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Study Finds Timing of Therapy Does Not Influence Outcomes in HER2-Positive Breast Cancer


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The sequencing of trastuzumab administration with chemotherapy in the neoadjuvant setting seems to have no effect on outcomes for patients with HER2-positive breast cancer, according to data presented at the 2019 Society of Surgical Oncology Annual Cancer Symposium.1

The results of a phase III study showed that pathologic complete response rates were greater than 50% with concurrent or sequential anthracycline-based and taxane-based chemotherapy in patients with HER2-positive breast cancer. However, the concurrent administration of anthracycline and trastuzumab did not offer any additional survival benefit or improvement in the rates of pathologic complete response. The study authors also noted that achieving a pathologic complete response was associated with improved disease-free and overall survival.


Conducting studies where subtype-specific breast cancers are treated with specific regimens are more likely to show improvements and help us understand which patients will benefit from additional therapies.
— Kelly K. Hunt, MD, FACS

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“Although locoregional recurrence rates were much lower than what has been reported in previous studies, achieving a pathologic complete response does not completely eliminate the risk of locoregional recurrence,” said Kelly K. Hunt, MD, FACS, Professor and Chair of the Department of Breast Surgical Oncology at MD Anderson Cancer Center, Houston. “Conducting studies where subtype-specific breast cancers are treated with specific regimens are more likely to show improvements and help us understand which patients may benefit from additional therapies after surgery.”

As Dr. Hunt reported, neoadjuvant systemic therapies have been utilized in breast cancer for over 30 years and have shown many advantages: converting inoperable patients to operable status, increasing rates of breast-conserving surgery, decreasing the incidence of positive nodes, being a useful tool for research and comparing new agents, and also demonstrating that response is prognostic for outcomes with few patients experiencing disease progression while on neoadjuvant therapy. Nevertheless, said Dr. Hunt, numerous trials investigating the neoadjuvant vs adjuvant approach with respect to survival outcomes have found no difference in survival based on the timing of the therapy.

“We now know that response to neoadjuvant therapy is based on approximated subtype, with higher rates of pathologic complete response seen in the breast in patients with HER2-positive and triple-negative disease,” said Dr. Hunt, who noted that systemic therapy for HER2-positive disease has changed significantly over the past decade.

“Initially, findings showed improved outcomes in HER2-positive disease when trastuzumab was delivered with chemotherapy in the adjuvant setting,” Dr. Hunt explained. “However, a trial from MD Anderson found pathologic complete responses as high as 66.7% when chemotherapy was delivered concurrently with trastuzumab in the neoadjuvant setting, but there were concerns about cardiac safety with the use of anthracyclines and trastuzumab concurrently.”2

Alliance Trial Design

The American College of Surgeons Oncology Group (ACOSOG) Z1041 (Alliance) trial was developed primarily to address the timing of trastuzumab and anthracycline therapy in the neoadjuvant setting in patients with HER2-positive disease. The study’s primary endpoint was pathologic complete response rates with concurrent vs sequential regimens. Secondary endpoints included disease-free and overall survival, locoregional recurrence, pathologic complete response in the breasts and nodes, and cardiac safety.

Sequence of Therapies in HER2-Positive Breast Cancer

  • Concurrent versus sequential anthracycline with trastuzumab shows no additional benefit in pathologic complete response for patients with HER2-positive breast cancer.
  • An estimated 4-year cumulative incidence of locoregional recurrence after surgery is 2.9%.

Patients with histologically confirmed disease with at least T2 disease or positive nodes were randomly assigned to either a concurrent regimen with trastuzumab, anthracycline, and paclitaxel or a sequential regimen with anthracycline given first without trastuzumab followed by paclitaxel and trastuzumab. The investigators stratified patients based on age, tumor size, and hormone receptor status. Patients then underwent surgery and completed 1 year of adjuvant trastuzumab therapy.

Disease-free survival was measured from the time of randomization to the first of the following events: progression of disease during neoadjuvant therapy; local, regional, or distant recurrence; contralateral breast disease; other second invasive primary cancers; and death due to any cause. Overall survival was also measured from the time of randomization. Patients without a disease event were censored at the time of their last known disease evaluation.

Improved Survival After Pathologic Complete Response

As Dr. Hunt reported, 282 patients from 36 different centers were enrolled in the study between 2007 and 2011, and 2 patients withdrew consent prior to treatment. The median follow-up for patients still alive at the time of the data analysis was 5.1 years, and approximately 60% had hormone receptor–positive disease.

Of the 280 eligible patients analyzed, disease-free and overall survival were not found to differ between patients with hormone receptor–positive disease and those with hormone receptor–negative disease, said Dr. Hunt. In the surgical cohort, 268 patients completed surgery after neoadjuvant therapy, and previously published rates of pathologic complete response did not differ between the concurrent and sequential regimens (55.6% vs 54.2%).3 Data also previously published showed no difference in disease-free or overall survival based on the timing of the therapy or estrogen receptor status.4

Of the 268 patients who underwent surgery after neoadjuvant chemotherapy, 155 patients had a pathologic complete response (57.8%). Although disease-free and overall survival did not differ between the regimens, said Dr. Hunt, improved disease-free survival and overall survival were observed in patients who achieved a pathologic complete response in the breast (P = .0001).

Of the 169 patients with nodal involvement at initial diagnosis, pathologic complete response in the breast and nodes was 50.9%. Among patients who achieved a pathologic complete response, disease-free survival and overall survival were found to be longer than in those who did not have a pathologic complete response.

There were only 7 patients (2.9%) who had a local or regional recurrence after surgery as well as several distant recurrences in both arms. Three of these patients had a partial mastectomy, three had a mastectomy, and one had a modified radical mastectomy. There was one local recurrence in a patient who achieved a pathologic complete response, said Dr. Hunt, who noted that the other six patients had residual disease either in the breast or in the breast and nodes.

“Which patients actually need anthracyclines is still an ongoing question in this disease,” Dr. Hunt concluded. “Future trials should focus on de-escalation of therapy in patients who achieve a pathologic complete response with standard regimens.” 

DISCLOSURE: Dr. Hunt reported no conflicts of interest.

REFERENCES

1. Hunt K, Suman V, Meric-Bernstam F, et al: Local-regional recurrence data from the American College of Surgeons Oncology Group Z1041 (Alliance): A randomized neoadjuvant trial of sequential versus concurrent anthracycline with trastuzumab and paclitaxel plus trastuzumab in HER2-positive breast cancer. 2019 Society of Surgical Oncology Annual Meeting. Abstract 1. Presented March 29, 2019.

2. Buzdar AU, Ibrahim NK, Francis D, et al: Significantly higher pathologic complete remission rate after neoadjuvant therapy with trastuzumab, paclitaxel, and epirubicin chemotherapy: Results of a randomized trial in human epidermal growth factor receptor 2-positive operable breast cancer. J Clin Oncol 23:3676-3685, 2005.

3. Buzdar AU, Suman VJ, Meric-Bernstam F, et al: Fluorouracil, epirubicin, and cyclophosphamide (FEC-75) followed by paclitaxel plus trastuzumab versus paclitaxel plus trastuzumab followed by FEC-75 plus trastuzumab as neoadjuvant treatment for patients with HER2-positive breast cancer (Z1041): A randomised, controlled, phase 3 trial. Lancet Oncol 14:1317-1325, 2013.

4. Buzdar AU, Suman VJ, Meric-Bernstam F, et al: Disease-free and overall survival among patients with operable HER2-positive breast cancer treated with sequential vs concurrent chemotherapy: The ACOSOG Z1041 (Alliance) randomized clinical trial. JAMA Oncol. September 6, 2018 (early release online).


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