Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Review
. 2022 Dec;19(12):763-774.
doi: 10.1038/s41571-022-00687-1. Epub 2022 Oct 17.

Systemic therapy for early-stage breast cancer: learning from the past to build the future

Elisa Agostinetto  1 , Joseph Gligorov  2 , Martine Piccart  3
Affiliations
Review

Systemic therapy for early-stage breast cancer: learning from the past to build the future

Elisa Agostinetto et al. Nat Rev Clin Oncol. 2022 Dec.

Abstract

The treatment of breast cancer has improved dramatically over the past century, from a strictly surgical approach to a coordinated one, including local and systemic therapies. Systemic therapies for early-stage disease were initially tested against observation or placebo only in adjuvant trials. Subsequent clinical trials focusing on treatment 'fine-tuning' had a marked increase in cohort size, duration and costs, leading to a growing interest in the neoadjuvant setting in the past decade. Neoadjuvant trial designs have the advantages of enabling the direct evaluation of treatment effects on tumour diameter and offer unique translational research opportunities through the comparative analysis of tumour biology before, during and after treatment. Current technologies enabling the identification of better predictive biomarkers are shaping the new era of (neo)adjuvant trials. An urgent need exists to reinforce collaboration between the pharmaceutical industry and academia to share data and thus establish large databases of biomarker data coupled with patient outcomes that are easily accessible to the scientific community. In this Review, we summarize the evolution of (neo)adjuvant trials from the pre-genomic to the post-genomic era and provide critical insights into how neoadjuvant studies are currently designed, discussing the need for better end points and treatment strategies that are more personalized, including in the post-neoadjuvant setting.

PubMed Disclaimer

Conflict of interest statement

E.A. has received fees or honoraria for consultant roles for Eli Lilly and Sandoz and support for attending medical conferences from Eli Lilly, Genetic, Istituto Gentili, Novartis and Roche, all unrelated to the submitted work. J.G. has received fees or honoraria for consultant roles for Daiichi, Eisai, Exact Science, Gilead, Lilly, Merck, Novartis, Onxeo, Pfizer, Roche Genentech and Seattle Genetics, and works in an institution that receives research grants from Eisai, Exact Science and Roche Genentech, all unrelated to the submitted work. M.P. has received fees or honoraria for consultant roles for AstraZeneca, Camel-IDS/Precirix, Frame Therapeutics, Gilead, Immunomedics, Immutep, Lilly, Menarini, MSD, NBE Therapeutics, Novartis, Odonate, Pfizer, Roche Genentech, Seagen and Seattle Genetics, is part of the scientific board at Oncolytics, and works in an institution that receives research grants from AstraZeneca, Immunomedics, Lilly, Menarini, MSD, Novartis, Pfizer, Radius, Roche Genentech, Servier and Synthon, all unrelated to the submitted work.

Figures

Fig. 1
Fig. 1. Residual cancer burden as an end point for neoadjuvant clinical trials.
Replacing pathological complete response (pCR) with a residual cancer burden (RCB) profile and event-free survival (EFS) is likely to improve the accuracy of data from neoadjuvant clinical trials as an early indicator of clinical benefit. RCB is a validated surrogate, of longer-term survival outcomes (such as EFS) that is also more granular than dichotomous comparisons of pCR versus non-pCR, with improved survival durations often seen for patients with more limited residual disease. Thus, post-neoadjuvant trials should increasingly explore treatment strategies directed at addressing the residual disease profile.
Fig. 2
Fig. 2. The post-neoadjuvant setting: an attractive scenario for future clinical trials.
The post-neoadjuvant setting offers the possibility of selecting patients with residual invasive disease at surgery who might benefit from additional adjuvant treatments (white text box) and also the avoidance of enrolling patients who are not likely to benefit from further therapy owing to a complete response to neoadjuvant therapy. Moreover, this approach allows translational analyses to be performed on the residual tumour material, thus enabling potential biomarkers to be identified (such as Ki67, tumour-infiltrating lymphocytes (TILs), circulating tumour DNA (ctDNA), and/or genetic and genomic alterations) (sepia text boxes), which could subsequently be validated prospectively. LVI, lymphovascular invasion; NGS, next-generation sequencing.
Fig. 3
Fig. 3. Proposed landscape of future post-(neo)adjuvant clinical trials in early-stage breast cancer.
Neoadjuvant trials are increasingly adopting residual cancer burden (RCB) as a surrogate end point for survival and should aim to be large (n = ~1,000–1,500), randomized, adequately powered for survival end points (such as event-free survival; EFS) and designed following successful phase II, ‘signal-finding’ studies. Interest in such trials is currently increasing, especially those designed to identify patients with residual disease at surgery who might benefit from treatment escalation strategies based on in-depth molecular dissection of residual invasive disease and/or the exploration of circulating tumour DNA (ctDNA) detection. Interest in traditional adjuvant strategies (without neoadjuvant treatment) is likely to decline, although such studies remain relevant to the assessment of quality-of-life (QOL) outcomes, adherence to study treatment and exploration of ‘delayed strategies’ designed to reduce the risk of late relapse (>5–10 years), especially in patients with hormone receptor-positive disease. iDFS, invasive disease-free survival.
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

See all "Cited by" articles

References

    1. Siegel RL, Miller KD, Fuchs HE, Jemal A. Cancer statistics, 2022. CA Cancer J. Clin. 2022;72:7–33. doi: 10.3322/caac.21708. - DOI - PubMed
    1. Yabroff KR, et al. Association of the COVID-19 pandemic with patterns of statewide cancer services. J. Natl Cancer Inst. 2021;114:907–909. doi: 10.1093/jnci/djab122. - DOI - PMC - PubMed
    1. Smith BD, et al. Improvement in breast cancer outcomes over time: are older women missing out? J. Clin. Oncol. 2011;29:4647–4653. doi: 10.1200/JCO.2011.35.8408. - DOI - PubMed
    1. Polyak K. Breast cancer: origins and evolution. J. Clin. Invest. 2007;117:3155–3163. doi: 10.1172/JCI33295. - DOI - PMC - PubMed
    1. Bonadonna G, et al. Combination chemotherapy as an adjuvant treatment in operable breast cancer. N. Engl. J. Med. 1976;294:405–410. doi: 10.1056/NEJM197602192940801. - DOI - PubMed
  NODES
Association 1
COMMUNITY 1
twitter 2