Treatment of Early HER2-Positive Breast Cancer: One Size Does Not Fit All

A Conversation With Edward H. Romond, MD

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[NSABP B-47] is a key trial. It’s B-31 all over again in HER2-normal breast cancer. Hopefully, we will identify the point at which trastuzumab starts to make a difference, specifically in adjuvant therapy.
— Edward H. Romond, MD

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Despite the routine use of HER2 blockade in early HER2-positive breast cancer, clinicians can always benefit from a refresher on key treatment considerations. Clinical pearls and controversial issues were the topic of a presentation at the 14th Annual School of Breast Oncology at Emory University, Atlanta, by Edward H. Romond, MD, Professor of Medicine at the University of Kentucky Markey Cancer Center, Lexington.1 The ASCO Post spoke with Dr. Romond about some of the major issues to be considered in this setting.

Predicting Response

Does the degree of HER2 amplification correlate with the degree of benefit from trastuzumab (Herceptin)?

No. HER2-positive is HER2-positive. In the North Central Cancer Treatment Group (NCCTG) N9831 trial, by fluorescence in situ hybridization (FISH) ratio, the benefit was largely similar across ratios ranging from 2.0 to 15.0, though the P value for significance was greatest (P = .004) for tumors with the highest ratios (11.0–15.0).2

As a predictor of response to trastuzumab plus chemotherapy, does the standard definition of HER2 positivity mean the same thing in the adjuvant setting as it does for metastatic breast cancer?

The criteria for HER2 positivity in discerning the benefit of adjuvant trastuzumab are being studied further. A central reexamination of samples from the National Surgical Adjuvant Breast and Bowel Project (NSABP) B-31 trial by Paik et al revealed 174 tumors that were HER2-negative by immunohistochemistry (IHC) and FISH both in the primary tumor and in the axillary node.3 In the patients with these HER2-negative tumors, an improvement in 7-year disease-free survival was seen with trastuzumab (hazard ratio [HR] = 0.64, P = .16).

HER2-Positive Early Breast Cancer

  • Degree of HER2 amplification does not correlate with trastuzumab benefit.
  • The definition of HER2 positivity in the adjuvant setting may prove to be different from that in the metastatic setting.
  • Trastuzumab is beneficial when used with non–anthracycline-containing regimens.
  • Chemotherapy is given concurrently with trastuzumab, and then trastuzumab is continued alone for 1 year.
  • Cardiac risk with anthracycline-based regimens is greatest for older patients with low or borderline-normal ejection fractions at baseline.
  • In patients with node-negative disease and tumors ≤ 3 cm, the distant recurrence rate at 3 years approaches 1% with trastuzumab treatment.
  • Dual anti-HER2 blockade raises pathologic complete response rates, but whether the benefit will extend to the adjuvant setting is still unclear.

That raised the question of whether the criteria for HER2 positivity, which were established in the metastatic setting, can be applied to the adjuvant setting, or should the bar be reset at a different level for these patients?” 

NSABP B-47 is addressing this question in more than 3,000 women with resected node-positive or high-risk, node-negative tumors determined to be HER2-low, who are randomized to adjuvant chemotherapy with or without trastuzumab. This is a key trial. It’s B-31 all over again in HER2-normal breast cancer. Hopefully, we will identify the point at which trastuzumab starts to make a difference specifically in adjuvant therapy.

Optimal Combination

What is the benefit of using trastuzu­mab with a non–anthracycline-containing regimen?

The Breast Cancer International Research Group (BCIRG)-006 trial examined this question by randomizing 3,222 patients with HER2-positive, node-negative or node-positive early breast cancer to doxorubicin plus cyclophosphamide followed by docetaxel (AC-T, the control arm), AC-T plus trastuzumab (AC-TH), or a non–anthracycline-containing arm, docetaxel, carboplatin, and trastuzu­mab (TCH).

At the 2015 San Antonio Breast Cancer Symposium, Slamon et al reported that disease-free survival continued to be superior at 10 years for both trastuzumab arms.4 The disease-free survival rate was 74.6% for AC-TH (P < .0001) and 73.0% for TCH (P = .0011) vs 67.9% for AC-T. The hazard ratio for overall survival for the AC-TH arm was 0.63, identical to that observed in the joint analysis of the B-31 and N9831 trials, which compared AC followed by paclitaxel with or without trastuzumab.5

What is the optimal way to give adjuvant trastuzumab?

In N9831, the 5-year disease-free survival rate was superior with concurrent treatment (84.2%) vs sequential treatment (79.8%)6; therefore, the preferred approach is to initiate trastuzumab concurrently with the taxane in the adjuvant setting. A number of trials have examined the optimal duration of trastuzumab therapy, with the general conclusion that 1 year of therapy is sufficient and better than 6 months of treatment.

Toxicity Considerations

What is the cardiac risk associated with anthracycline-based/trastuzumab regimens, and what is the optimal ­assessment?

In NSABP B-31, a 2.7% higher rate of severe cardiac dysfunction was observed in the trastuzumab arms, generating a hazard ratio of 3.30 (P = .00038).7 Two risk factors emerged from the multivariate analysis: older age and borderline-normal baseline left-ventricular ejection fraction.

Your older patient with borderline [left-ventricular ejection fraction at baseline] is the one at risk [with an anthracycline-based trastuzumab regimen]. On the other hand, a young patient with a very good ejection fraction starting out will have quite a low risk of significant cardiac toxicity.
— Edward H. Romond, MD

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The percentage of patients who developed cardiac failure was higher among patients whose baseline [left-ventricular ejection fraction] was barely normal. Your older patient with borderline [left-ventricular ejection fraction] is the one at risk. On the other hand, a young patient with a very good ejection fraction starting out will have quite a low risk of significant cardiac toxicity.

For asymptomatic patients with standard monitoring, depending on the magnitude of left-ventricular ejection fraction decrease, trastuzumab can be continued or held. If you do hold trastuzumab for a month or two, in three-quarters of patients the ejection fraction recovers, and you can continue treatment with careful follow-up.

Small, Node-Negative Cancers

What is the outcome for HER2-positive patients with node-negative disease and very small tumors?

In the British Columbia Tumor Registry, 10-year recurrence-free survival for untreated patients with T1, N0 cancers was 78.7% if they were HER2-negative and 71.6% if they were HER2-positive.8 The study confirmed that HER2-positive untreated patients had worse outcomes than HER2-negative patients.

The benefit of trastuzumab in node-negative disease was shown in BCIRG-006. The disease-free survival rate at 5 years in this cohort, half of whom had T2 and T3 tumors, was 93% with AC-TH (HR 0.47, P = .003) and 90% with TCH (HR = 0.64, P = .057), compared to 85% with AC-T.9 A US Oncology phase II trial looked specifically at low-risk T1/2, N0/1a HER2-positive tumors in patients receiving docetaxel/cyclophosphamide plus trastuzumab, finding that 2-year disease-free survival approached 98%, with overall survival of approximately 99%.10 These good outcomes were confirmed by the APT trial of patients with HER2-positive, node-negative tumors ≤ 3 cm, where 3-year recurrence-free survival after paclitaxel plus trastuzumab was 99.2%.11 Only 2 of 406 patients had a distant recurrence.

Should patients with very small (≤ 1 cm) node-negative breast cancers (T1a/b) receive trastuzumab?

In the US Oncology phase II trial mentioned previously, patients with tumors ≤ 1 cm had a 100% disease-free and overall survival rate at 3 years.10 This raises the question: Do all patients with T1a/b tumors benefit from trastuzu­mab? Or is there a low-risk limit below which trastuzumab therapy does not make an appreciable difference? Most studies of patients with tumors ≤ 1 cm do not separate T1a from T1b lesions.

However, an examination of 16,975 breast cancer patients treated from 2000 to 2006 at Kaiser Permanente Northern California has been informative.12 Of them, 237 had HER2-positive, node-negative T1a or T1b tumors, mostly untreated (prior to trastuzu­mab’s approval in the adjuvant setting). After a median 6 years of follow-up, there were 15 (6.3%) invasive recurrences, of which 4 (3.5%) were in T1a tumors and 11 (6.3%) in T1b tumors, and of these tumors, there were 7 (2.9%) distant recurrences, 6 of which were in patients with T1b tumors. The 5-year distant relapse–free rate was 94% for T1b and 99.1% for T1a tumors. Only 1 patient out of 101 with a T1a tumor not treated with chemotherapy experienced a distant recurrence. Half of the T1a cancers were hormone receptor–negative.

This 1% risk of the cancer spreading is the figure we also quote to our patients with ductal carcinoma in situ. The guidelines indicate that for node-negative, T1a and T1b tumors, chemotherapy plus trastuzumab can be considered. But we discuss with our patients who clearly have T1a cancers whether a risk for distant recurrence approaching 1% is worth a year of treatment.

Newer Agents

How will pertuzumab (Perjeta), ado-trastuzumab emtansine (Kadcyla), and the investigational agent neratinib be incorporated into adjuvant treatment?

Pertuzumab was studied in combination with trastuzumab and 3 different chemotherapy regimens in 225 patients in the neoadjuvant TRYPHAENA trial.13 Each arm achieved high pathologic complete response rates in the breast, especially in hormone receptor–negative patients (65.0%–83.8%). The non–anthracycline-based regimen of docetaxel/carboplatin/trastuzumab plus pertuzumab actually produced the most pathologic complete responses. Similarly, in the NeoSphere trial of 417 patients, those receiving pertuzumab/trastuzumab/docetaxel (PTD) achieved the highest pathologic complete response rate (45.8%) overall and the highest rate among hormone receptor–negative patients (63.2%).14

The question is whether these findings in the neoadjuvant setting will translate into the adjuvant setting or does a higher pathologic complete response simply identify which patients are more likely to do well without changing disease-free and overall survival. An early clue may be provided by a recent update of NeoSphere. Although patient numbers are very small and confidence intervals are wide, ­Gianni et al reported that the 5-year progression-free survival rate was highest for PTD (86%), an absolute improvement of 5% compared with trastuzumab/docetaxel.15 The combination of the two antibodies and taxane may matter in the long run.

The pivotal 4,800-patient ­APHINITY trial may ultimately determine the benefit of dual HER2 blockade in the adjuvant setting. Patients are randomly assigned to an anthracycline-based regimen followed by paclitaxel with trastuzumab alone or trastuzumab plus pertuzumab. Meanwhile, the National Comprehensive Cancer Network® guidelines allow for the neoadjuvant or adjuvant use of pertuzumab plus trastuzumab, based on benefit seen in the neoadjuvant trials.

Ado-trastuzumab emtansine will be studied in the international Katherine trial, which has completed accrual and randomized almost 1,500 patients with residual disease after neoadjuvant therapy to trastuzumab or ado-trastuzumab emtansine for 14 cycles. This study focuses on the group of patients most at risk, and it’s a group where we may see an impact of this drug.

Neratinib was evaluated in the recent phase III ExteNET adjuvant trial in 2,840 patients who finished standard anti-HER2 neoadjuvant or adjuvant treatment.16 Patients were randomized to neratinib or placebo, and a small but statistically significant benefit—2.3% improvement in 2-year disease-free survival (P = .009)—was shown.

“There may be a group of patients at higher risk for whom this drug could make a difference,” he commented. The issue with neratinib is diarrhea, which was grade 3 in the trial in almost 40% of patients. Protocols for ameliorating this toxicity are now in place and further follow-up will be important. ■

Disclosure: Dr. Romond reported no potential conflicts of interest.


1. Romond EH: Early-stage HER2-positive breast cancer. 2016 School of Breast Oncology, Emory University, Atlanta. Presented October 5, 2016.

2. Perez EA, Reinholz MM, Hillman DW, et al: HER2 and chromosome 17 effect on patient outcome in the N9831 adjuvant trastuzumab trial. J Clin Oncol 28:4307-4315, 2010.

3. Paik S, Kim C, Wolmark: HER2 status and benefit from adjuvant trastuzumab in breast cancer. N Engl J Med 358:1409-1411, 2008.

4. Slamon DJ, Eiermann W, Robert NJ, et al: Ten-year followup of the BCIRG-006 trial comparing doxorubicin plus cyclophosphamide followed by docetaxel with doxorubicin plus cyclophosphamide followed by docetaxel and trastuzumab with docetaxel, carboplatin and trastuzumab in HER2-positive early breast cancer patients. 2015 San Antonio Breast Cancer Symposium. Abstract S5-04. Presented December 11, 2015.

5. Perez EA, Romond EH, Suman VJ, et al: Trastuzumab plus adjuvant chemotherapy for human epidermal growth factor receptor 2-positive breast cancer: Planned joint analysis of overall survival from NSABP B-31 and NCCTG N9831. J Clin Oncol 32:3744-3752, 2014.

6. Perez EA, Suman VJ, Davidson NE, et al: Sequential versus concurrent trastuzumab in adjuvant chemotherapy for breast cancer. J Clin Oncol 29:4491-4497, 2011.

7. Romond EH, Jeong JH, Rastogi P, et al: Seven-year follow-up assessment of cardiac function in NSABP B-31: A randomized trial comparing doxorubicin and cyclophosphamide followed by paclitaxel (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 30:3792-3799, 2012.

8. Chia S, Norris B, Speers C, et al: Human epidermal growth factor receptor 2 overexpression as a prognostic factor in a large tissue microarray series of node-negative breast cancers. J Clin Oncol 26:5697-5704, 2008.

9. Slamon D, Eiermann W, Robert N, et al: Adjuvant trastuzumab in HER2-positive breast cancer. N Engl J Med 365:1273-1283, 2011.

10. Jones SE, Collea R, Paul D, et al: Adjuvant docetaxel and cyclophosphamide plus trastuzumab in patients with HER2-amplified early stage breast cancer: A single-group, open-label, phase 2 study. Lancet Oncol 14:1121-1128, 2013.

11. Tolaney SM, Barry WT, Dang CT, et al: Adjuvant paclitaxel and trastuzumab for node-negative, HER2-positive breast cancer. N Engl J Med 372:134-141, 2015.

12. Fehrenbacher L, Capra AM, Quesenberry CP Jr, et al: Distant invasive breast cancer recurrence risk in human epidermal growth factor receptor 2-positive T1a and T1b node-negative localized breast cancer diagnosed from 2000 to 2006: A cohort from an integrated health care delivery system. J Clin Oncol 32:2151-2158, 2014.

13. 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.

14. 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.

15. Gianni L, Pienkowski T, Im YH, et al: 5-year analysis of neoadjuvant pertuzumab and trastuzumab in patients with locally advanced, inflammatory, or early-stage HER2-positive breast cancer (NeoSphere): A multicentre, open-label, phase 2 randomised trial. Lancet Oncol 17:791-800, 2016.

16. Chan A, Delaloge S, Holmes FA, et al: Neratinib after trastuzumab-based adjuvant therapy in patients with HER2-positive breast cancer (ExteNET): A multicentre, randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol 17:367-377, 2016.