Breast cancer is the most common cancer in women, with over 180,000 new diagnoses of invasive disease annually in the United States, based on recent estimates. Despite advances in therapy, over 40,000 women still die of breast cancer each year in the US. While most women with breast cancer present with early-stage, potentially curable disease, young women face higher risks of recurrence and death compared to older women, which leads to challenges in selecting the optimal treatment strategy for these patients. The clinician is typically confronted with an otherwise healthy patient facing a life-threatening disease, and we are inclined to offer therapies with maximal benefit and minimal longterm toxicity, in the face of frequently inadequate or evolving data on how to achieve this.
This manuscript will review the challenge of managing breast cancer in women under 40 years old, the therapeutic choices facing us in the clinic, and emerging data from recent clinical trials.
Is Breast Cancer in Women Under 40 a Different Disease?
Given an otherwise similar cancer presentation, should women under 40 be treated differently from older women on the basis of age alone? The answer is not entirely clear. Even the age range that should be viewed as being at higher risk is somewhat controversial, with women under 35, 40, or 45 classified as “young” in different studies.[2-4] While breast cancer in women under 40 is rare, accounting for roughly 6.5% of all cases, it is more likely to be associated with high-risk features than the cancers seen in older women. In addition, breast cancer in women under 40 may signal a BRCA mutation—and testing should be considered in all young patients— but for most young women a specific etiology is not identified.
Breast cancers in young women are more likely to be estrogen receptor–negative and of higher grade.[6,7] Several studies suggest that HER2-positive disease is more common in younger women.[2,8] In addition, young African-American women are more likely to have triple-negative breast cancer (estrogen receptor–negative, progesterone receptor–negative, and HER2-negative) compared to older women and to young Caucasian women. Age also appears to play a role in risk of recurrence, independent of other disease features.
A recent study by Anders and colleagues suggests that there may be biologic pathways common to tumors from women under 45 compared to those from women over 65. This research identified differential expression within sets of genes related to cell signaling, survival, immune function, and other possible correlates of tumor pathogenesis that appeared to distinguish tumors in younger women from those in older women. Further investigation is needed to clarify whether any ofthese differences represent a specific high-risk feature of cancers prevalent in younger women but present in some older women vs a common process in all younger women with breast cancer. The latter possibility would suggest a need to view breast cancer in this population as a distinct breast cancer subtype.
At a minimum, it is clear that there are as yet unidentified biologic factors contributing to a higher risk of recurrence for young women with breast cancer. Even if these factors are neither present in all cancers in younger women nor confined to this age group, they still require us to consider more rather than less treatment for this patient population. When appropriate, we also need to discuss emerging treatment strategies and/or participation in clinical trials with these patients. This bias toward what many call “aggressive” treatment should, however, be tempered by the fact that women under 40 are also at higher risk for long-term consequences of initial treatments, and for many of our interventions the side effects 20 years and farther down the road are unknown.
Endocrine Therapy and Other Options
For premenopausal women with early-stage endocrine receptor–positive disease, standard therapy includes tamoxifen for 5 years. This strategy is supported by an analysis from the Early Breast Cancer Trialists’ Collaborative Group suggesting a 47% improvement in disease-free survival compared to no endocrine therapy, and a sustained improvement in overall survival of approximately 30% at 15 years, regardless of age.[11,12] Deferring for a moment the challenging question of chemotherapy, major questions for young women with endocrine receptor–positive breast cancer include: (1) How long should we continue tamoxifen? (2) Should we add ovarian suppression? (3) Is the use of aromatase inhibitors plus ovarian suppression superior to tamoxifen plus ovarian suppression? (4) Should we conduct CYP2D6 testing for tamoxifen metabolism? and (5) Should we add adjuvant bisphosphonate therapy (Table 1)?
Duration of Treatment
The standard of tamoxifen for 5 years is based on studies comparing 5 years to 1 or 2 years of therapy, finding 5 years superior in terms of disease-free and overall survival. In addition, the National Surgical Adjuvant Breast and Bowel Project (NSABP) B-14 trial randomized over 1,000 women with endocrine receptor– positive, lymph node–negative breast cancer completing 5 years of tamoxifen to 5 additional years of therapy vs placebo, and found no difference in outcomes, regardless of age.
Two large studies—the adjuvant Tamoxifen Treatment offer more (aTTom) and Adjuvant Tamoxifen Longer Against Shorter (ATLAS) trials—are continuing to explore the optimal duration of tamoxifen therapy. Although both trials are complicated by a pragmatic community- based design, variable initial duration of tamoxifen therapy, and unclear endocrine receptor status for some patients, these trials will provide data on close to 20,000 patients randomized to stopping tamoxifen (at 4 to 5 years for most patients) vs 5 additional years of therapy.
To date, with roughly 7,000 patients, the aTTom trial demonstrates no significant difference in recurrence risk for 10 vs 5 years of tamoxifen, but a small increase in the risk of endometrial cancer with longer therapy. On the other hand, in a preliminary report of the ATLAS trial, results from over 11,000 patients showed a small benefit in disease-free survival but no difference in overall survival.. At this time, the standard duration of therapy remains 5 years, and further data from these large trials are anticipated. Pending these results, it is reasonable to discuss the pros and cons of additional years of treatment and the limits of data in this area with individual patients who face a high risk of recurrence.
For patients at highest risk of recurrence who experience permanent ammenorhea due to chemotherapy, clinicians should consider the data from the MA.17 trial showing reduction in recurrence risk from 5 years of letrozole (Femara), an aromatase inhibitor (AI), following 5 years of tamoxifen. This trial included women rendered postmenopausal due to chemotherapy or ovarian ablation; some form of ovarian ablation/ suppression or frequent monitoring of menopausal status should be implemented if AI therapy is pursued.
Should We Add Ovarian Suppression?
Ovarian suppression is one of the oldest known therapies for breast cancer. The benefits of ovarian suppression alone have been reviewed previously. Whether the addition of ovarian suppression to tamoxifen is more beneficial than tamoxifen alone is currently unclear. This question is being addressed in the Suppression of Ovarian Function Trial (SOFT), in which patients are randomized to tamoxifen, tamoxifen plus ovarian suppression, or an AI plus ovarian suppression; the design of this trial reflects the clinical uncertainty in this area. Several randomized clinical trials, including the ongoing Tamoxifen/ Exemestane Trial (TEXT) and the recently reported Austrian Breast Cancer Study Group (ABCSG) 12 trial, have adopted ovarian suppression plus tamoxifen as the standard control arm for comparison with ovarian suppression plus an AI.
Patients who experience temporary or permanent amenorrhea secondary to chemotherapy have a lower risk of recurrence than patients who experience no cessation in menses, and this difference has long been attributed to the endocrine effects of chemotherapy. Presumably, a similar benefit should be seen through administration of ovarian suppression. There is both a greater rationale for administration of ovarian suppression among young women who may not experience the endocrine benefits of chemotherapy, and reason for caution and concern with the quality of life and late effects of early menopause in these patients. Routine use of ovarian suppression among young women with endocrine receptor–positive breast cancer is not recommended, but this author considers it a reasonable topic for discussion and consideration in select patients at high risk for recurrence.[20,23]
Is an AI-Based Strategy Superior to Tamoxifen?
Although AIs are a standard component of adjuvant endocrine therapy for postmenopausal women, their role in adjuvant therapy for younger women, if any, remains unclear. There may be important biologic differences between cancers that arise in pre- and postmenopausal settings and differences in the effect of further estrogen deprivation (above and beyond ovarian suppression), as opposed to estrogen receptor blockade with tamoxifen. As noted above, the SOFT and TEXT trials will address this question. Recent data from the ABCSG 12 trial found no benefit for ovarian suppression plus an AI vs ovarian suppression plus tamoxifen. Thus, tamoxifen remains the standard.[ 21] For young women with endocrine receptor–positive disease who are unable to tolerate tamoxifen or who have a strong contraindication to such therapy, treatment with an AI plus ovarian suppression can be considered a reasonable alternative. The lack of differences in the ABCSG trial is reassuring, although the study was not powered for noninferiority.
Some women will develop permanent or prolonged amenorrhea after treatment with chemotherapy, but AIs may increase the likelihood of ovarian recovery, making concurrent treatment with ovarian suppression—or, at minimum, frequent monitoring of menopausal status—important.
1. Jemal A, Siegel R, Ward E, et al: Cancer statistics, 2008. CA Cancer J Clin 58:71-96, 2008.
2. Anders CK, Hsu DS, Broadwater G, et al: Young age at diagnosis correlates with worse prognosis and defines a subset of breast cancers with shared patterns of gene expression. J Clin Oncol 26:3324-3330, 2008.
3. Colleoni M, Rotmensz N, Peruzzotti G, et al: Role of endocrine responsiveness and adjuvant therapy in very young women (below 35 years) with operable breast cancer and node negative disease. Ann Oncol 17:1497-1503, 2006.
4. Peppercorn J, Partridge AH: Breast cancer in young women: A new color or a different shade of pink? J Clin Oncol 26:3303-3305, 2008.
5. Hankey BF, Miller B, Curtis R, et al: Trends in breast cancer in younger women in contrast to older women. J Natl Cancer Inst Monogr 7-14, 1994.
6. Gajdos C, Tartter PI, Bleiweiss IJ, et al: Stage 0 to stage III breast cancer in young women. J Am Coll Surg 190:523-529, 2000.
7. Colleoni M, Rotmensz N, Robertson C, et al: Very young women (<35 years) with operable breast cancer: Features of disease at presentation. Ann Oncol 13:273-279, 2002.
8. Love RR, Duc NB, Dinh NV, et al: Young age as an adverse prognostic factor in premenopausal women with operable breast cancer. Clin Breast Cancer 2:294-298, 2002.
9. Carey LA, Perou CM, Livasy CA, et al: Race, breast cancer subtypes, and survival in the carolina breast cancer study. JAMA 295:2492-2502, 2006.
10. Han W, Kim SW, Park IA, et al: Young age: An independent risk factor for disease-free survival in women with operable breast cancer. BMC Cancer 4:82, 2004.
11. Tamoxifen for early breast cancer: An overview of the randomised trials. Early Breast Cancer Trialists’ Collaborative Group. Lancet 351:1451-1467, 1998.
12. Effects of chemotherapy and hormonal therapy for early breast cancer on recurrence and 15-year survival: An overview of the randomised trials. Lancet 365:1687-1717, 2005.
13. Fisher B, Dignam J, Bryant J, et al: Five versus more than five years of tamoxifen for lymph node-negative breast cancer: Updated findings from the National Surgical Adjuvant Breast and Bowel Project B-14 randomized trial. J Natl Cancer Inst 93:684-690, 2001.
14. Gray RG, Rea DW, Handley K, et al: aTTom (adjuvant Tamoxifen--To offer more?): Randomized trial of 10 versus 5 years of adjuvant tamoxifen among 6,934 women with estrogen receptor-positive (ER+) or ER untested breast cancer--preliminary results (abstract 513). J Clin Oncol 26(15S):10s, 2008.
15. Peto R, Davies C, on behalf of the ATLAS Collaboration: ATLAS (Adjuvant Tamoxifen, Longer Against Shorter): International randomized trial of 10 versus 5 years of adjuvant tamoxifen among 11,500 women—Preliminary results (abstract 48). Breast Cancer Res Treat 106(suppl 1), 2007.
16. Goss PE, Ingle JN, Martino S, et al: Randomized trial of letrozole following tamoxifen as extended adjuvant therapy in receptor-positive breast cancer: Updated findings from NCIC CTG MA.17. J Natl Cancer Inst 97:1262-1271, 2005.
17. Partridge AH, Gelber S, Peppercorn J, et al: Fertility and menopausal outcomes in young breast cancer survivors. Clin Breast Cancer 8:65-69, 2008.
18. Beatson G: On the treatment of inoperable cases of carcinoma of the mammary: Suggestions for a new method of treatment, with illustrative cases. Lancet 2:104-107, 1896.
19. Pritchard KI: Ovarian suppression/ablation in premenopausal ER-positive breast cancer patients Oncology (Williston Park) 23:27-33, 2009.
20. National Comprehensive Cancer Network: NCCN Clinical Practice Guidelines in Oncology: Breast cancer, version 1.2009. Available at www.nccn.org. Accessed Apr 19, 2009.
21. Gnant M, Mlineritsch B, Schippinger W, et al: Endocrine therapy plus zoledronic acid in premenopausal breast cancer. N Engl J Med 360:679-691, 2009.
22. Pagani O, O’Neill A, Castiglione M, et al: Prognostic impact of amenorrhoea after adjuvant chemotherapy in premenopausal breast cancer patients with axillary node involvement: Results of the International Breast Cancer Study Group (IBCSG) trial VI. Eur J Cancer 34:632-640, 1998.
23. Krop IE, Winer EP: Ovarian suppression for breast cancer: An effective treatment in search of a home. J Clin Oncol 23:5869-5872, 2005.
24. Smith IE, Dowsett M, Yap YS, et al: Adjuvant aromatase inhibitors for early breast cancer after chemotherapy-induced amenorrhoea: Caution and suggested guidelines. J Clin Oncol 24:2444-2447, 2006.
25. Goetz MP, Rae JM, Suman VJ, et al: Pharmacogenetics of tamoxifen biotransformation is associated with clinical outcomes of efficacy and hot flashes. J Clin Oncol 23:9312-9318, 2005.
26. Goetz MP, Knox SK, Suman VJ, et al: The impact of cytochrome P450 2D6 metabolism in women receiving adjuvant tamoxifen. Breast Cancer Res Treat 101:113-121, 2007.
27. Goetz M, Ames M, Gnant M, et al: Pharmacogenetic (CYP2D6) and gene expression profiles (HOXB13/IL17BR and molecular grade index) for prediction of adjuvant endocrine therapy benefit in the ABCSG 8 trial (abstract 57). Cancer Res 69(suppl):76s, 2008.
28. Higgins MJ, Rae JM, Flockhart DA, et al: Pharmacogenetics of tamoxifen: Who should undergo CYP2D6 genetic testing? J Natl Compr Canc Netw 7:203-213, 2009.
29. Henry NL, Rae JM, Li L, et al: Association between CYP2D6 genotype and tamoxifen-induced hot flashes in a prospective cohort. Breast Cancer Res Treat Jan 20, 2009 (epub ahead of print).
30. Jin Y, Desta Z, Stearns V, Ward B, et al: CYP2D6 genotype, antidepressant use, and tamoxifen metabolism during adjuvant breast cancer treatment. J Natl Cancer Inst 97:30-39, 2005.
31. Chlebowski RT: Bone health in women with early-stage breast cancer. Clin Breast Cancer 5(suppl):S35-S40, 2005.
32. Sverrisdottir A, Fornander T, Jacobsson H, et al: Bone mineral density among premenopausal women with early breast cancer in a randomized trial of adjuvant endocrine therapy. J Clin Oncol 22:3694-3699, 2004.
33. Powles TJ, Hickish T, Kanis JA, et al: Effect of tamoxifen on bone mineral density measured by dual-energy x-ray absorptiometry in healthy premenopausal and postmenopausal women. J Clin Oncol 14:78-84, 1996.
34. Hershman DL, McMahon DJ, Crew KD, et al: Zoledronic acid prevents bone loss in premenopausal women undergoing adjuvant chemotherapy for early-stage breast cancer. J Clin Oncol 26:4739-4745, 2008.
35. Gnant M, Mlineritsch B, Luschin-Ebengreuth G, et al: Adjuvant endocrine therapy plus zoledronic acid in premenopausal women with early-stage breast cancer: 5-year follow-up of the ABCSG-12 bone-mineral density substudy. Lancet Oncol 9:840-849, 2008.
36. Diel IJ, Solomayer EF, Costa SD, et al: Reduction in new metastases in breast cancer with adjuvant clodronate treatment. N Engl J Med 339:357-363, 1998.
37. Saarto T, Blomqvist C, Virkkunen P, et al: Adjuvant clodronate treatment does not reduce the frequency of skeletal metastases in node-positive breast cancer patients: 5-year results of a randomized controlled trial. J Clin Oncol 19:10-17, 2001.
38. Powles T, Paterson S, Kanis JA, et al: Randomized, placebo-controlled trial of clodronate in patients with primary operable breast cancer. J Clin Oncol 20:3219-3224, 2002.
39. Paik S, Shak S, Tang G, et al: A multigene assay to predict recurrence of tamoxifen-treated, node-negative breast cancer. N Engl J Med 351:2817-2826, 2004.
40. van ‘t Veer LJ, Dai H, van de Vijver MJ, et al: Gene expression profiling predicts clinical outcome of breast cancer. Nature 415:530-536, 2002.
41. 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 24:3726-3734, 2006.
42. Albain K, Barlow W, Shak S, et al: Prognostic and predictive value of the 21-gene recurrence score assay in postmenopausal, node-positive, ER-positive breast cancer (abstract 10). Breast Cancer Res Treat 106(suppl):1, 2007.
43. Henderson IC, Berry DA, Demetri GD, et al: Improved outcomes from adding sequential paclitaxel but not from escalating doxorubicin dose in an adjuvant chemotherapy regimen for patients with node-positive primary breast cancer. J Clin Oncol 21:976-983, 2003.
44. Mamounas EP, Bryant J, Lembersky B, et al: Paclitaxel after doxorubicin plus cyclophosphamide as adjuvant chemotherapy for node-positive breast cancer: Results from NSABP B-28. J Clin Oncol 23:3686-3696, 2005.
45. 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 21:1431-1439, 2003.
46. Roche H, Fumoleau P, Spielmann M, et al: Sequential adjuvant epirubicin-based and docetaxel chemotherapy for node-positive breast cancer patients: The FNCLCC PACS 01 trial. J Clin Oncol 24:5664-5671, 2006.
47. Martin M, Pienkowski T, Mackey J, et al: Adjuvant docetaxel for node-positive breast cancer. N Engl J Med 352:2302-2313, 2005.
48. Eiermann W, Pienkowski T, Crown J, et al: BCIRG 005 main efficacy analysis: A phase III randomized trial comparing docetaxel in combination with doxorubicin and cyclophosphamide (TAC) versus doxorubicin and cyclophosphamide followed by docetaxel (AC->T) in women with Her-2/neu negative axillary lymph node positive early breast cancer (abstract 77). San Antonio Breast Cancer Symposium; San Antonio, Tex; Dec 10-14, 2008.
49. Swain SM, Jeong J-H, Geyer CE, et al: NSABP-B30: Definitive analysis of patient outcome from a randomized trial evaluating different schedules and combinations of adjuvant therapy containing doxorubicin, docetaxel, and cyclophosphamide in women with operable, node positive breast cancer (abstract 75). San Antonio Breast Cancer Symposium; San Antonio, Tex; Dec 10-14, 2008.
50. Jones SE, Savin MA, Holmes FA, et al: Phase III trial comparing doxorubicin plus cyclophosphamide with docetaxel plus cyclophosphamide as adjuvant therapy for operable breast cancer. J Clin Oncol 24:5381-5387, 2006.
51. Slamon DJ, Clark GM, Wong SG, et al: Human breast cancer: Correlation of relapse and survival with amplification of the HER-2/neu oncogene. Science 235:177-182, 1987.
52. Romond EH, Perez EA, Bryant J, et al: Trastuzumab plus adjuvant chemotherapy for operable HER2-positive breast cancer. N Engl J Med 353:1673-1684, 2005.
53. Piccart-Gebhart MJ, Procter M, Leyland-Jones B, et al: Trastuzumab after adjuvant chemotherapy in HER2-positive breast cancer. N Engl J Med 353:1659-1672, 2005.
54. Slamon D, Eiermann W, Robert N, et al, on behalf of the BCIRG 006 investigators: Phase III randomized trial comparing doxorubicin and cyclophosphamide followed by docetaxel
(ACT) with doxorubicin and cyclophosphamide followed by docetaxel and trastuzumab (ACTH) with docetaxel, carboplatin and trastuzumab (TCH) in HER2 positive early breast cancer patients: BCIRG 006 study (abstract 1). Breast Cancer Res Treat 95(suppl 1):S5, 2005.
55. Rakkhit R, Broglio K, Peintinger F, et al: Significant increased recurrence rates among breast cancer patients with HER2-positive, T1a,bN0M0 tumors (abstract 701). Cancer Res 69(suppl 2):96s, 2009.
56. Fisher B, Bryant J, Wolmark N, et al: Effect of preoperative chemotherapy on the outcome of women with operable breast cancer. J Clin Oncol 16:2672-2685, 1998.
57. Mayer EL, Carey LA, Burstein HJ: Clinical trial update: Implications and management of residual disease after neoadjuvant therapy for breast cancer. Breast Cancer Res 9:110, 2007.
58. Partridge AH, Gelber S, Peppercorn J, et al: Web-based survey of fertility issues in young women with breast cancer. J Clin Oncol 22:4174-4183, 2004.
59. Ismail-Khan R, Minton S, Cox C, et al: Preservation of ovarian function in young women treated with neoadjuvant chemotherapy for breast cancer: A randomized trial using the GnRH agonist (triptorelin) during chemotherapy (abstract 524). J Clin Oncol 26(15S):12s, 2008.
60. Azim AA, Costantini-Ferrando M, Oktay K: Safety of fertility preservation by ovarian stimulation with letrozole and gonadotropins in patients with breast cancer: A prospective controlled study. J Clin Oncol 26:2630-2635, 2008.
61. Beadle BM, Woodward WA, Middleton LP, et al: The impact of pregnancy on breast cancer outcomes in women