Breast Cancer: Expanding the Old-Exploring the New

Maybe I could stop my statin now, but I know my cholesterol will quickly creep back up if I do. Are there other choices, such as a better drug? The two excellent reviews in this issue of ONCOLOGY[1,2] remind me of my statin dilemma. First, can knowledge of a patient’s breast tumor genome help select the optimal treatment, and second, when we have an effective treatment for a group of patients-in this case, for breast cancer patients in the adjuvant setting-how long should the course of treatment be?

The explosive gains in cancer genetics have ushered in a new age of targeted therapy. For those of us who have had long careers in oncology, the effectiveness of newer targeted agents in tumors where responses were previously almost never seen-such as melanoma and renal cell cancer-is nothing short of extraordinary. But it seems clear that there will be no “imatinib[3] equivalent” for breast cancer. Ma and Ellis’s meticulous review[1] of clinical applications from The Cancer Genome Atlas (TCGA) for breast cancer shows us that although several targets are common among breast cancer subtypes, no single genetic abnormality is dominant enough to make a “magic bullet” likely. In order to make progress, a concerted attack on several targets simultaneously will almost certainly be required-an approach similar to the dual-targeting recently attempted in melanoma, which has yielded impressive early results.[4] Even for a key target, such as human epidermal growth factor receptor 2 (HER2) in breast cancer, hitting that target at several different loci, eg, with different anti-HER2 agents, leads to superior results.[5-7] We will also need to change our ingrained “treatment by organ site” mindset. Clearly it is the target and not the tissue of origin that matters most, and significantly, many tumors from different sites share the same targets. We know this is true-for example, trastuzumab is effective in both gastric cancer[8] and breast cancer-and the list of such examples will keep growing. The TCGA project is the jewel in the crown of the identification of these key genetic pathways, and it will continue to provide important leads for targeted drug development.

Tamoxifen, and now aromatase inhibitors, have trumped all other systemic therapies for breast cancer in saving and extending lives. The MA-17 trial[9] and the Adjuvant Tamoxifen: Longer Against Shorter (ATLAS) trial[10] clearly show that longer durations of endocrine therapy in the adjuvant setting have significant survival benefits for patients with hormone receptor–positive tumors. This is because it takes a long course of endocrine therapy either to kill that last micrometastasis or to keep micometastases dormant. For premenopausal patients, 10 years of tamoxifen provides generally well-tolerated treatment that improves survival, while for postmenopausal patients, those who have had 5 years of tamoxifen have a choice of continuing on tamoxifen or changing to an aromatase inhibitor. Missing pieces of the adjuvant endocrine story that should fall into place in the next several years are whether extending aromatase inhibitor therapy for longer than 5 years will be as effective as 10 years of tamoxifen, and whether we can identify genes that will allow us to select those patients who will benefit most from this extended treatment. I suspect the main challenge of extended endocrine therapy will be to make certain that patients remain adherent to their medication. Although the ATLAS trial showed a high rate of adherence, not all studies confirm this.[11,12] Ensuring that patients use medications as prescribed will require close monitoring at a time when oncology services are expected to become scarcer.

Now, what about my statin? First, I hope that in the future our cardiology colleagues find new targets and more effective drugs. For now, I will continue to take it and hope my primary care physician continues to remind me to be compliant.

Financial Disclosure:Dr. Muss has served as a consultant to Pfizer and Sanofi.

References:

1. Ma CX, Ellis MJ. Clinical applications from the TCGA for breast cancer. Oncology (Williston Park). 2013;27:1263-79.

2. Jankowitz R, Davidson N. Adjuvant endocrine tehrapy for breast cancer: how long is enough? Oncology (Williston Park). 2013;27:1210-6.

3. O’Brien SG, Guilhot F, Larson RA, et al. Imatinib compared with interferon and low-dose cytarabine for newly diagnosed chronic-phase chronic myeloid leukemia. N.Engl.J Med. 2003;348:994-1004.

4. Flaherty KT, Infante JR, Daud A, et al. Combined BRAF and MEK inhibition in melanoma with BRAF V600 mutations. N Engl J Med. 2012;367:1694-703.

5. Blackwell KL, Burstein HJ, Storniolo AM, et al. Overall survival benefit with lapatinib in combination with trastuzumab for patients with human epidermal growth factor receptor 2-positive metastatic breast cancer: final results from the EGF104900 Study. J Clin Oncol. 2012;30:2585-92.

6. Baselga J, Cortes J, Kim SB, et al. Pertuzumab plus trastuzumab plus docetaxel for metastatic breast cancer. N Engl J Med. 2012;366:109-19.

7. Baselga J, Bradbury I, Eidtmann H, et al. Lapatinib with trastuzumab for HER2-positive early breast cancer (NeoALTTO): a randomised, open-label, multicentre, phase 3 trial. Lancet. 2012;379:633-40.

8. Sanford M. Trastuzumab: a review of its use in HER2-positive advanced gastric cancer. Drugs. 2013;73:1605-15.

9. Jin H, Tu D, Zhao N, et al. Longer-term outcomes of letrozole versus placebo after 5 years of tamoxifen in the NCIC CTG MA.17 trial: analyses adjusting for treatment crossover. J Clin Oncol. 2012;30:718-21.

10. Davies C, Pan H, Godwin J, et al. Long-term effects of continuing adjuvant tamoxifen to 10 years versus stopping at 5 years after diagnosis of oestrogen receptor-positive breast cancer: ATLAS, a randomised trial. Lancet. 2012;381:805-16.

11. Partridge AH, Wang PS, Winer EP, Avorn J. Nonadherence to adjuvant tamoxifen therapy in women with primary breast cancer. J Clin Oncol. 2003;21:602-06.

12. Hershman DL, Kushi LH, Shao T, et al. Early discontinuation and nonadherence to adjuvant hormonal therapy in a cohort of 8,769 early-stage breast cancer patients. J Clin Oncol. 2010;28:4120-28.