AI Neither Adds nor Detracts From Chemo in This Setting

Pam Harrison

December 14, 2016

SAN ANTONIO — The addition of estrogen deprivation therapy to neoadjuvant chemotherapy plus trastuzumab (Herceptin, Genentech) and pertuzumab (Perjeta, Genentech) in patients with hormone receptor (HR)–positive, human epidermal growth factor receptor 2 (HER2)–positive breast cancer is not antagonistic, as was once believed, according to a phase 3 trial presented here at the San Antonio Breast Cancer Symposium (SABCS) 2016.

However, the extra treatment is no help either, as it did not improve pathologic complete response (pCR) rates.

"Many patients with HR-positive, HER2-positive breast cancer who have large, operable breast tumors or evidence that the cancer has spread to underarm lymph nodes receive docetaxel, carboplatin, trastuzumab, and pertuzumab before surgery," said study lead author Mothaffar F. Rimawi, MD, from the Dan L Duncan Comprehensive Cancer Center at Baylor College of Medicine, Houston, Texas, in a meeting press statement.

"However, many of them don't respond optimally, especially if their tumors are also HR-positive. Preclinical and clinical data led us to test whether adding an aromatase inhibitor to this neoadjuvant treatment regimen in this patient group would increase the percentage of patients who have a pathological complete response," he continued.

However, there has been a historical inhibition against adding an aromatase inhibitor (AI) in this setting, appealing as the idea might have been.

That inhibition was based on research performed decades ago, led by Kent Osborne, MD, an SABCS director, who is also from the Dan L. Duncan Comprehensive Cancer Center. The work found that addition of tamoxifen to certain chemotherapy drugs diminished the effectiveness of the chemo. The field of oncology collectively decided that this detrimental effect also applied to AIs, said Dr Osborne in an interview with Medscape Medical News.

Ever since, "we have never given endocrine therapy with chemotherapy," he said.

The new results, which come from the NSABP-B52 trial, indicate there is neither a disadvantage nor an advantage from endocrine therapy with an AI.

At a meeting press conference, Dr Rimawi explained what this meant to reporters: "We cannot recommend a change to the standard-of-care neoadjuvant treatment regimen for patients with HR-positive, HER2-positive breast cancer."

The regimen, with or without the aromatase inhibitor, was very toxic, so the investigators envision attempting to reduce the total neoadjuvant treatment, not add even more drugs.

Dr Rimawi said it this way: "While we did not see a detrimental effect from the addition of estrogen deprivation to neoadjuvant chemotherapy, given the toxicity of standard chemotherapy observed in this trial, findings from NSABP-B52 argue quite strongly for a tailored de-escalation approach in which toxic treatments are omitted or replaced with less toxic ones without compromising outcomes."

Primary End Point

In the trial, a total of 315 patients with locally advanced HR-positive, HER2-positive invasive breast cancer with no evidence of metastatic disease were randomly assigned to docetaxel, carboplatin, trastuzumab, and pertuzumab (TCHP) plus or minus an AI alone if they were postmenopausal.

Premenopausal women were randomly assigned to the same background regimen given with or without an AI plus goserelin to suppress ovarian function.

Over one quarter of the group had T3 or T4 lesions, just under half were younger than age 50 years, and 57% had node-positive disease, so this was a high-risk population, as Dr Rimawi noted.

Patients received six cycles of treatment, then proceeded to surgery and axillary staging. The pCR rate in both breast and lymph nodes, the primary endpoint of the trial, was evaluable in 308 women overall.

In the overall study population, 41% of patients in the control group achieved a pCR, which was the primary endpoint, compared with 46% in the experimental group containing additional estrogen deprivation, a difference that was not statistically significant, Dr Rimawi reported.

Subgroup analysis by menopausal status and pCR rates in the breast alone showed very similar findings between the two treatment groups; none of the between-group differences were statistically significant.

Site pCR Rates: Control Group (%) pCR Rates: Experimental Group (%)
Breast and lymph nodes 44 46
Breast and lymph nodes: premenopausal women 44 47
Breast and lymph nodes: postmenopausal women 38 45
Breast alone (overall population) 44 47
Breast alone (postmenopausal women) 40 45
Breast alone (premenopausal women) 48 49


High Rates of Toxicity

"This TCHP regimen has considerable gastrointestinal toxicity, including diarrhea, nausea, vomiting, and dehydration," Dr Rimawi noted.

"And the overall rate of toxicity was quite high, with over 60% grade 3 and 4 toxicities," he added.

On the other hand, the addition of estrogen deprivation to the experimental group did not add to the toxicity because toxicity rates did not differ between the two study groups.

Dr Rimawi also noted that despite this "remarkable toxicity," 90% of patients in both treatment groups received at least five cycles of all four drugs, and the delivery of endocrine therapy was also achieved in about 90% of the experimental group as well, "so it was really quite a high delivery rate of all agents," he observed.

"Remember, these patients are going to get endocrine therapy anyway, so we are not really escalating treatment, we are just moving up the time line," Dr Rimawi said.

Commenting on the study, press briefing moderator Carlos Arteaga, MD, an SABCS director from the Vanderbilt-Ingram Cancer Center, Nashville, Tennessee, noted that just because pCR rates did not differ between the two treatment groups does not necessarily mean that patients are going to do poorly.

Indeed, most patients with HR-positive, HER2-positive breast cancer actually do quite well, both he and Dr Rimawi agreed.

The study was funded by the National Institutes of Health and Genentech. Dr Rimawi has disclosed no relevant financial relationships. Dr Osborne has financial ties to AstraZeneca, Genentech, Gilead Sciences, and Perkin Elmer.

San Antonio Breast Cancer Symposium (SABCS) 2016. Abstract S3-06. Presented December 8, 2016.

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