TOP2A alterations (HR for RFS = 0.67; 95% CI, 0.5-0.89; HR for OS = 0.67; 95% CI, 0.5-0.9) and CEP17 duplication (HR for RFS = 0.67; 95% CI, 0.52-0.86; HR for OS = 0.71; 95% CI, 0.54-0.93) but not for HER-2 amplification (HR for RFS = 0.81; 95 CI, 0.63-1.05; HR for OS = 0.8; 95% CI, 0.61-1.04).
An adjusted model that combined CEP17 and TOP2A predicted anthracycline benefit in all five trials for RFS (HR = 0.64; 95% CI, 0.51-0.82) and OS (HR = 0.66; 95% CI, 0.51-0.85).
The researchers acknowledged their inability to evaluate the addition of taxanes to an anthracycline chemotherapy regimen as a limitation to their study.
“There is now strong evidence that you can identify patients who benefit from anthracyclines and separate them from patients who do not benefit,” Bartlett said. “Additional research is needed in the context of modern chemotherapy that includes taxanes.” – by Cameron Kelsall
For more information:
John M.S. Bartlett, PhD, can be reached at Ontario Institute for Cancer Research, MaRS Centre, South Tower, 101 College St., Suite 800, Toronto, ON M5G 0A3; email: john.bartlett@oicr.on.ca.
Disclosure: Bartlett reports no relevant financial disclosures. Please see the full study for a list of all other researchers’ relevant financial disclosures.
Perspective
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Debu Tripathy, MD
The use of non-anthracycline adjuvant chemotherapy for HER-2–negative early-stage breast cancer has skyrocketed in the United States, but not as much so elsewhere. This has been driven, in part, by numerous reports that showed anthracycline benefit is confined to HER-2–expressing tumors, and also a single trial that showed superiority of docetaxel plus cyclophosphamide compared with doxorubicin (TC) and cyclophosphamide (AC). Subsequent studies showed a relationship between the amplification of HER-2 with either amplification or deletion of the gene encoding a direct target of anthracyclines, topoisomerase II-alpha (TOP2A). This patient-level meta-analysis on 3,846 of 4,864 eligible patients from five trials that compared CMF (cyclophosphamide, methotrexate and fluorouracil) to anthracycline therapy showed that either duplication of the chromosome 17 centromere (CEP17) or TOP2A aberrations (either deletion or amplification) but not HER-2 amplification independently predicts doxorubicin benefit. The authors posit that CEP17 duplication and TOP2A amplification or deletion provide a unifying biomarker for anthracycline benefit, and this might be biologically explained by a more global phenotype of chromosomal instability.However, there are still pieces of this puzzle that remain unsolved — in particular, why this phenotype would provide a benefit from anthracyclines but not from other DNA-targeting drugs such as alkylators. Also, cellular events ultimately are driven by proteins as opposed to genomic aberrations, and often in the context of post-translational modifications such as phosphorylation, as is the case with topoisomerase 2-alpha. Why both TOP2A deletion or amplification should modulate anthracycline sensitivity remains unclear. In fact, one of the central themes of the REMARK checklist for tumor prognostic marker studies calls for an underlying biological hypothesis, which in this case is still elusive. It is therefore premature to apply HER-2, TOP2A or CEP17 assays in clinical decisions regarding anthracycline therapy. Nevertheless, these and other studies form the foundation to set parameters and cutpoints for their validation — ideally in the NSABP B-49 trial, which aimed to determine if TC is noninferior to the several anthracycline-based chemotherapy regimens in terms of invasive DFS specifically in HER-2–negative, node-positive or high-risk node-negative cases. This trial closed in late 2013 and is not yet mature, and tissue blocks are available for analysis. This trial should be able to reject or accept a meaningful benefit of anthracycline in the whole population studied. Still, it may be that CEP17 and TOP2A status are not as informative in HER-2–negative disease as these genetic changes, as they are less frequent, and it will indeed be challenging to explore this question in HER-2–positive breast cancer in the context of contemporary HER-2–targeted treatment approaches.
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