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Genomics and Challenges Toward Personalized Breast Cancer Local Control

Department of Surgery, Surgical Oncology Research Unit, Ioannina University School of Medicine, Ioannina, Greece

Efstathios Lykoudis

Department of Plastic Surgery, Ioannina University School of Medicine, Ioannina, Greece

Theodore Liakakos

Departmet of Surgery, Attiko University Hospital, University of Athens, Athens, Greece

To the Editor:

The article by Nguyen et al¹ in Journal of Clinical Oncology demonstrates an overall low local recurrence rate after breast-conserving surgery, but varying magnitude of this risk among gene expression profiling–based subtypes. The 5-year local recurrence rates of 793 patients were higher for HER-2 (8.4%) and basal (7.1%) subtypes than for luminal A (0.8%) or luminal B (1.5%) subtypes. Approximating this molecular classification using human epidermal growth factor receptor 2 (HER-2), estrogen receptor (ER), and progesterone receptor (PR) status currently used in routine clinical practice,² the authors provide clinically useful information on a potential link among these subtypes and local control.

Why is local control important for long-term survival given the systemic nature of breast cancer? Local failures include local recurrence or a new ipsilateral breast cancer and contralateral breast cancer. With an increasing number of long-term survivors and long-term follow-up data available, objective evidence documents that ipsilateral breast cancer and/or contralateral breast cancer as first isolated events may be associated with increased mortality.^3-5

Potential pretreatment risk stratification into high, moderate, and low risk for local failure may affect treatment decision. High-risk patients may benefit from a more aggressive surgery, such as unilateral mastectomy and contralateral prophylactic mastectomy rather than the standard breast-conserving surgery for localized disease. Recent data show a dramatic increase of more aggressive surgery in the United States to prevent this local failure.⁶ Instead, this generalized surgical overtreatment, a personalized aggressive surgery only to high-risk patients, may prevent local failure and improve survival in these women while sparing unnecessary complications of an aggressive surgery in low-risk patients.⁵

Of the data reported by Nguyen et al, most clinical interest is focused on the basal-like subtype because the updated treatment has not changed. In contrast, there are limitations for the other subtypes. The current standard targeted agents, trastuzumab for HER-2–positive disease^7,8 and aromatase inhibitors for postmenopausal women with ER/PR-positive disease⁹ were not used. These newer therapies reduce local failure^7-9 and thus, data from the Nguyen report on these subtypes are of limited clinical utility.

Basal-like subtype is characterized by lack of expression of HER-2/ER/PR (triple negative), aggressive behavior, limited or no efficacy of available targeted agents, and poor prognosis. These tumors are remarkably similar to tumors arising in BRCA1 mutation carriers.¹⁰ Given that the patient subgroup with BRCA1 inherited mutations is thought to be associated with the highest risk of local failure and may benefit from aggressive surgery,^5,11-13 it could be supposed that women with early-stage sporadic triple-negative tumors might also benefit from such an aggressive surgery for local control. However, at present, evidence is still insufficient to support this hypothesis, and long-term results from prospective, large-scale studies should be awaited to drawn rigorous conclusions.

Although all types of recurrence (local, contralateral, or distant) are important, identification of high-risk patients for local failure still remains a dream. Pretreatment genetic testing allows identification of BRCA1/2 mutations carriers, who account for only a small fraction of high-risk patients.¹⁴ The identification of the remaining high-risk patients among familial BRCA-negative patients and those patients with sporadic cancer (no breast cancer family history) is currently impossible. Novel genetic variants have already been identified by genomewide association studies, but they confer only a modest risk to breast cancer initiation.^15-17 Although several other new susceptibility gene variants will be detected by new larger genomewide association studies, the major challenge will remain the assessment of sophisticated interactions between these gene variants and environmental exposure. Future prospective, large-scale, population-based studies (familial BRCA and non-BRCA patients and sporadic patients with and without local failure) may lead to identification of combined genetic and environmental risk factors as predictive tools for accurate risk stratification and truly personalized local control.

AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

The author(s) indicated no potential conflicts of interest.

REFERENCES

1. Nguyen PL, Taghian AG, Katz MS, et al: Breast cancer subtype approximated by estrogen receptor, progesterone receptor, and HER-2 is associated with local and distant recurrence after breast-conserving therapy. J Clin Oncol 26:2373-2378, 2008[Abstract/Free Full Text]

2. Goldhirsch A, Wood WC, Gelber RD, et al: Progress and promise: Highlights of the international expert consensus on the primary therapy of early breast cancer 2007. Ann Oncol 18:1133-1144, 2007[Abstract/Free Full Text]

3. Clarke M, Collins R, Darby S, et al: Effects of radiotherapy and of differences in the extent of surgery for early breast cancer on local recurrence and 15-year survival: An overview of the randomized trials. Lancet 366:2087-2106, 2005[Medline]

4. Punglia RS, Morrow M, Winer EP, et al: Local therapy and survival in breast cancer. N Engl J Med 356:2399-2405, 2007[Free Full Text]

5. Roukos DH: Genetics and genomewide association studies: Surgery-guided algorithm and promise for future breast cancer personalized surgery. Exp Rev Mol Diagn 8:587-597, 2008[CrossRef][Medline]

6. Tuttle TM, Habermann EB, Grund EH, et al: Increasing use of contralateral prophylactic mastectomy for breast cancer patients: A trend toward more aggressive surgical treatment. J Clin Oncol 25:5203-5209, 2007[Abstract/Free Full Text]

7. Piccart-Gebhart MJ, Procter M, Leyland-Jones B, et al: Trastuzumab after adjuvant chemotherapy in HER-2-positive breast cancer. N Engl J Med 353:1659-1672, 2005[Abstract/Free Full Text]

8. Romond EH, Perez EA, Bryant J, et al: Trastuzumab plus adjuvant chemotherapy for operable HER-2-positive breast cancer. N Engl J Med 353:1673-1684, 2005[Abstract/Free Full Text]

9. Forbes JF, Cuzick J, Buzdar A, et al: Effect of anastrozole and tamoxifen as adjuvant treatment for early-stage breast cancer: 100-month analysis of the ATAC trial. Lancet Oncol 9:45-53, 2008[CrossRef][Medline]

10. Rakha EA, Reis-Filho JS, Ellis IO: Basal-like breast cancer: A critical review. J Clin Oncol 26:2568-2581, 2008[Abstract/Free Full Text]

11. Metcalfe K, Lynch HT, Ghadirian P, et al: Contralateral breast cancer in BRCA1 and BRCA2 mutation carriers. J Clin Oncol 22:2328-2335, 2004[Abstract/Free Full Text]

12. Roukos DH: Linking contralateral breast cancer with genetics. Radiother Oncol 86:139-141, 2008[CrossRef][Medline]

13. Pierce LJ, Levin AM, Rebbeck TR, et al: Ten-year multi-institutional results of breast-conserving surgery and radiotherapy in BRCA1/2-associated stage I/II breast cancer. J Clin Oncol 24:2437-2443, 2006[Abstract/Free Full Text]

14. Roukos DH: Prognosis of breast cancer in carriers of BRCA1 and BRCA2 mutations. N Engl J Med 357:1555-1556, 2007[Free Full Text]

15. Easton DF, Pooley KA, Dunning AM: Genome-wide association study identifies novel breast cancer susceptibility loci. Nature 447:1087-1093, 2007[CrossRef][Medline]

16. Gold B, Kirchhoff T, Stefanov S, et al: Genome-wide association study provides evidence for a breast cancer risk locus at 6q22.33. Proc Natl Acad Sci U S A 105:4340-4345, 2008[Abstract/Free Full Text]

17. Hunter DJ, et al: A genome-wide association study identifies alleles in FGFR2 associated with risk of sporadic postmenopausal breast cancer. Nat Genet 39:870-874, 2007[CrossRef][Medline]

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