SKIP CHEMO IN LUMINAL-A BREAST CANCER

SAN ANTONIO, Texas — Premenopausal women with Luminal A breast cancer, a common, intrinsic subtype, can consider skipping chemotherapy altogether and still expect a good prognosis, even when they are node positive, according to a new analysis of an old Danish study.

"This is clearly part of a body of evidence [in breast cancer] that's building up…that we can probably back off on the aggressiveness of our treatments and still achieve the same results," said investigator Torsten Nielsen, MD, PhD, from the University of British Columbia, Vancouver, British Columbia, Canada.

The new findings from the Danish Breast Cancer Cooperative Group 77B DBCG77B) study, which Dr Nielsen presented here at the San Antonio Breast Cancer Symposium (SABCS), raised some eyebrows given that chemotherapy is considered standard in premenopausal breast cancer.

But the question is a relevant one, noted Virginia Kaklamani, MD, of the University of Texas Health Science Center San Antonio and a codirector of the meeting.

As an investigator on the ongoing prospective SWOG RxPONDER trial (S1007) which is investigating a similar question, Dr Kaklamani said that the DBCG77B results "confirm what we thought — that we kind of don't need chemotherapy for these patients."

She also said the results expand her own sense of what is possible.

"This is another step and for me it gives me a little more confidence in my premenopausal women not to push chemotherapy. In our practice we would consider at least for a 55 or 60-year-old woman not giving chemotherapy if she had no hormone positive disease, but in premenopausal women we tend to not think about it," Dr Kaklamani said.

The new analysis used a prospective-retrospective design — in that it used tissue samples taken 25 years ago when the DBCG77B trial randomized patients to chemotherapy or no chemotherapy — a process that would not be considered ethical today (Cancer. 2010 May 1;116(9):2081-9).

At that time, 1146 premenopausal women with high-risk disease (tumors > 5 cm or positive axillary lymph nodes regardless of hormone receptor or HER2 status) were randomized to one of two active treatments — single-agent oral cyclophosphamide (C), or classic combination cyclophosphamide, methotrexate, and 5-fluorouracil (CMF); or 1 of 2 nonchemotherapy arms — levamisole, or placebo.

"They did not receive endocrine therapy, but they did however get what would be considered adequate local therapy by today's standards — a mastectomy supported by axillary node dissection and chest wall radiation," he said.

Ten-year disease-free survival (DFS) was better in the chemotherapy arms (55.5% in the C arm, 48.8% in the CMF arm) than the nonchemotherapy arms (38.6% in the control arm and 35.2% in the levamisole arm).

Immunohistochemical staining of the remaining available DBCG77B tissue samples revealed that chemotherapy improved DFS in 468 non-Luminal A patients (hazard ratio [HR] 0.50), but it had no benefit in 165 Luminal A patients (HR 1.07, P < .05).

Molecular testing is the key to differentiating between breast cancer subtypes, and Luminal A subtype can be determined by adding Ki67 to the regular biomarker panel run on every breast cancer, Dr Nielsen told Medscape Medical News, adding that this test is frequently available at local pathology labs.

Subtyping is also possible using the BluePrint test from Mammaprint/Agendia or the Prosigna test from NanoString — the latter of which he helped develop (see disclosures) — although both tests are only US Food and Drug Administration-approved for risk-profiling and not subtype reporting.

"One of the limitations of this study is the chemotherapy being used doesn't include anthracyclines or taxanes which we would have included," said Dr Kaklamani.

Grumblings From the Audience

"Would a more accurate title be no benefit from CMF chemotherapy in non-endocrine treated patients with Luminal A breast cancer?" added Steve Sugarman, MD, from Memorial Sloan Kettering Cancer Center, New York, during the question period.

"Yes, that would be more accurate," said Dr Nielsen, "but we were really trying to address the issue of chemotherapy versus no chemotherapy and it's very hard to find a trial that randomizes anthracycline or taxane versus nothing," he said.

Another clinician was underwhelmed by the results. During the question period, Steven Vogl, MD, a medical oncologist in private practice in New York City, said "There were only 31 Luminal A patients who didn't get chemotherapy, right. I'll go home saying small numbers, old study, I don't know what it means. Convince me I should do something about it."

Asked by Medscape to comment on the findings, Aleix Prat, MD, PhD, a medical oncologist at the Hospital Clínic University of Barcelona in Spain, said "these results fill the gap that we had regarding the ability of the breast cancer intrinsic subtypes to predict chemotherapy benefit. It is the first study to evaluate, in the adjuvant setting, that surrogate-based definitions of the intrinsic subtypes predict survival benefit following chemotherapy."

Intrinsic subtyping with immunohistochemical techniques is already being used in many countries, especially in Europe, as a prognostic indicator. Dr Prat said that the new study indicates that the subtypes are even more valuable in the clinic.

"Results of this new study show us that not only are subtypes prognostic, but also predictive of chemotherapy benefit….These results should help us better identify those patients that should not be treated with adjuvant multi-agent chemotherapy not only because they have a low risk of relapse without chemotherapy, but because they do not derive benefit from it," he commented."

He added "future investigations should evaluate if these findings are also valid in cohorts of patients treated with more modern chemotherapy regimens that include taxanes and anthracyclines, and if intrinsic biology defined by gene expression (the gold-standard) better predicts chemotherapy benefit than immunohistochemical-based definitions."

Dr Nielsen has disclosed that he is a consultant, speaker, and receives royalties from Nanostring technologies. He has disclosed that he holds a patent as coinventor of the PAM50 algorithm that underlies the Prosigna test. 

San Antonio Breast Cancer Symposium 2015: Abstract S1-08. Presented December 9, 2015.