JO U R N A L OF GE RI A TRI C O N COL O G Y 5 (2 0 1 4) 2–7
Available online at www.sciencedirect.com
ScienceDirect
Meet the Experts
Managing metastatic human epidermal growth factor receptor 2 (HER2)-positive breast cancer in the older patient Rachel A. Freedmana,⁎, Hyman B. Mussb a
Department of Medical Oncology, Harvard Medical School, Dana–Farber Cancer Institute, 450 Brookline Avenue, Boston, MA 02215, USA Lineberger Comprehensive Cancer Center, Department of Medicine, University of North Carolina, 170 Manning Drive, Chapel Hill, NC 27514, USA
b
AR TIC LE I N FO
ABS TR ACT
Article history:
Treating older patients with metastatic human epidermal growth factor receptor 2
Received 6 September 2013
(HER2)-positive breast cancer is often challenging. This is largely due to the issues
Accepted 10 October 2013
providers face in making decisions in the setting of limited efficacy and toxicity data
Available online 30 October 2013
specific to older women in addition to the competing challenges of managing comorbidity and preserving functional status. Here, we discuss currently available treatment regimens
Keywords:
and other important issues to consider when treating older patients with metastatic,
Older women
HER2-positive disease.
Breast cancer
© 2013 Elsevier Ltd. All rights reserved.
Metastatic Human Epidermal Growth Factor Receptor 2
Contents 1. 2. 3.
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2 3 Selecting Chemotherapy Partners for Trastuzumab in the Older Patient: Combination vs. Single Agent Chemotherapy . . . 3 Trastuzumab Monotherapy and HER2-Directed Therapy with Hormonal Therapy . . . . . . . . . . . . . . . . . . . . . 3
4. New Anti-HER2 Agents . . . . . . . . . . . 5. Toxicity and Dose Selection . . . . . . . . 6. Clinical Trials . . . . . . . . . . . . . . . . 7. Summary . . . . . . . . . . . . . . . . . . Disclosures and Conflict of Interest Statements Author Contributions . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . .
. . . . . . .
. . . . . . .
. . . . . . .
. . . . . . .
. . . . . . .
. . . . . . .
. . . . . . .
. . . . . . .
. . . . . . .
. . . . . . .
. . . . . . .
. . . . . . .
. . . . . . .
. . . . . . .
. . . . . . .
. . . . . . .
. . . . . . .
. . . . . . .
. . . . . . .
. . . . . . .
. . . . . . .
. . . . . . .
. . . . . . .
. . . . . . .
. . . . . . .
. . . . . . .
. . . . . . .
. . . . . . .
. . . . . . .
. . . . . . .
. . . . . . .
. . . . . . .
. . . . . . .
. . . . . . .
. . . . . . .
. . . . . . .
. . . . . . .
. . . . . . .
. . . . . . .
. . . . . . .
. . . . . . .
. . . . . . .
4 4 5 5 5 6 6
⁎ Corresponding author at: Dana–Farber Cancer Institute, 450 Brookline Avenue, Boston, MA 02215, USA. Tel.: +1 617 632 4587; fax: +1 617 632 1930. E-mail addresses: [email protected] (R.A. Freedman), [email protected] (H.B. Muss). 1879-4068/$ – see front matter © 2013 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.jgo.2013.10.001
JO U R N A L OF GE RI A TR IC O N COL O G Y 5 (2 0 1 4) 2 –7
1.
Introduction
Rates of human epidermal growth factor receptor 2 (HER2)positive breast cancer in older populations have not been well described, although a recent analysis from the National Comprehensive Cancer Network (NCCN) demonstrated that 26% of patients with stage I–III, HER2-positive breast cancers diagnosed during 2005–2008 were aged ≥60.1 The incidence of metastatic HER2-positive breast cancer among older women is not known but is likely to be in the 10–20% range. In the adjuvant setting, older women are less likely to receive chemotherapy and trastuzumab-based therapy compared with younger women, likely impacting survival.1–6,57 The reasons for lower rates of infusional treatment administration in older women are likely multifactorial and include physician bias, patient and family preferences, or concerns for competing comorbidity.7–9 In addition, robust prospective data for standard adjuvant treatments are lacking for older patients because of their persistent underrepresentation in clinical trials. Although pooled analyses and cancer registry studies have suggested substantial benefits of chemotherapy for older women,4,5,10,11 the expected treatment benefits and toxicities in older patients are often extrapolated from observations in younger women and not always generalizable. Data for older patients with metastatic HER2-positive breast cancer are even more limited with regard to treatment patterns, toxicity, and outcomes. In the registHER study,12 1001 women with newly diagnosed metastatic, HER2-positive breast cancer during 2003–2006 were followed over time. Among the 209 women aged 65 and older in this cohort, approximately 22% were diagnosed with de novo metastatic disease and nearly 50% had estrogen receptor or progesterone receptor-positive tumors. The oldest patients in registHER were the least likely to receive a trastuzumab-based first-line treatment regimen (77% of women age ≥ 75, 81% of women age 65–74, and 85% of women age < 65 received first-line trastuzumab). Not surprisingly, among all women receiving trastuzumab within registHER, the oldest patients were more likely to receive either trastuzumab monotherapy or trastuzumab with hormonal therapy rather than trastuzumab-based chemotherapy regimens. Despite these differences in treatments, rates of breast cancer-specific survival were similar among age groups, although when data were analyzed by receipt of first-line trastuzumab or not, progression-free survival (PFS) and overall survival (OS) were both significantly longer for older women receiving trastuzumab vs. not (median PFS = 11.0 vs. 3.4 months and OS = 40.4 vs. 25.9 months).12 In addition, another study using Surveillance, Epidemiology, and End Results (SEER)—Medicare data showed that older women with metastatic disease receiving first-line chemotherapy with trastuzumab had improved adjusted cancer-related survival compared to those receiving trastuzumab monotherapy (hazard ratio [HR] =0.54; 95% Confidence Interval [CI] 0.39– 0.74).13 Since the introduction of trastuzumab, improved outcomes for all women with metastatic HER2-positive disease have been observed with median survival times now reaching 3.5 years from the time of initiation of therapy.14,15 Despite the absence of prospective, randomized data for older women
3
with HER2-positive metastatic breast cancer, the limited observational data discussed above strongly suggest that older women significantly benefit from HER2-directed therapy with the largest benefit likely from combinations of trastuzumab and chemotherapy. Unlike the adjuvant setting where combination chemotherapy is the standard, the judicious use of sequential single agents in older patients is generally well tolerated and adding trastuzumab is not usually associated with major increases in toxicity compared to chemotherapy alone. Since the major goals of therapy in the metastatic setting are maintenance or improvement in quality of life as well as controlling the progression of metastases, palliation of an older patient's symptoms and reducing disease burden with acceptable toxicity for long periods of time is an achievable goal.
2. Selecting Chemotherapy Partners for Trastuzumab in the Older Patient: Combination vs. Single Agent Chemotherapy Ongoing controversy in the literature exists regarding the benefits of single-agent vs. combination chemotherapy for first-line treatment for metastatic breast cancer.16–18 Although response rates are often higher when doublet rather than single-agent chemotherapy is administered, overall survival for these two treatment strategies is equivalent18 and a sequential, singleagent chemotherapy approach allows for reduced toxicity, improved quality of life, and preservation of options for the next line. In addition, given the greater toxicity experienced by older patients compared with younger patients receiving chemotherapy,19 avoiding combination chemotherapy in this setting is optimal for the vast majority of patients — unless faced with extenuating circumstances (i.e. visceral crisis). Using a single chemotherapeutic agent coupled with HER2-directed therapy in the metastatic disease setting can result in enhanced efficacy and without a major increase in toxicity in older patients, as is the case for paclitaxel,20–23 vinorelbine,24–27 and capecitabine (either with trastuzumab or lapatinib).28–30 Emerging data have also demonstrated impressive efficacy for regimens that combine trastuzumab with other anti-HER2 agents but without cytotoxic chemotherapy such as trastuzumab and the oral anti-HER2 tyrosine kinase inhibitor, lapatinib.31 This biologic regimen may be an appealing option for some older women and has shown efficacy for women who have received prior lines of anti-HER2 therapy.31 Protocol NCT01273610 at City of Hope is currently addressing the efficacy and tolerability of lapatinib and trastuzumab for patients of 60 and older with metastatic, HER2-positive disease and will greatly inform clinical practice for older patients.
3. Trastuzumab Monotherapy and HER2-Directed Therapy with Hormonal Therapy In patients where competing comorbidity, patient/family preferences, and/or poor functional status may limit chemotherapy administration, trastuzumab monotherapy is a reasonable alternative to chemotherapy administration. In firstline metastatic disease, trastuzumab alone resulted in a 34%
4
JO U R N A L OF GE RI A TRI C O N COL O G Y 5 (2 0 1 4) 2–7
response rate in those with HER2 amplification by fluorescence in situ hybridization (FISH) with a median time to progression of approximately 3.5 months for those treated with either weekly or every-three-week trastuzumab administration and a median overall survival of 24.4 months (95% CI 16.9–31.7 months).32 In addition, trastuzumab and hormonal therapy improved outcomes over hormonal therapy alone for patients with hormone receptor-positive and HER2-positive disease. When combined with hormonal therapy, trastuzumab-treated patients have superior outcomes than with hormonal therapy alone33 with a median PFS of 4.8 months for the combination vs. 2.4 months with anastrozole alone (P = .0016). Whether this strategy is better than sequential use of hormonal therapy followed by trastuzumab is uncertain. Lapatinib in combination with letrozole has also shown improved efficacy compared to letrozole alone in the metastatic setting (PFS = 8.2 vs. 3.0 months; HR = 0.71, 95% CI 0.53–0.96, P = 0.019) but with the combination showing a higher frequency of diarrhea.34 These treatment combinations are appealing for the older women with advanced comorbidity and/or minimal disease burden and for those who have hormone receptor-positive disease.
4.
New Anti-HER2 Agents
Over the past year, two exciting new agents gained U.S. Food and Drug Administration (FDA) approval for metastatic HER2-positive breast cancer: trastuzumab emtansine (T-DM1, Kadcyla®, Genentech/Roche) and pertuzumab (Perjeta®, Genentech/Roche). Both of these agents have demonstrated improved efficacy in large randomized trials (Trastuzumab Emtansine for HER2-Positive Advanced Breast Cancer [EMILIA] for T-DM1 and Clinical Evaluation of Pertuzumab and Trastuzumab [CLEOPATRA] for pertuzumab), when compared with standard chemotherapy and HER2-directed therapy. However, it is of note that neither of the pivotal trials for these agents included a substantial proportion of older patients (median age of EMILIA was 53 years and median age of CLEOPATRA was 54 years).35,36 In EMILIA, women who were previously treated with a taxane and trastuzumab in the metastatic setting were randomized to receive T-DM1 or lapatinib–capecitabine upon disease progression. Women receiving T-DM1 on study experienced improved PFS (median survival = 9.6 vs. 6.4 months; HR for progression or death = 0.65, 95% CI 0.55–0.77; P < .001) and also had fewer grade 3 or higher toxicity events (40.8% with T-DM1 vs. 57% with lapatinib–capecitabine), including lower rates of diarrhea, hand–foot symptoms, neutropenia, nausea, and fatigue. Despite the limitations in applying these results to older women, the toxicity profile of T-DM1 was certainly more favorable,35 making this an appealing treatment option for older women with metastatic breast cancer. A multi-center study of T-DM1 in the adjuvant setting for older patients with breast cancer will soon be opening nationwide, with the ability to get initial efficacy and toxicity data for older women with HER2-positive disease, although patients with metastatic disease will be excluded from this trial.
In the CLEOPATRA trial, the combination of pertuzumab, trastuzumab, and docetaxel was more efficacious than trastuzumab–docetaxel alone in the first-line setting and did not result in significantly worsened toxicity (median PFS = 18.5 vs. 12.4 months; HR = 0.62, 95% CI 0.51–0.75; P < .001).36 In the setting of treating the older patient, one might consider weekly taxane administration rather than every-three-week administration because of potentially better tolerance.37–39 It is also of note that on CLEOPATRA, patients were permitted to stop taxane therapy after disease stabilization and continue antibody therapies until progression.36 The ability to transition to an all-biologics regimen is a nice option for the older patient who will experience cumulative toxicity with chemotherapy over time. In the future, more information on toxicity for older women receiving these novel therapies will be required with special attention paid to worsening physical function in addition to hematologic and cardiac toxicities. In the meantime, because of the favorable toxicity profiles and efficacy associated with T-DM1 and pertuzumab, healthy older women with metastatic HER2-positive disease should be treated similarly to younger women. Currently, pertuzumab has approval for the first-line setting while T-DM1 was approved for women whose cancers have progressed on a taxane and trastuzumab. A schema showing our recommendations for anti-HER2 directed therapy is shown in Fig. 1.
5.
Toxicity and Dose Selection
When thinking about HER2-directed therapy, toxicity considerations must include those related to cardiotoxicity. Although the rates of any trastuzumab-related cardiac toxicity in clinical trials have been low (1–4%),40–43 recent population-based studies have raised concerns that the incidence of heart failure or cardiomyopathy may be higher outside of clinical trials, particularly for older women.44–46 Because of these concerns, close observation of cardiotoxicity with serial monitoring of ejection fraction for older women receiving HER2-directed agents is necessary. In addition, early and aggressive management of pre-existing cardiac conditions can help optimize tolerance to treatment with consideration of up-front beta blockers and angiotensin-converting enzyme (ACE) inhibitors in patients at risk for the development of congestive heart failure.47–51 Close collaboration with a patient's primary care physician and a cardiologist is crucial to optimally co-manage cardiac conditions. Recently, more attention has been paid to predicting toxicity with chemotherapy in older patients with cancer. In work led by Drs. Hurria and Extermann,52,53 the development of models to predict toxicity has been immensely informative and has included clinical factors in addition to geriatric assessment tools.54 Although these models require further validation in specific disease sites and with specific treatments, they demonstrate the power of such tools in helping clinicians make decisions about treatment and possibly dose-modifications. However, until these models are readily available for clinical use, it is recommended that treatment and dosing be individualized based on the clinical and pharmacological data
JO U R N A L OF GE RI A TR IC O N COL O G Y 5 (2 0 1 4) 2 –7
5
Fig. 1 – Proposed schema for managing HER2-positive metastatic disease in the older patient.
for each agent being used, the predicted toxicities from each agent, the disease setting, and the co-existing conditions and functional assessment, including kidney and liver function as well as the hydration and nutritional status of the patient. Although trastuzumab rarely requires dose reduction or treatment cessation except in the case of cardiac toxicity, other HER2-directed therapies such as lapatinib may require dose adjustments because of diarrhea or skin toxicity. In EMILIA, more patients treated with lapatinib–capecitabine required a dose reduction (lapatinib: 27.3% required dose reduction, capecitabine: 53.4%, T-DM1: 16.3%) and came off study for toxicity (7.6% discontinued lapatinib, 9.4% discontinued capecitabine, and 5.9% discontinued T-DM1).35 Because of these data, one may consider initiating lower doses of lapatinib–capecitabine in the older patient with the ability to titrate doses upward for good tolerance. Dose reductions in older patients should also be considered for agents that are excreted renally such as capecitabine, because of the decreased creatinine clearance that is associated with increasing age.55 However, a priori dose reductions may not be necessary for agents such as alkylaters, vinca alkaloids, and taxanes unless significant frailty and comorbidity exist.56 Because the goal of treatment in metastatic disease is primarily one of palliation with a focus on reduction in symptoms and maintenance of quality of life, these issues are ever more important in a frail or functionally limited older patient with cancer.56
6.
older women is crucial. Currently, there are multiple active trials for older women with metastatic breast cancer, including evaluating lapatinib and trastuzumab (NCT01 273610), evaluating lapatinib and capecitabine in patients aged 70 and over (NCT01262469), and a trial led by the European Organisation for Research and Treatment of Cancer (EORTC) comparing pertuzumab–trastuzumab vs. pertuzumab– trastuzumab–metronomic chemotherapy, followed by T-DM1 in patients age 60 and older (NCT01597414).
7.
Summary
As the options for the treatment of metastatic, HER2-positive disease expand and outcomes improve, we must remember that older women are capable of experiencing similar benefits as younger women with regard to palliation and extension of life. Multiple, evidence-based treatment options for metastatic disease are currently available, with the ability to tailor chemotherapy and HER2-directed therapy readily to the individual. Consideration of functional status, comorbid conditions, and disease burden for each patient is crucial in selecting treatment regimens and dosing of agents. Because of the limited toxicity and efficacy data in older patients, careful monitoring and dose adjustment is warranted. Improved accrual of older women with metastatic disease to clinical trials will help answer the ongoing questions that arise when treating this growing population of patients.
Clinical Trials
Ongoing pursuit of trials dedicated for older women with breast cancer continues to be a priority for optimizing the delivery of care. Although we can extrapolate and dose-adjust regimens developed in younger populations, having prospective data for
Disclosures and Conflict of Interest Statements The authors declare that they do not have any conflicts of interest.
6
JO U R N A L OF GE RI A TRI C O N COL O G Y 5 (2 0 1 4) 2–7
Author Contributions Concept and design: R. Freedman and H. Muss Manuscript writing and approval: R. Freedman and H. Muss
REFERENCES
1. Freedman RA, Hughes ME, Ottesen RA, Weeks JC, He Y, Wong YN, et al. Use of adjuvant trastuzumab in women with human epidermal growth factor receptor 2 (HER2)-positive breast cancer by race/ethnicity and education within the National Comprehensive Cancer Network. Cancer 2013;119(4):839–846 [Epub 2012/09/27]. 2. Bouchardy C, Rapiti E, Fioretta G, Laissue P, Neyroud-Caspar I, Schafer P, et al. Undertreatment strongly decreases prognosis of breast cancer in elderly women. J Clin Oncol 2003;21(19): 3580–3587 [Epub 2003/08/13]. 3. Hebert-Croteau N, Brisson J, Latreille J, Blanchette C, Deschenes L. Compliance with consensus recommendations for the treatment of early stage breast carcinoma in elderly women. Cancer 1999;85(5):1104–1113 [Epub 1999/03/26]. 4. Elkin EB, Hurria A, Mitra N, Schrag D, Panageas KS. Adjuvant chemotherapy and survival in older women with hormone receptor-negative breast cancer: assessing outcome in a population-based, observational cohort. J Clin Oncol 2006;24(18):2757–2764. 5. Giordano SH, Duan Z, Kuo YF, Hortobagyi GN, Goodwin JS. Use and outcomes of adjuvant chemotherapy in older women with breast cancer. J Clin Oncol 2006;24(18):2750–2756. 6. Yancik R, Wesley MN, Ries LA, Havlik RJ, Edwards BK, Yates JW. Effect of age and comorbidity in postmenopausal breast cancer patients aged 55 years and older. Jama 2001;285(7): 885–892 [Epub 2001/03/17]. 7. Castiglione M, Gelber RD, Goldhirsch A. Adjuvant systemic therapy for breast cancer in the elderly: competing causes of mortality. International Breast Cancer Study Group. J Clin Oncol 1990;8(3):519–526 [Epub 1990/03/01]. 8. Yancik R, Havlik RJ, Wesley MN, Ries L, Long S, Rossi WK, et al. Cancer and comorbidity in older patients: a descriptive profile. Ann Epidemiol 1996;6(5):399–412 [Epub 1996/09/01]. 9. Satariano WA, Ragland DR. The effect of comorbidity on 3-year survival of women with primary breast cancer. Ann Intern Med 1994;120(2):104–110. 10. Muss HB, Woolf S, Berry D, Cirrincione C, Weiss RB, Budman D, et al. Adjuvant chemotherapy in older and younger women with lymph node-positive breast cancer. Jama 2005;293(9): 1073–1081 [Epub 2005/03/03]. 11. Crivellari D, Aapro M, Leonard R, von Minckwitz G, Brain E, Goldhirsch A, et al. Breast cancer in the elderly. J Clin Oncol 2007;25(14):1882–1890. 12. Kaufman PA, Brufsky AM, Mayer M, Rugo HS, Tripathy D, Yood MU, et al. Treatment patterns and clinical outcomes in elderly patients with HER2-positive metastatic breast cancer from the registHER observational study. Breast Cancer Res Treat 2012;135(3):875–883 [Epub 2012/08/28]. 13. Griffiths RI, Lalla D, Herbert RJ, Doan JF, Brammer MG, Danese MD. Infused therapy and survival in older patients diagnosed with metastatic breast cancer who received trastuzumab. Cancer Invest 2011;29(9):573–584 [Epub 2011/09/21]. 14. Olson EM, Najita JS, Sohl J, Arnaout A, Burstein HJ, Winer EP, et al. Clinical outcomes and treatment practice patterns of patients with HER2-positive metastatic breast cancer in the post-trastuzumab era. Breast 2013;22(4):525–531 [Epub 2013/01/29].
15. Chia SK, Speers CH, D'Yachkova Y, Kang A, Malfair-Taylor S, Barnett J, et al. The impact of new chemotherapeutic and hormone agents on survival in a population-based cohort of women with metastatic breast cancer. Cancer 2007;110(5): 973–979 [Epub 2007/07/25]. 16. Miles D, von Minckwitz G, Seidman AD. Combination versus sequential single-agent therapy in metastatic breast cancer. Oncologist 2002;7(Suppl 6):13–19 [Epub 2002/11/28]. 17. O'Shaughnessy J, Miles D, Vukelja S, Moiseyenko V, Ayoub JP, Cervantes G, et al. Superior survival with capecitabine plus docetaxel combination therapy in anthracycline-pretreated patients with advanced breast cancer: phase III trial results. J Clin Oncol 2002;20(12):2812–2823 [Epub 2002/06/18]. 18. Sledge GW, Neuberg D, Bernardo P, Ingle JN, Martino S, Rowinsky EK, et al. Phase III trial of doxorubicin, paclitaxel, and the combination of doxorubicin and paclitaxel as front-line chemotherapy for metastatic breast cancer: an intergroup trial (E1193). J Clin Oncol 2003;21(4):588–592 [Epub 2003/02/15]. 19. Muss HB, Berry DA, Cirrincione C, Budman DR, Henderson IC, Citron ML, et al. Toxicity of older and younger patients treated with adjuvant chemotherapy for node-positive breast cancer: the Cancer and Leukemia Group B Experience. J Clin Oncol 2007;25(24):3699–3704 [Epub 2007/08/21]. 20. Slamon DJ, Leyland-Jones B, Shak S, Fuchs H, Paton V, Bajamonde A, et al. Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2. N Engl J Med 2001;344(11):783–792 [Epub 2001/03/15]. 21. Leyland-Jones B, Gelmon K, Ayoub JP, Arnold A, Verma S, Dias R, et al. Pharmacokinetics, safety, and efficacy of trastuzumab administered every three weeks in combination with paclitaxel. J Clin Oncol 2003;21(21):3965–3971 [Epub 2003/09/26]. 22. Del Mastro L, Perrone F, Repetto L, Manzione L, Zagonel V, Fratino L, et al. Weekly paclitaxel as first-line chemotherapy in elderly advanced breast cancer patients: a phase II study of the Gruppo Italiano di Oncologia Geriatrica (GIOGer). Ann Oncol 2005;16(2):253–258 [Epub 2005/01/26]. 23. Hainsworth JD, Burris III HA, Yardley DA, Bradof JE, Grimaldi M, Kalman LA, et al. Weekly docetaxel in the treatment of elderly patients with advanced breast cancer: a Minnie Pearl Cancer Research Network phase II trial. J Clin Oncol 2001;19(15): 3500–3505 [Epub 2001/08/02]. 24. Burstein HJ, Harris LN, Marcom PK, Lambert-Falls R, Havlin K, Overmoyer B, et al. Trastuzumab and vinorelbine as first-line therapy for HER2-overexpressing metastatic breast cancer: multicenter phase II trial with clinical outcomes, analysis of serum tumor markers as predictive factors, and cardiac surveillance algorithm. J Clin Oncol 2003;21(15):2889–2895 [Epub 2003/07/30]. 25. Burstein HJ, Kuter I, Campos SM, Gelman RS, Tribou L, Parker LM, et al. Clinical activity of trastuzumab and vinorelbine in women with HER2-overexpressing metastatic breast cancer. J Clin Oncol 2001;19(10):2722–2730 [Epub 2001/05/16]. 26. Sorio R, Robieux I, Galligioni E, Freschi A, Colussi AM, Crivellari D, et al. Pharmacokinetics and tolerance of vinorelbine in elderly patients with metastatic breast cancer. Eur J Cancer 1997;33(2):301–303 [Epub 1997/02/01]. 27. Vogel C, O'Rourke M, Winer E, Hochster H, Chang A, Adamkiewicz B, et al. Vinorelbine as first-line chemotherapy for advanced breast cancer in women 60 years of age or older. Ann Oncol 1999;10(4):397–402 [Epub 1999/06/17]. 28. von Minckwitz G, du Bois A, Schmidt M, Maass N, Cufer T, de Jongh FE, et al. Trastuzumab beyond progression in human epidermal growth factor receptor 2-positive advanced breast cancer: a German Breast Group 26/Breast International Group 03-05 study. J Clin Oncol 2009;27(12):1999–2006 [Epub 2009/03/18].
JO U R N A L OF GE RI A TR IC O N COL O G Y 5 (2 0 1 4) 2 –7
29. Geyer CE, Forster J, Lindquist D, Chan S, Romieu CG, Pienkowski T, et al. Lapatinib plus capecitabine for HER2-positive advanced breast cancer. N Engl J Med 2006;355(26):2733–2743 [Epub 2006/12/29]. 30. Bajetta E, Procopio G, Celio L, Gattinoni L, Della Torre S, Mariani L, et al. Safety and efficacy of two different doses of capecitabine in the treatment of advanced breast cancer in older women. J Clin Oncol 2005;23(10):2155–2161 [Epub 2005/02/16]. 31. Blackwell KL, Burstein HJ, Storniolo AM, Rugo H, Sledge G, Koehler M, et al. Randomized study of lapatinib alone or in combination with trastuzumab in women with ErbB2-positive, trastuzumab-refractory metastatic breast cancer. J Clin Oncol 2010;28(7):1124–1130 [Epub 2010/02/04]. 32. Vogel CL, Cobleigh MA, Tripathy D, Gutheil JC, Harris LN, Fehrenbacher L, et al. Efficacy and safety of trastuzumab as a single agent in first-line treatment of HER2-overexpressing metastatic breast cancer. J Clin Oncol 2002;20(3):719–726. 33. Kaufman B, Mackey JR, Clemens MR, Bapsy PP, Vaid A, Wardley A, et al. Trastuzumab plus anastrozole versus anastrozole alone for the treatment of postmenopausal women with human epidermal growth factor receptor 2-positive, hormone receptor-positive metastatic breast cancer: results from the randomized phase III TAnDEM study. J Clin Oncol 2009;27(33):5529–5537 [Epub 2009/09/30]. 34. Johnston S, Pippen Jr J, Pivot X, Lichinitser M, Sadeghi S, Dieras V, et al. Lapatinib combined with letrozole versus letrozole and placebo as first-line therapy for postmenopausal hormone receptor-positive metastatic breast cancer. J Clin Oncol 2009;27(33):5538–5546 [Epub 2009/09/30]. 35. Verma S, Miles D, Gianni L, Krop IE, Welslau M, Baselga J, et al. Trastuzumab emtansine for HER2-positive advanced breast cancer. N Engl J Med 2012;367(19):1783–1791 [Epub 2012/10/02]. 36. Baselga J, Cortes J, Kim SB, Im SA, Hegg R, Im YH, et al. Pertuzumab plus trastuzumab plus docetaxel for metastatic breast cancer. N Engl J Med 2012;336(2):109–119. 37. Tabernero J, Climent MA, Lluch A, Albanell J, Vermorken JB, Barnadas A, et al. A multicentre, randomised phase II study of weekly or 3-weekly docetaxel in patients with metastatic breast cancer. Ann Oncol 2004;15(9):1358–1365 [Epub 2004/08/21]. 38. Baselga J, Tabernero JM. Weekly docetaxel in breast cancer: applying clinical data to patient therapy. Oncologist 2001;6(Suppl 3):26–29 [Epub 2001/05/11]. 39. Eniu A, Palmieri FM, Perez EA. Weekly administration of docetaxel and paclitaxel in metastatic or advanced breast cancer. Oncologist 2005;10(9):665–685 [Epub 2005/10/27]. 40. Perez EA, Romond EH, Suman VJ, Jeong JH, Davidson NE, Geyer Jr CE, et al. Four-year follow-up of trastuzumab plus adjuvant chemotherapy for operable human epidermal growth factor receptor 2-positive breast cancer: joint analysis of data from NCCTG N9831 and NSABP B-31. J Clin Oncol 2011;29(25): 3366–3373 [Epub 2011/07/20]. 41. Piccart-Gebhart MJ, Procter M, Leyland-Jones B, Goldhirsch A, Untch M, Smith I, et al. Trastuzumab after adjuvant chemotherapy in HER2-positive breast cancer. N Engl J Med 2005;353(16):1659–1672. 42. Joensuu H, Kellokumpu-Lehtinen PL, Bono P, Alanko T, Kataja V, Asola R, et al. Adjuvant docetaxel or vinorelbine with or without trastuzumab for breast cancer. N Engl J Med 2006;354(8):809–820. 43. Romond EH, Jeong JH, Rastogi P, Swain SM, Geyer Jr CE, Ewer MS, et al. Seven-year follow-up assessment of cardiac function in NSABP B-31, a randomized trial comparing doxorubicin and cyclophosphamide followed by paclitaxel
44.
45.
46.
47.
48.
49.
50.
51.
52.
53.
54.
55.
56.
57.
7
(ACP) with ACP plus trastuzumab as adjuvant therapy for patients with node-positive, human epidermal growth factor receptor 2-positive breast cancer. J Clin Oncol 2012;30(31): 3792–3799 [Epub 2012/09/19]. Bowles EJ, Wellman R, Feigelson HS, Onitilo AA, Freedman AN, Delate T, et al. Risk of heart failure in breast cancer patients after anthracycline and trastuzumab treatment: a retrospective cohort study. J Natl Cancer Inst 2012;104(17): 1293–1305 [Epub 2012/09/06]. Chen J, Long JB, Hurria A, Owusu C, Steingart RM, Gross CP. Incidence of heart failure or cardiomyopathy after adjuvant trastuzumab therapy for breast cancer. J Am Coll Cardiol 2012;60(24):2504–2512 [Epub 2012/11/20]. Freedman RA, Luis IV, Lin N, Lii J, Winer EP, Keating NL. Completion of adjuvant trastuzumab for older patients with early-stage breast cancer. To be presented at the 2013 American Society of Clinical Oncology Meeting; General Poster Session: Breast Cancer — HER2/ER, Abstract# 616; 2013. Seicean S, Seicean A, Alan N, Plana JC, Budd GT, Marwick TH. Cardioprotective effect of beta-adrenoceptor blockade in patients with breast cancer undergoing chemotherapy: follow-up study of heart failure. Circ Heart Fail 2013;6(3): 420–426 [Epub 2013/02/22]. Nohria A. beta-Adrenergic blockade for anthracycline- and trastuzumab-induced cardiotoxicity: is prevention better than cure? Circ Heart Fail 2013;6(3):358–361. Kalay N, Basar E, Ozdogru I, Er O, Cetinkaya Y, Dogan A, et al. Protective effects of carvedilol against anthracycline-induced cardiomyopathy. J Am Coll Cardiol 2006;48(11):2258–2262 [Epub 2006/12/13]. Georgakopoulos P, Roussou P, Matsakas E, Karavidas A, Anagnostopoulos N, Marinakis T, et al. Cardioprotective effect of metoprolol and enalapril in doxorubicin-treated lymphoma patients: a prospective, parallel-group, randomized, controlled study with 36-month follow-up. Am J Hematol 2010;85(11):894–896 [Epub 2010/09/28]. Cardinale D, Colombo A, Sandri MT, Lamantia G, Colombo N, Civelli M, et al. Prevention of high-dose chemotherapy-induced cardiotoxicity in high-risk patients by angiotensin-converting enzyme inhibition. Circulation 2006;114(23):2474–2481 [Epub 2006/11/15]. Hurria A, Togawa K, Mohile SG, Owusu C, Klepin HD, Gross CP, et al. Predicting chemotherapy toxicity in older adults with cancer: a prospective multicenter study. J Clin Oncol 2011;29(25):3457–3465 [Epub 2011/08/04]. Extermann M, Boler I, Reich RR, Lyman GH, Brown RH, DeFelice J, et al. Predicting the risk of chemotherapy toxicity in older patients: the Chemotherapy Risk Assessment Scale for High-Age Patients (CRASH) score. Cancer 2012;118(13): 3377–3386 [Epub 2011/11/11]. Hurria A, Cirrincione CT, Muss HB, Kornblith AB, Barry W, Artz AS, et al. Implementing a geriatric assessment in cooperative group clinical cancer trials: CALGB 360401. J Clin Oncol 2011;29(10):1290–1296 [Epub 2011/03/02]. Balducci L, Yates J. General guidelines for the management of older patients with cancer. Oncology (Williston Park) 2000;14(11A): 221–227 [Epub 2001/02/24]. Wildiers H. Mastering chemotherapy dose reduction in elderly cancer patients. Eur J Cancer 2007;43(15):2235–2241 [Epub 2007/08/10]. Clarke CA, Keegan TH, Yang J, et al. Age-specific incidence of breast cancer subtypes: understanding the black-white crossover. J Natl Cancer Inst 2012;104:1094–1101.
Available online at www.sciencedirect.com
ScienceDirect
Meet the Experts
Managing metastatic human epidermal growth factor receptor 2 (HER2)-positive breast cancer in the older patient Rachel A. Freedmana,⁎, Hyman B. Mussb a
Department of Medical Oncology, Harvard Medical School, Dana–Farber Cancer Institute, 450 Brookline Avenue, Boston, MA 02215, USA Lineberger Comprehensive Cancer Center, Department of Medicine, University of North Carolina, 170 Manning Drive, Chapel Hill, NC 27514, USA
b
AR TIC LE I N FO
ABS TR ACT
Article history:
Treating older patients with metastatic human epidermal growth factor receptor 2
Received 6 September 2013
(HER2)-positive breast cancer is often challenging. This is largely due to the issues
Accepted 10 October 2013
providers face in making decisions in the setting of limited efficacy and toxicity data
Available online 30 October 2013
specific to older women in addition to the competing challenges of managing comorbidity and preserving functional status. Here, we discuss currently available treatment regimens
Keywords:
and other important issues to consider when treating older patients with metastatic,
Older women
HER2-positive disease.
Breast cancer
© 2013 Elsevier Ltd. All rights reserved.
Metastatic Human Epidermal Growth Factor Receptor 2
Contents 1. 2. 3.
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2 3 Selecting Chemotherapy Partners for Trastuzumab in the Older Patient: Combination vs. Single Agent Chemotherapy . . . 3 Trastuzumab Monotherapy and HER2-Directed Therapy with Hormonal Therapy . . . . . . . . . . . . . . . . . . . . . 3
4. New Anti-HER2 Agents . . . . . . . . . . . 5. Toxicity and Dose Selection . . . . . . . . 6. Clinical Trials . . . . . . . . . . . . . . . . 7. Summary . . . . . . . . . . . . . . . . . . Disclosures and Conflict of Interest Statements Author Contributions . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . .
. . . . . . .
. . . . . . .
. . . . . . .
. . . . . . .
. . . . . . .
. . . . . . .
. . . . . . .
. . . . . . .
. . . . . . .
. . . . . . .
. . . . . . .
. . . . . . .
. . . . . . .
. . . . . . .
. . . . . . .
. . . . . . .
. . . . . . .
. . . . . . .
. . . . . . .
. . . . . . .
. . . . . . .
. . . . . . .
. . . . . . .
. . . . . . .
. . . . . . .
. . . . . . .
. . . . . . .
. . . . . . .
. . . . . . .
. . . . . . .
. . . . . . .
. . . . . . .
. . . . . . .
. . . . . . .
. . . . . . .
. . . . . . .
. . . . . . .
. . . . . . .
. . . . . . .
. . . . . . .
. . . . . . .
. . . . . . .
4 4 5 5 5 6 6
⁎ Corresponding author at: Dana–Farber Cancer Institute, 450 Brookline Avenue, Boston, MA 02215, USA. Tel.: +1 617 632 4587; fax: +1 617 632 1930. E-mail addresses: [email protected] (R.A. Freedman), [email protected] (H.B. Muss). 1879-4068/$ – see front matter © 2013 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.jgo.2013.10.001
JO U R N A L OF GE RI A TR IC O N COL O G Y 5 (2 0 1 4) 2 –7
1.
Introduction
Rates of human epidermal growth factor receptor 2 (HER2)positive breast cancer in older populations have not been well described, although a recent analysis from the National Comprehensive Cancer Network (NCCN) demonstrated that 26% of patients with stage I–III, HER2-positive breast cancers diagnosed during 2005–2008 were aged ≥60.1 The incidence of metastatic HER2-positive breast cancer among older women is not known but is likely to be in the 10–20% range. In the adjuvant setting, older women are less likely to receive chemotherapy and trastuzumab-based therapy compared with younger women, likely impacting survival.1–6,57 The reasons for lower rates of infusional treatment administration in older women are likely multifactorial and include physician bias, patient and family preferences, or concerns for competing comorbidity.7–9 In addition, robust prospective data for standard adjuvant treatments are lacking for older patients because of their persistent underrepresentation in clinical trials. Although pooled analyses and cancer registry studies have suggested substantial benefits of chemotherapy for older women,4,5,10,11 the expected treatment benefits and toxicities in older patients are often extrapolated from observations in younger women and not always generalizable. Data for older patients with metastatic HER2-positive breast cancer are even more limited with regard to treatment patterns, toxicity, and outcomes. In the registHER study,12 1001 women with newly diagnosed metastatic, HER2-positive breast cancer during 2003–2006 were followed over time. Among the 209 women aged 65 and older in this cohort, approximately 22% were diagnosed with de novo metastatic disease and nearly 50% had estrogen receptor or progesterone receptor-positive tumors. The oldest patients in registHER were the least likely to receive a trastuzumab-based first-line treatment regimen (77% of women age ≥ 75, 81% of women age 65–74, and 85% of women age < 65 received first-line trastuzumab). Not surprisingly, among all women receiving trastuzumab within registHER, the oldest patients were more likely to receive either trastuzumab monotherapy or trastuzumab with hormonal therapy rather than trastuzumab-based chemotherapy regimens. Despite these differences in treatments, rates of breast cancer-specific survival were similar among age groups, although when data were analyzed by receipt of first-line trastuzumab or not, progression-free survival (PFS) and overall survival (OS) were both significantly longer for older women receiving trastuzumab vs. not (median PFS = 11.0 vs. 3.4 months and OS = 40.4 vs. 25.9 months).12 In addition, another study using Surveillance, Epidemiology, and End Results (SEER)—Medicare data showed that older women with metastatic disease receiving first-line chemotherapy with trastuzumab had improved adjusted cancer-related survival compared to those receiving trastuzumab monotherapy (hazard ratio [HR] =0.54; 95% Confidence Interval [CI] 0.39– 0.74).13 Since the introduction of trastuzumab, improved outcomes for all women with metastatic HER2-positive disease have been observed with median survival times now reaching 3.5 years from the time of initiation of therapy.14,15 Despite the absence of prospective, randomized data for older women
3
with HER2-positive metastatic breast cancer, the limited observational data discussed above strongly suggest that older women significantly benefit from HER2-directed therapy with the largest benefit likely from combinations of trastuzumab and chemotherapy. Unlike the adjuvant setting where combination chemotherapy is the standard, the judicious use of sequential single agents in older patients is generally well tolerated and adding trastuzumab is not usually associated with major increases in toxicity compared to chemotherapy alone. Since the major goals of therapy in the metastatic setting are maintenance or improvement in quality of life as well as controlling the progression of metastases, palliation of an older patient's symptoms and reducing disease burden with acceptable toxicity for long periods of time is an achievable goal.
2. Selecting Chemotherapy Partners for Trastuzumab in the Older Patient: Combination vs. Single Agent Chemotherapy Ongoing controversy in the literature exists regarding the benefits of single-agent vs. combination chemotherapy for first-line treatment for metastatic breast cancer.16–18 Although response rates are often higher when doublet rather than single-agent chemotherapy is administered, overall survival for these two treatment strategies is equivalent18 and a sequential, singleagent chemotherapy approach allows for reduced toxicity, improved quality of life, and preservation of options for the next line. In addition, given the greater toxicity experienced by older patients compared with younger patients receiving chemotherapy,19 avoiding combination chemotherapy in this setting is optimal for the vast majority of patients — unless faced with extenuating circumstances (i.e. visceral crisis). Using a single chemotherapeutic agent coupled with HER2-directed therapy in the metastatic disease setting can result in enhanced efficacy and without a major increase in toxicity in older patients, as is the case for paclitaxel,20–23 vinorelbine,24–27 and capecitabine (either with trastuzumab or lapatinib).28–30 Emerging data have also demonstrated impressive efficacy for regimens that combine trastuzumab with other anti-HER2 agents but without cytotoxic chemotherapy such as trastuzumab and the oral anti-HER2 tyrosine kinase inhibitor, lapatinib.31 This biologic regimen may be an appealing option for some older women and has shown efficacy for women who have received prior lines of anti-HER2 therapy.31 Protocol NCT01273610 at City of Hope is currently addressing the efficacy and tolerability of lapatinib and trastuzumab for patients of 60 and older with metastatic, HER2-positive disease and will greatly inform clinical practice for older patients.
3. Trastuzumab Monotherapy and HER2-Directed Therapy with Hormonal Therapy In patients where competing comorbidity, patient/family preferences, and/or poor functional status may limit chemotherapy administration, trastuzumab monotherapy is a reasonable alternative to chemotherapy administration. In firstline metastatic disease, trastuzumab alone resulted in a 34%
4
JO U R N A L OF GE RI A TRI C O N COL O G Y 5 (2 0 1 4) 2–7
response rate in those with HER2 amplification by fluorescence in situ hybridization (FISH) with a median time to progression of approximately 3.5 months for those treated with either weekly or every-three-week trastuzumab administration and a median overall survival of 24.4 months (95% CI 16.9–31.7 months).32 In addition, trastuzumab and hormonal therapy improved outcomes over hormonal therapy alone for patients with hormone receptor-positive and HER2-positive disease. When combined with hormonal therapy, trastuzumab-treated patients have superior outcomes than with hormonal therapy alone33 with a median PFS of 4.8 months for the combination vs. 2.4 months with anastrozole alone (P = .0016). Whether this strategy is better than sequential use of hormonal therapy followed by trastuzumab is uncertain. Lapatinib in combination with letrozole has also shown improved efficacy compared to letrozole alone in the metastatic setting (PFS = 8.2 vs. 3.0 months; HR = 0.71, 95% CI 0.53–0.96, P = 0.019) but with the combination showing a higher frequency of diarrhea.34 These treatment combinations are appealing for the older women with advanced comorbidity and/or minimal disease burden and for those who have hormone receptor-positive disease.
4.
New Anti-HER2 Agents
Over the past year, two exciting new agents gained U.S. Food and Drug Administration (FDA) approval for metastatic HER2-positive breast cancer: trastuzumab emtansine (T-DM1, Kadcyla®, Genentech/Roche) and pertuzumab (Perjeta®, Genentech/Roche). Both of these agents have demonstrated improved efficacy in large randomized trials (Trastuzumab Emtansine for HER2-Positive Advanced Breast Cancer [EMILIA] for T-DM1 and Clinical Evaluation of Pertuzumab and Trastuzumab [CLEOPATRA] for pertuzumab), when compared with standard chemotherapy and HER2-directed therapy. However, it is of note that neither of the pivotal trials for these agents included a substantial proportion of older patients (median age of EMILIA was 53 years and median age of CLEOPATRA was 54 years).35,36 In EMILIA, women who were previously treated with a taxane and trastuzumab in the metastatic setting were randomized to receive T-DM1 or lapatinib–capecitabine upon disease progression. Women receiving T-DM1 on study experienced improved PFS (median survival = 9.6 vs. 6.4 months; HR for progression or death = 0.65, 95% CI 0.55–0.77; P < .001) and also had fewer grade 3 or higher toxicity events (40.8% with T-DM1 vs. 57% with lapatinib–capecitabine), including lower rates of diarrhea, hand–foot symptoms, neutropenia, nausea, and fatigue. Despite the limitations in applying these results to older women, the toxicity profile of T-DM1 was certainly more favorable,35 making this an appealing treatment option for older women with metastatic breast cancer. A multi-center study of T-DM1 in the adjuvant setting for older patients with breast cancer will soon be opening nationwide, with the ability to get initial efficacy and toxicity data for older women with HER2-positive disease, although patients with metastatic disease will be excluded from this trial.
In the CLEOPATRA trial, the combination of pertuzumab, trastuzumab, and docetaxel was more efficacious than trastuzumab–docetaxel alone in the first-line setting and did not result in significantly worsened toxicity (median PFS = 18.5 vs. 12.4 months; HR = 0.62, 95% CI 0.51–0.75; P < .001).36 In the setting of treating the older patient, one might consider weekly taxane administration rather than every-three-week administration because of potentially better tolerance.37–39 It is also of note that on CLEOPATRA, patients were permitted to stop taxane therapy after disease stabilization and continue antibody therapies until progression.36 The ability to transition to an all-biologics regimen is a nice option for the older patient who will experience cumulative toxicity with chemotherapy over time. In the future, more information on toxicity for older women receiving these novel therapies will be required with special attention paid to worsening physical function in addition to hematologic and cardiac toxicities. In the meantime, because of the favorable toxicity profiles and efficacy associated with T-DM1 and pertuzumab, healthy older women with metastatic HER2-positive disease should be treated similarly to younger women. Currently, pertuzumab has approval for the first-line setting while T-DM1 was approved for women whose cancers have progressed on a taxane and trastuzumab. A schema showing our recommendations for anti-HER2 directed therapy is shown in Fig. 1.
5.
Toxicity and Dose Selection
When thinking about HER2-directed therapy, toxicity considerations must include those related to cardiotoxicity. Although the rates of any trastuzumab-related cardiac toxicity in clinical trials have been low (1–4%),40–43 recent population-based studies have raised concerns that the incidence of heart failure or cardiomyopathy may be higher outside of clinical trials, particularly for older women.44–46 Because of these concerns, close observation of cardiotoxicity with serial monitoring of ejection fraction for older women receiving HER2-directed agents is necessary. In addition, early and aggressive management of pre-existing cardiac conditions can help optimize tolerance to treatment with consideration of up-front beta blockers and angiotensin-converting enzyme (ACE) inhibitors in patients at risk for the development of congestive heart failure.47–51 Close collaboration with a patient's primary care physician and a cardiologist is crucial to optimally co-manage cardiac conditions. Recently, more attention has been paid to predicting toxicity with chemotherapy in older patients with cancer. In work led by Drs. Hurria and Extermann,52,53 the development of models to predict toxicity has been immensely informative and has included clinical factors in addition to geriatric assessment tools.54 Although these models require further validation in specific disease sites and with specific treatments, they demonstrate the power of such tools in helping clinicians make decisions about treatment and possibly dose-modifications. However, until these models are readily available for clinical use, it is recommended that treatment and dosing be individualized based on the clinical and pharmacological data
JO U R N A L OF GE RI A TR IC O N COL O G Y 5 (2 0 1 4) 2 –7
5
Fig. 1 – Proposed schema for managing HER2-positive metastatic disease in the older patient.
for each agent being used, the predicted toxicities from each agent, the disease setting, and the co-existing conditions and functional assessment, including kidney and liver function as well as the hydration and nutritional status of the patient. Although trastuzumab rarely requires dose reduction or treatment cessation except in the case of cardiac toxicity, other HER2-directed therapies such as lapatinib may require dose adjustments because of diarrhea or skin toxicity. In EMILIA, more patients treated with lapatinib–capecitabine required a dose reduction (lapatinib: 27.3% required dose reduction, capecitabine: 53.4%, T-DM1: 16.3%) and came off study for toxicity (7.6% discontinued lapatinib, 9.4% discontinued capecitabine, and 5.9% discontinued T-DM1).35 Because of these data, one may consider initiating lower doses of lapatinib–capecitabine in the older patient with the ability to titrate doses upward for good tolerance. Dose reductions in older patients should also be considered for agents that are excreted renally such as capecitabine, because of the decreased creatinine clearance that is associated with increasing age.55 However, a priori dose reductions may not be necessary for agents such as alkylaters, vinca alkaloids, and taxanes unless significant frailty and comorbidity exist.56 Because the goal of treatment in metastatic disease is primarily one of palliation with a focus on reduction in symptoms and maintenance of quality of life, these issues are ever more important in a frail or functionally limited older patient with cancer.56
6.
older women is crucial. Currently, there are multiple active trials for older women with metastatic breast cancer, including evaluating lapatinib and trastuzumab (NCT01 273610), evaluating lapatinib and capecitabine in patients aged 70 and over (NCT01262469), and a trial led by the European Organisation for Research and Treatment of Cancer (EORTC) comparing pertuzumab–trastuzumab vs. pertuzumab– trastuzumab–metronomic chemotherapy, followed by T-DM1 in patients age 60 and older (NCT01597414).
7.
Summary
As the options for the treatment of metastatic, HER2-positive disease expand and outcomes improve, we must remember that older women are capable of experiencing similar benefits as younger women with regard to palliation and extension of life. Multiple, evidence-based treatment options for metastatic disease are currently available, with the ability to tailor chemotherapy and HER2-directed therapy readily to the individual. Consideration of functional status, comorbid conditions, and disease burden for each patient is crucial in selecting treatment regimens and dosing of agents. Because of the limited toxicity and efficacy data in older patients, careful monitoring and dose adjustment is warranted. Improved accrual of older women with metastatic disease to clinical trials will help answer the ongoing questions that arise when treating this growing population of patients.
Clinical Trials
Ongoing pursuit of trials dedicated for older women with breast cancer continues to be a priority for optimizing the delivery of care. Although we can extrapolate and dose-adjust regimens developed in younger populations, having prospective data for
Disclosures and Conflict of Interest Statements The authors declare that they do not have any conflicts of interest.
6
JO U R N A L OF GE RI A TRI C O N COL O G Y 5 (2 0 1 4) 2–7
Author Contributions Concept and design: R. Freedman and H. Muss Manuscript writing and approval: R. Freedman and H. Muss
REFERENCES
1. Freedman RA, Hughes ME, Ottesen RA, Weeks JC, He Y, Wong YN, et al. Use of adjuvant trastuzumab in women with human epidermal growth factor receptor 2 (HER2)-positive breast cancer by race/ethnicity and education within the National Comprehensive Cancer Network. Cancer 2013;119(4):839–846 [Epub 2012/09/27]. 2. Bouchardy C, Rapiti E, Fioretta G, Laissue P, Neyroud-Caspar I, Schafer P, et al. Undertreatment strongly decreases prognosis of breast cancer in elderly women. J Clin Oncol 2003;21(19): 3580–3587 [Epub 2003/08/13]. 3. Hebert-Croteau N, Brisson J, Latreille J, Blanchette C, Deschenes L. Compliance with consensus recommendations for the treatment of early stage breast carcinoma in elderly women. Cancer 1999;85(5):1104–1113 [Epub 1999/03/26]. 4. Elkin EB, Hurria A, Mitra N, Schrag D, Panageas KS. Adjuvant chemotherapy and survival in older women with hormone receptor-negative breast cancer: assessing outcome in a population-based, observational cohort. J Clin Oncol 2006;24(18):2757–2764. 5. Giordano SH, Duan Z, Kuo YF, Hortobagyi GN, Goodwin JS. Use and outcomes of adjuvant chemotherapy in older women with breast cancer. J Clin Oncol 2006;24(18):2750–2756. 6. Yancik R, Wesley MN, Ries LA, Havlik RJ, Edwards BK, Yates JW. Effect of age and comorbidity in postmenopausal breast cancer patients aged 55 years and older. Jama 2001;285(7): 885–892 [Epub 2001/03/17]. 7. Castiglione M, Gelber RD, Goldhirsch A. Adjuvant systemic therapy for breast cancer in the elderly: competing causes of mortality. International Breast Cancer Study Group. J Clin Oncol 1990;8(3):519–526 [Epub 1990/03/01]. 8. Yancik R, Havlik RJ, Wesley MN, Ries L, Long S, Rossi WK, et al. Cancer and comorbidity in older patients: a descriptive profile. Ann Epidemiol 1996;6(5):399–412 [Epub 1996/09/01]. 9. Satariano WA, Ragland DR. The effect of comorbidity on 3-year survival of women with primary breast cancer. Ann Intern Med 1994;120(2):104–110. 10. Muss HB, Woolf S, Berry D, Cirrincione C, Weiss RB, Budman D, et al. Adjuvant chemotherapy in older and younger women with lymph node-positive breast cancer. Jama 2005;293(9): 1073–1081 [Epub 2005/03/03]. 11. Crivellari D, Aapro M, Leonard R, von Minckwitz G, Brain E, Goldhirsch A, et al. Breast cancer in the elderly. J Clin Oncol 2007;25(14):1882–1890. 12. Kaufman PA, Brufsky AM, Mayer M, Rugo HS, Tripathy D, Yood MU, et al. Treatment patterns and clinical outcomes in elderly patients with HER2-positive metastatic breast cancer from the registHER observational study. Breast Cancer Res Treat 2012;135(3):875–883 [Epub 2012/08/28]. 13. Griffiths RI, Lalla D, Herbert RJ, Doan JF, Brammer MG, Danese MD. Infused therapy and survival in older patients diagnosed with metastatic breast cancer who received trastuzumab. Cancer Invest 2011;29(9):573–584 [Epub 2011/09/21]. 14. Olson EM, Najita JS, Sohl J, Arnaout A, Burstein HJ, Winer EP, et al. Clinical outcomes and treatment practice patterns of patients with HER2-positive metastatic breast cancer in the post-trastuzumab era. Breast 2013;22(4):525–531 [Epub 2013/01/29].
15. Chia SK, Speers CH, D'Yachkova Y, Kang A, Malfair-Taylor S, Barnett J, et al. The impact of new chemotherapeutic and hormone agents on survival in a population-based cohort of women with metastatic breast cancer. Cancer 2007;110(5): 973–979 [Epub 2007/07/25]. 16. Miles D, von Minckwitz G, Seidman AD. Combination versus sequential single-agent therapy in metastatic breast cancer. Oncologist 2002;7(Suppl 6):13–19 [Epub 2002/11/28]. 17. O'Shaughnessy J, Miles D, Vukelja S, Moiseyenko V, Ayoub JP, Cervantes G, et al. Superior survival with capecitabine plus docetaxel combination therapy in anthracycline-pretreated patients with advanced breast cancer: phase III trial results. J Clin Oncol 2002;20(12):2812–2823 [Epub 2002/06/18]. 18. Sledge GW, Neuberg D, Bernardo P, Ingle JN, Martino S, Rowinsky EK, et al. Phase III trial of doxorubicin, paclitaxel, and the combination of doxorubicin and paclitaxel as front-line chemotherapy for metastatic breast cancer: an intergroup trial (E1193). J Clin Oncol 2003;21(4):588–592 [Epub 2003/02/15]. 19. Muss HB, Berry DA, Cirrincione C, Budman DR, Henderson IC, Citron ML, et al. Toxicity of older and younger patients treated with adjuvant chemotherapy for node-positive breast cancer: the Cancer and Leukemia Group B Experience. J Clin Oncol 2007;25(24):3699–3704 [Epub 2007/08/21]. 20. Slamon DJ, Leyland-Jones B, Shak S, Fuchs H, Paton V, Bajamonde A, et al. Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2. N Engl J Med 2001;344(11):783–792 [Epub 2001/03/15]. 21. Leyland-Jones B, Gelmon K, Ayoub JP, Arnold A, Verma S, Dias R, et al. Pharmacokinetics, safety, and efficacy of trastuzumab administered every three weeks in combination with paclitaxel. J Clin Oncol 2003;21(21):3965–3971 [Epub 2003/09/26]. 22. Del Mastro L, Perrone F, Repetto L, Manzione L, Zagonel V, Fratino L, et al. Weekly paclitaxel as first-line chemotherapy in elderly advanced breast cancer patients: a phase II study of the Gruppo Italiano di Oncologia Geriatrica (GIOGer). Ann Oncol 2005;16(2):253–258 [Epub 2005/01/26]. 23. Hainsworth JD, Burris III HA, Yardley DA, Bradof JE, Grimaldi M, Kalman LA, et al. Weekly docetaxel in the treatment of elderly patients with advanced breast cancer: a Minnie Pearl Cancer Research Network phase II trial. J Clin Oncol 2001;19(15): 3500–3505 [Epub 2001/08/02]. 24. Burstein HJ, Harris LN, Marcom PK, Lambert-Falls R, Havlin K, Overmoyer B, et al. Trastuzumab and vinorelbine as first-line therapy for HER2-overexpressing metastatic breast cancer: multicenter phase II trial with clinical outcomes, analysis of serum tumor markers as predictive factors, and cardiac surveillance algorithm. J Clin Oncol 2003;21(15):2889–2895 [Epub 2003/07/30]. 25. Burstein HJ, Kuter I, Campos SM, Gelman RS, Tribou L, Parker LM, et al. Clinical activity of trastuzumab and vinorelbine in women with HER2-overexpressing metastatic breast cancer. J Clin Oncol 2001;19(10):2722–2730 [Epub 2001/05/16]. 26. Sorio R, Robieux I, Galligioni E, Freschi A, Colussi AM, Crivellari D, et al. Pharmacokinetics and tolerance of vinorelbine in elderly patients with metastatic breast cancer. Eur J Cancer 1997;33(2):301–303 [Epub 1997/02/01]. 27. Vogel C, O'Rourke M, Winer E, Hochster H, Chang A, Adamkiewicz B, et al. Vinorelbine as first-line chemotherapy for advanced breast cancer in women 60 years of age or older. Ann Oncol 1999;10(4):397–402 [Epub 1999/06/17]. 28. von Minckwitz G, du Bois A, Schmidt M, Maass N, Cufer T, de Jongh FE, et al. Trastuzumab beyond progression in human epidermal growth factor receptor 2-positive advanced breast cancer: a German Breast Group 26/Breast International Group 03-05 study. J Clin Oncol 2009;27(12):1999–2006 [Epub 2009/03/18].
JO U R N A L OF GE RI A TR IC O N COL O G Y 5 (2 0 1 4) 2 –7
29. Geyer CE, Forster J, Lindquist D, Chan S, Romieu CG, Pienkowski T, et al. Lapatinib plus capecitabine for HER2-positive advanced breast cancer. N Engl J Med 2006;355(26):2733–2743 [Epub 2006/12/29]. 30. Bajetta E, Procopio G, Celio L, Gattinoni L, Della Torre S, Mariani L, et al. Safety and efficacy of two different doses of capecitabine in the treatment of advanced breast cancer in older women. J Clin Oncol 2005;23(10):2155–2161 [Epub 2005/02/16]. 31. Blackwell KL, Burstein HJ, Storniolo AM, Rugo H, Sledge G, Koehler M, et al. Randomized study of lapatinib alone or in combination with trastuzumab in women with ErbB2-positive, trastuzumab-refractory metastatic breast cancer. J Clin Oncol 2010;28(7):1124–1130 [Epub 2010/02/04]. 32. Vogel CL, Cobleigh MA, Tripathy D, Gutheil JC, Harris LN, Fehrenbacher L, et al. Efficacy and safety of trastuzumab as a single agent in first-line treatment of HER2-overexpressing metastatic breast cancer. J Clin Oncol 2002;20(3):719–726. 33. Kaufman B, Mackey JR, Clemens MR, Bapsy PP, Vaid A, Wardley A, et al. Trastuzumab plus anastrozole versus anastrozole alone for the treatment of postmenopausal women with human epidermal growth factor receptor 2-positive, hormone receptor-positive metastatic breast cancer: results from the randomized phase III TAnDEM study. J Clin Oncol 2009;27(33):5529–5537 [Epub 2009/09/30]. 34. Johnston S, Pippen Jr J, Pivot X, Lichinitser M, Sadeghi S, Dieras V, et al. Lapatinib combined with letrozole versus letrozole and placebo as first-line therapy for postmenopausal hormone receptor-positive metastatic breast cancer. J Clin Oncol 2009;27(33):5538–5546 [Epub 2009/09/30]. 35. Verma S, Miles D, Gianni L, Krop IE, Welslau M, Baselga J, et al. Trastuzumab emtansine for HER2-positive advanced breast cancer. N Engl J Med 2012;367(19):1783–1791 [Epub 2012/10/02]. 36. Baselga J, Cortes J, Kim SB, Im SA, Hegg R, Im YH, et al. Pertuzumab plus trastuzumab plus docetaxel for metastatic breast cancer. N Engl J Med 2012;336(2):109–119. 37. Tabernero J, Climent MA, Lluch A, Albanell J, Vermorken JB, Barnadas A, et al. A multicentre, randomised phase II study of weekly or 3-weekly docetaxel in patients with metastatic breast cancer. Ann Oncol 2004;15(9):1358–1365 [Epub 2004/08/21]. 38. Baselga J, Tabernero JM. Weekly docetaxel in breast cancer: applying clinical data to patient therapy. Oncologist 2001;6(Suppl 3):26–29 [Epub 2001/05/11]. 39. Eniu A, Palmieri FM, Perez EA. Weekly administration of docetaxel and paclitaxel in metastatic or advanced breast cancer. Oncologist 2005;10(9):665–685 [Epub 2005/10/27]. 40. Perez EA, Romond EH, Suman VJ, Jeong JH, Davidson NE, Geyer Jr CE, et al. Four-year follow-up of trastuzumab plus adjuvant chemotherapy for operable human epidermal growth factor receptor 2-positive breast cancer: joint analysis of data from NCCTG N9831 and NSABP B-31. J Clin Oncol 2011;29(25): 3366–3373 [Epub 2011/07/20]. 41. Piccart-Gebhart MJ, Procter M, Leyland-Jones B, Goldhirsch A, Untch M, Smith I, et al. Trastuzumab after adjuvant chemotherapy in HER2-positive breast cancer. N Engl J Med 2005;353(16):1659–1672. 42. Joensuu H, Kellokumpu-Lehtinen PL, Bono P, Alanko T, Kataja V, Asola R, et al. Adjuvant docetaxel or vinorelbine with or without trastuzumab for breast cancer. N Engl J Med 2006;354(8):809–820. 43. Romond EH, Jeong JH, Rastogi P, Swain SM, Geyer Jr CE, Ewer MS, et al. Seven-year follow-up assessment of cardiac function in NSABP B-31, a randomized trial comparing doxorubicin and cyclophosphamide followed by paclitaxel
44.
45.
46.
47.
48.
49.
50.
51.
52.
53.
54.
55.
56.
57.
7
(ACP) with ACP plus trastuzumab as adjuvant therapy for patients with node-positive, human epidermal growth factor receptor 2-positive breast cancer. J Clin Oncol 2012;30(31): 3792–3799 [Epub 2012/09/19]. Bowles EJ, Wellman R, Feigelson HS, Onitilo AA, Freedman AN, Delate T, et al. Risk of heart failure in breast cancer patients after anthracycline and trastuzumab treatment: a retrospective cohort study. J Natl Cancer Inst 2012;104(17): 1293–1305 [Epub 2012/09/06]. Chen J, Long JB, Hurria A, Owusu C, Steingart RM, Gross CP. Incidence of heart failure or cardiomyopathy after adjuvant trastuzumab therapy for breast cancer. J Am Coll Cardiol 2012;60(24):2504–2512 [Epub 2012/11/20]. Freedman RA, Luis IV, Lin N, Lii J, Winer EP, Keating NL. Completion of adjuvant trastuzumab for older patients with early-stage breast cancer. To be presented at the 2013 American Society of Clinical Oncology Meeting; General Poster Session: Breast Cancer — HER2/ER, Abstract# 616; 2013. Seicean S, Seicean A, Alan N, Plana JC, Budd GT, Marwick TH. Cardioprotective effect of beta-adrenoceptor blockade in patients with breast cancer undergoing chemotherapy: follow-up study of heart failure. Circ Heart Fail 2013;6(3): 420–426 [Epub 2013/02/22]. Nohria A. beta-Adrenergic blockade for anthracycline- and trastuzumab-induced cardiotoxicity: is prevention better than cure? Circ Heart Fail 2013;6(3):358–361. Kalay N, Basar E, Ozdogru I, Er O, Cetinkaya Y, Dogan A, et al. Protective effects of carvedilol against anthracycline-induced cardiomyopathy. J Am Coll Cardiol 2006;48(11):2258–2262 [Epub 2006/12/13]. Georgakopoulos P, Roussou P, Matsakas E, Karavidas A, Anagnostopoulos N, Marinakis T, et al. Cardioprotective effect of metoprolol and enalapril in doxorubicin-treated lymphoma patients: a prospective, parallel-group, randomized, controlled study with 36-month follow-up. Am J Hematol 2010;85(11):894–896 [Epub 2010/09/28]. Cardinale D, Colombo A, Sandri MT, Lamantia G, Colombo N, Civelli M, et al. Prevention of high-dose chemotherapy-induced cardiotoxicity in high-risk patients by angiotensin-converting enzyme inhibition. Circulation 2006;114(23):2474–2481 [Epub 2006/11/15]. Hurria A, Togawa K, Mohile SG, Owusu C, Klepin HD, Gross CP, et al. Predicting chemotherapy toxicity in older adults with cancer: a prospective multicenter study. J Clin Oncol 2011;29(25):3457–3465 [Epub 2011/08/04]. Extermann M, Boler I, Reich RR, Lyman GH, Brown RH, DeFelice J, et al. Predicting the risk of chemotherapy toxicity in older patients: the Chemotherapy Risk Assessment Scale for High-Age Patients (CRASH) score. Cancer 2012;118(13): 3377–3386 [Epub 2011/11/11]. Hurria A, Cirrincione CT, Muss HB, Kornblith AB, Barry W, Artz AS, et al. Implementing a geriatric assessment in cooperative group clinical cancer trials: CALGB 360401. J Clin Oncol 2011;29(10):1290–1296 [Epub 2011/03/02]. Balducci L, Yates J. General guidelines for the management of older patients with cancer. Oncology (Williston Park) 2000;14(11A): 221–227 [Epub 2001/02/24]. Wildiers H. Mastering chemotherapy dose reduction in elderly cancer patients. Eur J Cancer 2007;43(15):2235–2241 [Epub 2007/08/10]. Clarke CA, Keegan TH, Yang J, et al. Age-specific incidence of breast cancer subtypes: understanding the black-white crossover. J Natl Cancer Inst 2012;104:1094–1101.
