A New Era in the Management of Advanced HER2-Positive Breast Cancer

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Karen Lisa Smith, MD, MPH

Vered Stearns, MD

The fact that a new guideline for the management of advanced HER2-positive breast cancer is required speaks to the rapid progress in this field of late.

—Karen Lisa Smith, MD, MPH, and Vered Stearns, MD

Approximately 20% of all breast cancers are human epidermal growth factor receptor 2 (HER2)-positive. Prior to the era of HER2-targeted therapy, HER2-positive breast cancer was characterized by a poor prognosis.1,2 The development of the first HER2-targeted therapy, trastuzumab (Herceptin), led to dramatically improved outcomes for this population in both the early-stage and metastatic settings.3-7

In recent years, outcomes for women with advanced HER2-positive breast cancer have improved further with the development and approval of three additional HER2-targeted therapies—lapatinib (Tykerb), pertuzumab (Perjeta), and ado-trastuzumab emtansine, formerly known as T-DM1 (Kadcyla).
With the addition of these agents to the therapeutic armamentarium, metastatic HER2-positive breast cancer is no longer characterized by a rapid disease course, but rather by median survival rates in excess of 3 years.8

The approval of these new HER2-targeted therapies prompted ASCO to release the first clinical guideline for systemic therapy for advanced HER2-positive breast cancer; the guideline was published in the Journal of Clinical Oncology9 and is reviewed in this issue of The ASCO Post. Since the brain is a sanctuary site for HER2-positive breast cancer, with up to 50% of patients developing brain metastases,10-12 ASCO also released a companion guideline regarding the management of brain metastases in this population.13

Four Key Questions

The ASCO guideline for systemic therapy for advanced HER2-positive breast cancer was developed by a multidisciplinary expert panel using evidence from two systematic reviews incorporating data published prior to 2009 and from a systematic review of phase III trials published in 2009 to 2012 in conjunction with clinical experience.9

The guideline addresses four key clinical questions: (1) In which line(s) of treatment should HER2-targeted therapy be incorporated? (2) Which regimens are recommended for first-line treatment? (3) Which regimens are recommended for later lines of treatment? And (4) What is the recommended treatment approach for hormone receptor–positive, HER2-positive metastatic breast cancer?

When to Use

With the exception of carefully chosen hormone receptor–positive patients in whom a trial of endocrine therapy alone can be considered, the expert panel recommends incorporation of HER2-targeted therapy into the treatment of patients with advanced HER2-positive breast cancer in first-line therapy and in second-line and later lines of therapy after progression on prior HER2-targeted therapy.9

The recommendation to incorporate HER2-targeted therapy into first-line treatment is supported by the pivotal trial by Slamon et al demonstrating improved time to progression and overall survival with chemotherapy plus trastuzumab compared to chemotherapy alone.3 More recent data demonstrate benefit of first-line HER2-targeted therapy using dual HER2-targeted therapy and the newer HER2-targeted agents, although these regimens have not been compared to therapeutic approaches that do not incorporate HER2-targeted treatments.14,15

The principle of continuing HER2-targeted therapy after progression and using serial lines of therapy against the same molecular target (HER2) is similar to that applied in the management of hormone receptor–positive metastatic breast cancer, for which serial endocrine therapies can be beneficial.16,17 Indeed, the continuation of trastuzumab along with chemotherapy improves progression-free survival compared to chemotherapy alone in this population.18 Data evaluating the newer HER2-targeted therapies in patients who have had disease progression following first-line trastuzumab-based therapy further confirm the benefit of continuing HER2-targeted treatment in later lines of therapy.15,19-21

First-Line Options

In the first-line setting, the expert panel recommends the combination of pertuzumab, trastuzumab, and a taxane for patients without a contraindication to taxane therapy. This recommendation is based on results from the CLEOPATRA trial, in which the addition of pertuzumab to trastuzumab and docetaxel was associated with significant improvement in median progression-free survival (12.4 vs 18.7 months) and median overall survival (37.6 months vs not reached).8,14 Solid preclinical and clinical data demonstrating improved outcomes with dual HER2-targeted therapy supported the development of this regimen.2126

Notably, the expert panel does not specify which taxane should be used in combination with pertuzumab and trastuzumab, and it proposes paclitaxel as a possible alternative to docetaxel.9 We agree that a taxane combined with trastuzumab and pertuzuamb should be considered as first-line therapy for HER2-positive metastatic breast cancer, but caution that data to support the use of paclitaxel in this setting are currently not available.

Extrapolating from literature in the HER2-negative setting, we remind readers that when dosed every 3 weeks, docetaxel is more efficacious than paclitaxel for metastatic breast cancer.27 However, weekly paclitaxel is more efficacious than paclitaxel every 3 weeks,28 and thus, it may be reasonable to combine weekly paclitaxel with trastuzumab and pertuzumab in the first-line setting for HER2-positive advanced breast cancer.

It is hoped that studies such as the PERUSE trial (ClinicalTrials.gov Identifier NCT01572038), evaluating pertuzumab and trastuzumab in combination with a taxane (paclitaxel, docetaxel, or nab-paclitaxel [Abraxane]) will help clarify whether one taxane is more appropriate than another in this setting.

Considering the risk of cumulative toxicity, the expert panel recommends discontinuing the taxane after 4 to 6 months or when maximal clinical response has been achieved. After discontinuation of the taxane, the expert panel recommends maintaining the dual HER2-targeted therapy alone. For hormone receptor–positive patients, endocrine therapy can be added at this time, although there are no data to support this approach.9

Participants in the CLEOPATRA trial received a median of eight cycles of docetaxel therapy14; thus, we agree that the 4- to 6-month time frame for discontinuation of taxane therapy proposed in the guideline is reasonable to reduce cumulative toxicity.9 For patients who show progression on dual HER2-targeted therapy after the taxane has been discontinued, we feel it is appropriate to consider resuming the taxane or treating according to guidelines for second-line therapy, although data to support either approach are lacking.

While results from CLEOPATRA have defined the current standard of care for first-line therapy for HER2-positive metastatic breast cancer, several questions remain. For example, the role of ado-trastuzumab emtansine in this setting has not been determined. Only a small proportion of participants in the EMILIA trial, comparing capecitabine and lapatinib to ado-trastuzumab emtansine in patients who previously received taxane and trastuzumab therapy, were treated in the first-line setting. Thus, data supporting ado-trastuzumab emtansine in this setting are currently limited.15

Results from the ongoing MARIANNE trial (ClinicalTrials.gov Identifier NCT01120184), comparing first-line ado-trastuzumab emtansine plus pertuzumab and ado-trastuzumab emtansine plus placebo to trastuzumab plus taxane therapy, have the potential to change first-line therapy for HER2-positive metastatic breast cancer further. If equally efficacious, use of ado-trastuzumab emtansine in the first-line setting may be preferable to therapy with pertuzumab, trastuzumab, and a taxane, since toxicity with the agent is minimal.15

Further First-Line Considerations

Whether there is a subgroup of patients with HER2-positive advanced breast cancer for whom first-line HER2-targeted therapy alone (in the absence of chemotherapy) is appropriate remains to be determined. Data from the neoadjuvant setting demonstrate an overall pathologic complete response rate of 16.8% with pertuzumab and trastuzumab alone; however, the rate was 27% in women with hormone receptor–negative tumors,29 suggesting that some hormone receptor–negative and HER2-positive patients, if properly identified, may be able to avoid the toxicity of chemotherapy without compromising outcomes.

Inoue et al addressed this question in a small trial comparing first-line treatment with concurrent trastuzumab plus chemotherapy to trastuzumab with delayed chemotherapy for metastatic HER2-positive breast cancer, and results favored upfront chemotherapy.30 However, this study was performed with trastuzumab alone and findings may differ with dual or newer HER2-targeted therapies. At this time, we do not recommend HER2-targeted therapy alone as a standard first-line option, although it is reasonable to consider this approach in asymptomatic patients with low disease burden, especially in the presence of comorbidities or poor performance status.

The guidelines do not address which therapy should be recommended for patients with metastatic disease who received pertuzumab in the adjuvant or neoadjuvant settings. Pertuzumab-based regimens were recently approved in the neoadjuvant setting based on phase II data29,31 and are under evaluation in the adjuvant setting in the AFFINITY trial (ClinicalTrials.gov Identifier NCT01358877).

Recent guidelines from the National Comprehensive Cancer Network (NCCN) incorporate pertuzumab-based regimens as management options in both the adjuvant and neoadjuvant algorithms for HER2-positive early-stage breast cancer,32 and first-line management of these patients should they develop metastatic disease is not defined at this time. The expert panel recommends treating patients who completed adjuvant trastuzumab-based treatment > 12 months prior to development of metastatic disease with docetaxel, pertuzumab, and trastuzumab, since they would have been eligible for the CLEOPATRA trial.9,14 For those who develop metastatic disease < 12 months after completing adjuvant trastuzumab-based therapy, the panel recommends treating as if the patients are in the second-line setting.9 Notably, very few patients in the CLEOPATRA trial received prior adjuvant trastuzumab.14 Until additional data are available, we agree with these recommendations.

Subsequent Options

Based on solid efficacy and toxicity data from the EMILIA trial, the guideline recommends ado-trastuzumab emtansine as second-line therapy. In EMILIA, ado-trastuzumab emtansine use was associated with improvements in progression-free survival (9.6 vs 6.4 months) and overall survival (30.9 vs 25.1 months) along with reduced toxicity compared to the combination of lapatinib and capecitabine.15

For third-line and later lines of therapy, the expert panel does not recommend specific regimens, since data regarding the relative merits of one regimen over another in these settings are lacking. The guideline suggests consideration of ado-trastuzumab emtansine or pertuzumab-based regimen in these settings for patients who have not received these therapies in earlier lines of care.9

The recommendation for ado-trastuzumab emtansine in this scenario is appropriate given that most participants in the EMILIA trial had received multiple lines of prior therapy.15 Although data to support the use of pertuzumab beyond the first-line setting are currently limited to a small phase II trial of trastuzumb and pertuzumab in patients who received prior trastuzumab,24 we agree that offering pertuzumab-based regimens in later lines of care is reasonable for patients who did not have the opportunity to receive pertuzumab earlier.

For patients who have received ado-trastuzumab emtansine and pertuzumab-based therapy in earlier lines of care, the guideline proposes multiple therapeutic options for the third-line and later settings, including dual HER2-targeted therapy with trastuzumab and lapatinib, various combinations of chemotherapy with trastuzumab, the combination of lapatinib and capecitabine, and, for hormone receptor–positive patients, combinations of endocrine therapy with trastuzumab or lapatinib.9,19-21,33,34 Since data to guide clinicians in selecting the optimal regimen in these later settings are not currently available, we suggest making selections based on factors such as prior treatments, extent of disease, performance status, and toxicity.

Hormone Receptor–Positive Disease

After suggesting HER2-targeted regimens for each line of care, the expert panel turns to the management of advanced breast cancer that is both hormone receptor– and HER2-positive. Unfortunately, optimal management of these patients remains uncertain, although the panel indicates that it expects most patients to be treated according to the standard recommendations for chemotherapy plus HER2-targeted therapy regardless of hormone receptor status.

The guideline recommends consideration of a trial of endocrine therapy alone for select patients.9 Although not supported by data, the proposed selection criteria for this approach, which include patient-related factors (such as presence of a contraindication to HER2-targeted therapy or comorbidities) and disease-related factors (such as a long time to recurrence and low disease burden), are appropriate.9 Although there may be some HER2-positive patients in whom endocrine therapy alone is reasonable, we encourage caution in applying this approach, since trials evaluating endocrine therapy alone for the treatment of HER2-positive metastatic breast cancer have revealed a short time to progression.33-35

Another option proposed by the ASCO panel for patients who are both hormone receptor– and HER2-positive is the combination of endocrine therapy and HER2-targeted therapy, which can be used during first-line therapy after discontinuation of the taxane or at another time point.9 This is a reasonable recommendation, but we note that, to date, trials evaluating the combination of HER2-targeted therapy and endocrine therapy compared to endocrine therapy alone have demonstrated improvement in progression-free survival but not in overall survival, a finding which may be partially explained by crossover of patients from the endocrine therapy alone arms to the combination arms.33-35

The lack of an overall survival benefit in the trials of HER2-targeted therapy and endocrine therapy contrasts with trials evaluating the combination of chemotherapy and HER2-targeted therapy, such as the CLEOPATRA trial, in which a survival benefit was noted for the experimental arm regardless of hormone receptor status.14 However, to the best of our knowledge, upfront treatment using endocrine therapy plus HER2-targeted therapy with delayed initiation of chemotherapy has not been compared to upfront chemotherapy plus HER2-targeted therapy in this population.

Such an approach may be desirable for select patients who are both hormone receptor– and HER2-positive, as it can allow patients to delay chemotherapy-associated toxicity. However, validation of criteria to select patients in whom this approach is safe is required. Regardless, the panel suggests that most hormone receptor– and HER2-positive patients should receive endocrine therapy at some point during their treatment course.9 We agree with this recommendation and also encourage considering different clinical trial opportunities for women with HER2-positive advanced breast cancer who are hormone receptor–positive and those who are hormone receptor–negative, since these diseases may be biologically distinct.

Areas of Uncertainty

While the ASCO guideline for systemic therapy for advanced HER2-positive breast cancer covers management decisions for many common clinical scenarios, areas of uncertainty remain. For example, given the success with today’s HER2-targeted therapies, one occasionally encounters a patient in whom all evidence of disease is eradicated by systemic therapy. Whether it is of benefit to administer HER2-targeted therapy indefinitely in such patients is unknown. Moreover, given the substantial cost associated with the newer HER2-targeted therapies, we feel incorporation of economic considerations into future trials and guidelines is appropriate.

The optimal regimens and sequencing in later lines of care for HER2-positive metastatic breast cancer are still not well defined. It is our hope that observational studies, such as the ongoing SystHERS prospective cohort study (ClinicalTrials.gov Identifier NCT01615068), describing treatment patterns and outcomes in this population will better characterize the optimal treatment trajectory for these patients.

Furthermore, the use of HER2-targeted therapies requires adequate cardiac function. More studies such as the SAFE-HEaRt trial (ClinicalTrials.gov Identifier NCT01904903), a pilot study assessing the cardiac safety of HER2-targeted therapy in patients with mildly reduced ejection fraction, are needed to define safety parameters for the use of these important agents in women with compromised cardiac function. Finally, many ongoing investigations will help define mechanisms of resistance to HER2-targeted therapy and therapeutic approaches to overcome resistance to HER2-targeted therapy.

In Conclusion

The fact that a new guideline for the management of advanced HER2-positive breast cancer is required speaks to the rapid progress in this field of late. The three recently approved HER2-targeted therapies, along with trastuzumab, together with promising new HER2-targeted agents, such as neratinib and afatinib (Gilotrif), and agents that may overcome resistance to HER2-targeted therapy, such as phosphatidylinositol 3-kinase inhibitors,36 are bringing us toward a new era in the management of HER2-positive metastatic breast cancer. ■

Disclosure: Dr. Stearns has received research grants from Abbive, Abraxis, Merck,  Medimmune, Novartis, and Pfizer. Dr. Smith reported no potential conflicts of interest.


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3. Slamon DJ, Leyland-Jones B, Shak S, et al: Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2. N Engl J Med 344:783-792, 2001.

4. 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.

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10. Pestalozzi BC, Holmes E, de Azambuja E, et al: CNS relapses in patients with HER2-positive early breast cancer who have and have not received adjuvant trastuzumab: A retrospective substudy of the HERA trial (BIG 1-01). Lancet Oncol 14:244-248, 2013.

11. Olson EM, Abdel-Rasoul M, Maly J, et al: Incidence and risk of central nervous system metastases as site of first recurrence in patients with HER2-positive breast cancer treated with adjuvant trastuzumab. Ann Oncol 24:1526-1533, 2013.

12. Brufsky AM, Mayer M, Rugo HS, et al: Central nervous system metastases in patients with HER2-positive metastatic breast cancer: Incidence, treatment, and survival in patients from registHER. Clin Cancer Res 17:4834-4843, 2011.

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16. Chia S, Gradishar W, Mauriac L, et al: Double-blind, randomized placebo controlled trial of fulvestrant compared with exemestane after prior nonsteroidal aromatase inhibitor therapy in postmenopausal women with hormone receptor-positive, advanced breast cancer: results from EFECT. J Clin Oncol 26:1664-1670, 2008.

17. Di Leo A, Jerusalem G, Petruzelka L, et al: Results of the CONFIRM phase III trial comparing fulvestrant 250 mg with fulvestrant 500 mg in postmenopausal women with estrogen receptor-positive advanced breast cancer. J Clin Oncol 28:4594-4600, 2010.

18. von Minckwitz G, Schwedler K, Schmidt M, et al: Trastuzumab beyond progression: overall survival analysis of the GBG 26/BIG 3-05 phase III study in HER2-positive breast cancer. Eur J Cancer 47:2273-2281, 2011.

19. Cameron D, Casey M, Oliva C, et al: Lapatinib plus capecitabine in women with HER-2-positive advanced breast cancer: Final survival analysis of a phase III randomized trial. Oncologist 15:924-934, 2010.

20. Geyer CE, Forster J, Lindquist D, et al: Lapatinib plus capecitabine for HER2-positive advanced breast cancer. N Engl J Med 355:2733-2743, 2006.

21. Blackwell KL, Burstein HJ, Storniolo AM, 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 28:1124-1130, 2010.

22. Konecny GE, Pegram MD, Venkatesan N, et al: Activity of the dual kinase inhibitor lapatinib (GW572016) against HER-2-overexpressing and trastuzumab-treated breast cancer cells. Cancer Res 66:1630-1639, 2006.

23. 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 30:2585-2592, 2012.

24. Baselga J, Gelmon KA, Verma S, et al: Phase II trial of pertuzumab and trastuzumab in patients with human epidermal growth factor receptor 2-positive metastatic breast cancer that progressed during prior trastuzumab therapy. J Clin Oncol 28:1138-1144, 2010.

25. Cortes J, Fumoleau P, Bianchi GV, et al: Pertuzumab monotherapy after trastuzumab-based treatment and subsequent reintroduction of trastuzumab: Activity and tolerability in patients with advanced human epidermal growth factor receptor 2-positive breast cancer. J Clin Oncol 30:1594-1600, 2012.

26. Scheuer W, Friess T, Burtscher H, et al: Strongly enhanced antitumor activity of trastuzumab and pertuzumab combination treatment on HER2-positive human xenograft tumor models. Cancer Res 69:9330-9336, 2009.

27. Jones SE, Erban J, Overmoyer B, et al: Randomized phase III study of docetaxel compared with paclitaxel in metastatic breast cancer. J Clin Oncol 23:5542-5551, 2005.

28. Seidman AD, Berry D, Cirrincione C, et al: Randomized phase III trial of weekly compared with every-3-weeks paclitaxel for metastatic breast cancer, with trastuzumab for all HER-2 overexpressors and random assignment to trastuzumab or not in HER-2 nonoverexpressors: Final results of Cancer and Leukemia Group B protocol 9840. J Clin Oncol 26:1642-1649, 2008.

29. Gianni L, Pienkowski T, Im YH, et al: Efficacy and safety of neoadjuvant pertuzumab and trastuzumab in women with locally advanced, inflammatory, or early HER2-positive breast cancer (NeoSphere): A randomised multicentre, open-label, phase 2 trial. Lancet Oncol 13:25-32, 2012.

30. Inoue K, Nakagami K, Mizutani M, et al: Randomized phase III trial of trastuzumab monotherapy followed by trastuzumab plus docetaxel versus trastuzumab plus docetaxel as first-line therapy in patients with HER2-positive metastatic breast cancer: The JO17360 Trial Group. Breast Cancer Res Treat 119:127-136, 2010.

31. Schneeweiss A, Chia S, Hickish T, et al: Pertuzumab plus trastuzumab in combination with standard neoadjuvant anthracycline-containing and anthracycline-free chemotherapy regimens in patients with HER2-positive early breast cancer: A randomized phase II cardiac safety study (TRYPHAENA). Ann Oncol 24:2278-2284, 2013.

32. National Comprehensive Cancer Network Guidelines: Breast Cancer Version 3.2014, 2014.

33. Kaufman B, Mackey JR, Clemens MR, 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 27:5529-5537, 2009.

34. Huober J, Fasching PA, Barsoum M, et al: Higher efficacy of letrozole in combination with trastuzumab compared to letrozole monotherapy as first-line treatment in patients with HER2-positive, hormone-receptor-positive metastatic breast cancer—results of the eLEcTRA trial. Breast 21:27-33, 2012.

35. Schwartzberg LS, Franco SX, Florance A, et al: Lapatinib plus letrozole as first-line therapy for HER-2+ hormone receptor-positive metastatic breast cancer. Oncologist 15:122-129, 2010.

36. Tsang RY, Finn RS: Beyond trastuzumab: Novel therapeutic strategies in HER2-positive metastatic breast cancer. Br J Cancer 106:6-13, 2012.


Dr. Smith is Assistant Professor of Oncology and Dr. Stearns is Professor of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins School of Medicine, Baltimore.


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