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two conclusive therapeutic de-escalation trials

Chicago, USA – Two therapeutic de-escalation trials in breast cancer were presented and highlighted at the annual congress of the American Society of Clinical Oncology (ASCO) .

Chemo: no significant benefit in ≥ 70 years old with high genomic index

The benefit of adjuvant chemotherapy in addition to hormone therapy remains controversial for patients aged 70 years and older with primary estrogen receptor-positive (ER+) and HER2-negative (HER2-) or relapsed breast cancer local isolated.

In this context, the study ASTER 70s is the first multicenter therapeutic trial based on the analysis of the tumor genomic signature, reflecting the risk of relapse, to choose whether or not to perform adjuvant chemotherapy in people over 70[1]. The objective of the study was to evaluate the contribution of postoperative chemotherapy in addition to hormone therapy versus hormone therapy alone if the tumor is aggressive (high genomic grade).



Dr Etienne Brain

The results were presented on June 7, 2022 at ASCO by the Dr Etienne Brainmedical oncologist, specialist in breast cancer and care of elderly patients at the Institut Curie, who also received the BJ Kennedy prize for scientific excellence in oncogeriatrics from the ASCO (see box).

In this prospective trial, researchers first assessed Genomic Tumor Grade Index (GGI) in all patients. Then, patients with a high GGI (high risk of relapse) were randomized between chemotherapy plus endocrine therapy vs endocrine therapy alone.

Patients with low GGI did not receive chemotherapy and were followed in an observation cohort.

Doctors chose between 3 chemotherapy regimens: 4 cycles of doxorubicin/cyclophosphamide, non-pegylated liposomal doxorubicin/cyclophosphamide, or docetaxel/cyclophosphamide, given every 3 weeks with G-CSF. Hormone therapy consisted of 5 years of aromatase inhibitor, tamoxifen, or a tolerance-related sequence.

The primary objective was to demonstrate a chemotherapy-related overall survival (OS) benefit in the intention-to-treat population.

Between April 2012 and May 2016, 1,969 patients from 61 French centers and 12 Belgian centers were enrolled in the study. Of these, 1,089 (55%) were randomized to one of the two arms of the study. The median follow-up was 5.8 years at the data cut-off date (12/17/2021). The median age was 75 years (70-92). The tumors were ≥ pT2, pN+, isolated local relapses, of histological grade III, respectively in 56%, 46%, 11% and 39% of cases.

No significant difference in overall survival was observed between the arms (RR 0.85 [0,64-1,13], p=0.2538). OS at 4 years was 90.5% in the chemotherapy plus endocrine therapy arm and 89.7% in the endocrine therapy alone arm. The researchers could not identify any subgroup that benefited significantly from chemotherapy.

“This is the first time that we have a study of such magnitude in a population that is usually excluded from clinical trials”, commented Dr. Brain who adds: “Our results raise questions about the therapeutic de-escalation in some of our elderly patients and on the considerable bias of our attitudes, resorting by default, without demonstration, to the same standards as in our younger patients. The mass of information gathered in Aster 70s will make it possible to study the necessary adjustments and adaptations of these treatments, which are often over-prescribed like chemotherapy”.

Aster 70s will make it possible to study the necessary adjustments and adaptations of these treatments, which are often over-prescribed, such as chemotherapy.
Dr Etienne Brain

ASCO BJ Kennedy Geriatric Oncology Award 2022 awarded to Dr. E. Brain

This prize rewards a doctor for his exceptional contributions to the research, diagnosis and treatment of cancer in the elderly, and in recognition of his international animation of the theme on the educational and political level.

“I am very proud of this prize which is being awarded to me today because it is the culmination of numerous works carried out over several years for the care of elderly people with cancer, in particular those with breast cancer. We must continue to develop specific clinical research for this elderly population,” said Dr. Etienne Brain.

Dr. Brain is the former chairman of the “Breast Cancer” group at the EORTC (European Organization for Research and Treatment of Cancer). He chairs the DIALOG Intergroup (GERICO/UCOG) dedicated to clinical research for elderly patients. He is also former president of the International Society of Onco-Geriatrics (SIOG).

“I am delighted with this prestigious recognition across the Atlantic which today honors Dr Etienne Brain for his work carried out for years at the Institut Curie”, indicated the Professor Steven Le GouillDirector of the Institut Curie Hospital Complex in a press release[2].

Could we do without conservative post-surgery radiotherapy from the age of 55?

Another trial of therapeutic de-escalation in breast cancer presented at ASCO, the trial LUMINAwhich showed that some patients may be able to avoid radiation therapy after breast-conserving surgery[3].

Adjuvant radiation therapy is usually prescribed after breast-sparing surgery to reduce the risk of recurrence, but treatment is associated with both acute and long-term toxicity.

The women in this trial who did not receive radiotherapy and who were treated with breast-conserving surgery followed by hormone therapy, had an overall survival rate of 97.2%. The local recurrence rate was 2.3%, the study’s primary endpoint.



Dr. Timothy Joseph Whelan

“Women 55 years and older with low-grade luminal type A breast cancer after breast-conserving surgery and treated with hormone therapy alone had a very low rate of local recurrence at 5 years,” said commented the main author, the Dr. Timothy Joseph Whelan during his presentation at the ASCO [3].

Women aged 55 and over with low-grade luminal type A breast cancer after breast-conserving surgery and treated with hormone therapy alone had a very low rate of local recurrence at 5 years.
Dr. Timothy Joseph Whelan

“More than 300,000 [personnes] are diagnosed with invasive breast cancer in North America each year, the majority in the United States,” Dr. Whelan said. “We estimate that these results could apply to 10 to 15% of them, or approximately 30,000 to 40,000 women per year who could avoid the morbidity, cost and inconvenience of radiotherapy”.

Previous studies have shown that in women over the age of 60 with low-grade luminal type A breast cancer who have had only breast-conserving surgery, the rate of local recurrence is low. In women over the age of 70, the risk of local recurrence was about 4 to 5%. This new study shows that this option can be considered even earlier.

The LUMINA study involved patients with breast cancer with a luminal A subtype associated with pathological clinical factors (defined as: ER ≥ 1%, PR > 20%, HER2-negative and Ki67 ≤ 13 .25%).

The multicenter prospective cohort study included 501 patients aged 55 and over who underwent breast-conserving surgery for grade 1-2 T1N0 cancer.

The median age of patients was 67 years, of whom 442 (88%) were over 75 years old. The median tumor size was 1.1 cm.

The median follow-up was 5 years. The cohort was followed every 6 months for the first 2 years and then annually.

At five years, there were 10 local recurrences, i.e. a rate of 2.3% (primary endpoint); eight contralateral breast cancers (1.9%), a recurrence-free survival rate of 97.3%, a disease-free survival rate of 89.9% and an overall survival of 97.2% (secondary endpoints).

“This is an extremely well-designed and important study,” commented the Pre Penny R. Anderson (Department of Radiation Oncology, Fox Chase Cancer Center, Philadelphia) before adding that this trial is “a significant addition and a very relevant contribution to the literature demonstrating that adjuvant breast radiotherapy may not be performed safely in this particular subgroup of patients with breast cancer”.

Commenting on the study, the Dr Julie GralowExecutive Vice President of ASCO, told Medscape Medical News “I think there will be a discussion about how best to identify this group,” because in this study, patients were screened for Ki67, a marker of proliferation. However, the Ki67 test is not performed routinely. “Do we need this Ki67 test? Do we need to develop guidelines on how to do this? Is it better than if you have already done an Oncotype or MammaPrint test to see if the patient needs chemotherapy? “, she asks. “That’s where the discussion will be.”

Is it better than if you have already done an Oncotype or MammaPrint test to see if the patient needs chemotherapy?
Dr Julie Gralow

Also commenting on the study, the Dr. Deborah Axelrod (Perlmutter Cancer Center of NYU Langone, New York), praised the prospective and multicenter nature of the LUMINA study while underlining some limitations: “The follow-up is 5 years and the local recurrence of ER-positive cancers continues to increase after 5 years, so longer term follow-up would be important”. In addition, she clarified that this was a single-arm study, and therefore without a comparison arm.

She added that in practice, patients may prefer a week of accelerated partial breast irradiation, rather than committing to 5 years of hormone therapy as this study does.

“Overall, the take-home message for patients is that bypassing radiation therapy should be considered an option for older women with localized breast cancer with favorable features who are receiving hormone therapy,” concludes Dr. Axelrod.

The take-home message for patients is that going without radiation therapy should be considered an option for older women with localized breast cancer with favorable features who are receiving hormone therapy.
Dr. Deborah Axelrod

The LUMINA study was sponsored by the Canadian Breast Cancer Foundation and the Canadian Cancer Society. Dr. Whelan reported research funding from Exact Sciences (Inst). Drs Axelrod and Anderson did not report any conflicts of interest. Dr. Gralow reported links of interest with Genentech, AstraZeneca, Hexal, Puma BioTechnology, Roche, Novartis, Seagen and Genomic Health.

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