Variety of Adjuvant Strategies Explored in HER2‑Positive and Other Breast Cancer Types

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Andrew D. Seidman, MD

We shouldn’t be selecting for the use of trastuzumab based on hormone receptor status…. I think the more pressing question … is whether smaller T1 cancers warrant adjuvant trastuzumab.

—Andrew D. Seidman, MD

Adjuvant trastuzumab (Herceptin) was shown to be effective in patients with breast cancers ≤ 2 cm, regardless of estrogen receptor status, in a meta-analysis1 of five chemotherapy trials, but a “pressing question” remaining is whether T1a/b, N0 tumors warrant the use of adjuvant trastuzumab, Andrew D. Seidman, MD, commented at the Best of ASCO meeting in Chicago. Dr. Seidman is Attending Physician at Memorial Sloan Kettering Cancer Center and Professor of Medicine at Weill Cornell Medical Center, New York.

Among a total of 12,589 patients with HER2-positive tumors, 4,220 had tumors ≤ 2 cm, with 2,588 receiving trastuzumab and 1,632 not receiving the monoclonal antibody. “Proportional benefit was similar for [hormone receptor]–positive and [hormone receptor]–negative cohorts, but the patterns and incidence of relapse appeared to differ over follow-up time,” Dr. Seidman noted.

At 8 years, the cumulative recurrence rate for patients with hormone receptor–positive disease was 12.7% for those receiving trastuzumab vs 19.4% for those in the observation arm—an 8-year gain of 6.7% (hazard ratio [HR] = 0.64, P = .005)—and the respective cumulative mortality rates were 5.3% vs 7.4%, a gain of 2.1% (HR = 0.68, P = .12). For patients with hormone receptor–negative disease, the cumulative recurrence rates at 8 years were 24.0% for those receiving trastuzumab vs 33.4% for patients in the observation arm—an 8-year gain of 9.4% (HR = 0.7, P = .0001)—and the respective cumulative mortality rates were 12.4% vs 21.2%, a gain of 8.8% (HR = 0.6, P =.0001).

The five studies were the Herceptin Adjuvant (HERA) trial, North Central Cancer Treatment Group (NCCTG) N9831 trial, National Surgical Adjuvant Breast and Bowel Project (NSABP) B-31 trial, PACS 04 trial, and Finland Herceptin (FinHER) trial. The analysis was conducted by researchers at the National Cancer Institute and others in this country and in Europe.

More Pressing Question

Dr. Seidman posed the question of whether hormone receptor status predicts specific benefit from adjuvant trastuzumab in small tumors. The answer, he said, is no.

“We shouldn’t be selecting for the use of trastuzumab based on hormone receptor status. This is consistent with and reinforces current guidelines. I think the more pressing question that these data don’t really get at, is whether smaller T1 cancers warrant adjuvant trastuzumab. These patients were underrepresented in this analysis,” Dr. Seidman.

Single-center studies have looked at the smaller T1a/b, N0 tumors. Dr. Seidman cited an MD Anderson Cancer Center series finding worse outcomes for patients with small node-negative cancers that are HER2-positive compared to HER2-negative in the absence of trastuzumab therapy.2 At 5 years, the relapse-free survival rate was 77.1% in HER2-positive patients vs 93.7% in HER2-negative patients. Similarly, the National Comprehensive Cancer Network (NCCN) series presented at the 2013 ASCO Annual Meeting showed a worse outcome for HER2-positive patients, with a 5-year disease-free survival rate of 83.3% vs 89.0% for HER2-negative patients.3

Standard of Care for Select Patients

In a nonrandomized registry study, patients with breast cancer that was HER2-positive, estrogen receptor–negative or –positive, node-negative, and with tumors ≤ 3 cm were treated with paclitaxel plus trastuzumab, followed by continuation of trastuzumab every 3 weeks for a up to a year. There was no randomization, and patients were compared to historical controls.

“These results show excellent outcomes for these patients, with very few events, a 3-year disease-free survival rate of 98% for T1c breast cancers, and of 99.5% for T1a/b breast cancers,” Dr. Seidman stated. “In my institution, this does represent the standard of care for select patients with smaller, node-negative, HER2-positive breast cancers, specifically in scenarios where you might think anthracyclines are to be avoided, even the use of regimens such as TCH [docetaxel, carboplatin, trastuzumab].”

The paclitaxel-plus-trastuzumab regimen used in the study described above will be compared to ado-trastuzumab emtansine (Kadcyla, formerly known as T-DMI) for women with stage I, HER2-positive breast cancer in the ATEMPT trial.4 The primary outcome measure is disease-free survival. Secondary outcome measures include overall survival and, within a 2-year time frame, the percentage of participants with grade 3/4 cardiac dysfunction, grade 2–4 thrombocytopenia, and amenorrhea at various time points after start of treatment in premenopausal women. Estimated enrollment is 500 patients, and recruitment is still open.

Bevacizumab Not Very Promising in Breast Cancer

Incorporating bevacizumab (Avastin) into adjuvant therapy containing an anthracycline and a taxane did not improve invasive disease–free survival or overall survival, the primary endpoints of Eastern Cooperative Oncology Group (ECOG) 5103,5 one of several other breast cancer studies reviewed at the Best of ASCO. At a median follow-up of 47.5 months, “there was absolutely no signal that survival would be improved [with the addition of bevacizumab],” Dr. Seidman said. “This is another negative study for bevacizumab.”

He noted that the results “are similar and consistent with two previous adjuvant studies,” the BEATRICE6 and BETH7 trials. “For the moment, it doesn’t look very promising for bevacizumab in breast cancer,” he stated.

The rationale for the study was that since tumor growth is dependent on angiogenesis, and proangiogenic pathways are more numerous and redundant as cancer progresses, giving bevacizumab in the adjuvant setting might provide greater benefit. The drug has been shown to improve progression-free survival, although not overall survival, in patients with metastatic breast cancer.

All patients received doxorubicin and cyclophosphamide followed by weekly paclitaxel. In addition, patients were randomly assigned to one of three groups and received either placebo (arm A), bevacizumab during chemotherapy (arm B), or bevacizumab during chemotherapy followed by bevacizumab monotherapy for 10 cycles, administered concurrently with radiation and hormonal therapy (arm C). Bevacizumab exposure “was less than anticipated,” according to the study abstract, with about 24% of patients in arm B and 55% in arm C discontinuing bevacizumab before completing planned therapy.

Higher Rate of Congestive Heart Failure

The median age of patients was 52, and 62% of patients in all treatment arms had estrogen receptor–positive breast cancer. Between 50% and 52% of patients in all arms had tumors in the > 2 to ≤ 5 cm range, and 10% had tumors > 5 cm. Lymph node status was similar for patients in all three arms, with 26% negative, 43% with one to three positive nodes, and 31 with at least three positive nodes.

Local therapy was also similar across arms, with the most common treatments being breast-conserving surgery plus whole-body radiation therapy (42%) and mastectomy plus radiation therapy (35%). Most patients received dose-dense doxorubicin and cyclophosphamide.

“As an aficionado of dose density, I was happy to see 80% of physicians did choose to give dose-dense anthracycline at least,” Dr. Seidman said.

At 5 years, invasive disease–free survival was 77% in arm A, 76% in arm B, and 80% in arm C. The hazard ratio for arm C vs A was 0.87, with a two-sided P value of .17. Overall survival at 5 years was 90% in arm A, 86% in arm B, and 90% in arm C. The hazard ratio for arm C vs A was 0.89, with a two-sided P value of .41.

Toxicities were similar in all arms during concurrent chemotherapy, with few of any grade, and no new toxicities identified. “One significant difference I want to point out is that there was a statistically significant increase in clinical congestive heart failure in the bevacizumab arms compared to the no-bevacizumab arm,” Dr. Seidman observed. Clinical congestive heart failure rates were 1.9% in arm B and 3.0% in arm C (the two bevacizumab arms) vs 1.0% in arm A.

Vitamin D Levels Not Prognostic

A substudy of the phase III National Cancer Institute of Canada Clinical Trials Group MA.21 trial, comparing three different chemotherapy regimens in high-risk breast cancer, looked at the prognostic associations of vitamin D levels and found none.8 At a median follow-up of 9.2 years, there was no evidence that vitamin D was associated with relapse-free survival, breast-specific survival, or overall survival. Most patients—752 of 935 (80.5%) whose fasting blood was collected before chemotherapy—had adequate vitamin D levels.

“Currently, there is no indication to provide vitamin D supplementation to improve breast cancer outcomes,” Dr. Seidman said. He noted that other studies had shown some association between low vitamin D levels and worse outcomes for patients with breast cancer, and that the overall link between vitamin D and breast cancer outcomes is still inconclusive.

Previously Reported Studies

Dr. Seidman also summarized the results and implications of two other breast cancer studies originally presented at the 2014 ASCO Annual Meeting in Chicago. Results from the phase III ALTTO trial9 found that adding lapatinib (Tykerb) to trastuzumab produced no additional benefit in the adjuvant treatment of HER2-positive early breast cancer. Those results were reported in detail in the June 10, 2014, issue of The ASCO Post.

A joint analysis of the Tamoxifen and Exemestane Trial (TEXT) and Suppression of Ovarian Function Trial (SOFT) found exemestane plus ovarian function suppression reduced the risk of recurrence compared to tamoxifen plus ovarian suppression in premenopausal women with hormone-sensitive breast cancers.10 Details of that study were included in the June 25, 2014, issue of The ASCO Post. 

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


1. O’Sullivan CCM, Bradbury I, De Azambuja E, et al: Efficacy of adjuvant trastuzumab (T) compared with no T for patients (pts) with HER2-positive breast cancer and tumors ≤ 2 cm: A meta-analysis of the randomized trastuzumab trials. ASCO Annual Meeting. Abstract 508. Presented May 31, 2014.

2. Gonzalez-Angulo AM, Litton JK, Broglio KR, et al: High risk of recurrence for patients with breast cancer who have human epidermal growth factor receptor 2-positive, node-negative tumors 1 cm or smaller. J Clin Oncol 27:5700-5706, 2009.

3. Vaz Duarte Luis IM, Ottesen RA, Hughes ME, et al: Time trends in the use of adjuvant chemotherapy (CTX) and outcomes in women with T1N0 breast cancer (BC) in the National Comprehensive Cancer Network (NCCN). ASCO Annual Meeting. Abstract 1006. Presented June 3, 2013.

4. U.S. National Institutes of Health: T-DM1 vs paclitaxel/trastuzumab for breast (ATEMPT trial). Available at Accessed October 10, 2014.

5. Miller K, O’Neill AM, Dang CT, et al: Bevacizumab (Bv) in the adjuvant treatment of HER2-negative breast cancer: Final results from Eastern Cooperative Oncology Group E5103. ASCO Annual Meeting. Abstract 500. Presented May 31, 2014.

6. Cameron D, Brown J, Dent R, et al: Adjuvant bevacizumab-containing therapy in triple-negative breast cancer (BEATRICE): Primary results of a randomised, phase 3 trial. Lancet Oncol 10:933-942, 2013.

7. Slamon D, Swain S, Buyse M, et al: Primary results from BETH, a phase 3 controlled study of adjuvant chemotherapy and trastuzumab ± bevacizumab in patients with HER2-positive, node-positive or high risk node-negative breast cancer. San Antonio Breast Cancer Symposium. Abstract S1-03. Presented December 11, 2013.

8. Lohmann AE, Chapman J-A W, Burnell MJ, et al: Prognostic associations of 25OH vitamin D in NCIC CTG MA.21, a phase III adjuvant RCT of three chemotherapy regimens (EC/T, CEF, AC/T) in high-risk breast cancer (BC). ASCO Annual Meeting. Abstract 504. Presented May 31, 2014.

9. Piccart-Gebhart MJ, Holmes AP, Baselga J, et al: First results from the phase III ALTTO trial (BIG 2-06l; NCCTG [Alliance] N063D) comparing one year of anti-HER2 therapy with lapatinib alone (L), trastuzumab alone (T), their sequence (T→L), or their combination (T+L) in the adjuvant treatment of HER2-positive early breast cancer (EBC). ASCO Annual Meeting. Abstract LBA4. Presented June 1, 2014.

10. Pagani O, Ryan MM, Walley B, et al: Randomized comparison of adjuvant aromatase inhibitor (AI) exemestane (E) plus ovarian function suppression (OFS) vs tamoxifen (T) plus OFS in premenopausal women with hormone receptor-positive (HR+) early breast cancer (BC): Joint analysis of IBCSG TEXT and SOFT trials. ASCO Annual Meeting. Abstract LBA1. Presented June 1, 2014.