Adjuvant breast cancer treatments—chemotherapy, human epidermal growth factor receptor 2 (HER2)–targeted therapies, and endocrine therapy—prevent recurrence and extend survival. Unfortunately, because risk assessment is imprecise and treatments are not uniformly effective, many women are treated to benefit a small number. If these therapies were entirely harmless, we would have few qualms about overtreatment. Chemotherapy has the most onerous short-term side effects and is the treatment that patients most wish to avoid. Moreover, long-term toxicities include secondary leukemia, heart failure, neuropathy, premature menopause, and infertility. Some women who receive adjuvant chemotherapy do not return to work or face difficulty in role functioning (1,2). The recognition that benefits are limited and that toxicity can be formidable has led to gradual adjustments in most oncologists’ approach. There has also been a steady improvement in prognosis over the past decades, partially attributed to better outcomes associated with screen-detected cancers (3,4). Over the past 15 years, multiple genomic assays have been developed that more precisely characterize the risk of developing recurrent breast cancer (5). The 70-gene assay (Mammaprint) was evaluated in a complex randomized trial, which demonstrated that women with clinically high-risk but genomically low-risk cancers derive little benefit from adjuvant chemotherapy (6). In the United States, the most widely used genomic assay for estrogen receptor–positive (ER+) breast cancer is the 21-gene recurrence score (RS). In 2004, Paik et al. demonstrated that the RS was prognostic in a group of node-negative patients (7). Subsequently, these investigators found that the RS was predictive of chemotherapy benefit and that patients with low and intermediate scores do not appear to achieve substantial risk reduction (7,8). The results of randomized trials are pending, but US oncologists have embraced the RS in decision-making. Its use, initially in node-negative patients, has expanded to include many women with node-positive disease, particularly those with limited lymph node involvement (9). Kurian and colleagues demonstrate that use of adjuvant chemotherapy for patients with stage I–II ER+/HER2- disease declined from 26.6% to 14.1% and 81.1% to 64.2% among node-negative and node-positive patients, respectively, between 2013 and 2015 (10). The frequency of RS use remained unchanged among node-negative patients. RS use increased among node-positive patients from 26.1% to 42.7%, but the authors determined that the test accounted for only one-third of the decline in chemotherapy administration. The increased use of RS among node-negative patients extended for years beyond the initial publications (11). Similarly, uptake in node-positive patients appears to be evolving gradually since the 2010 publication (9). Data from the prospective randomized trials with RS will likely lead to increased and more informed use in the future, particularly if the trials substantiate the retrospective studies (12). There is little doubt that genomic assays that predict risk and possible chemotherapy benefit have played a major role in reduction of chemotherapy utilization. But genomic assays are only part of the story. With the advent of targeted therapy for breast cancer, both oncologists and their patients appear less willing than in the past to take a toxic treatment for a very small benefit. In the 1990s, the assumption that guided oncologists was that a benefit as small as 1% would be sufficient for patients to accept adjuvant chemotherapy (13–15). While there is a high degree of variability in patient preferences, our strong sense is that such small benefits are no longer acceptable. Oncologists have also found that they can identify patients at very low risk of recurrence based on clinical characteristics (tumor size, nodal status, hormone receptors, grade). Some oncologists may even skip ordering a genomic assay if they believe the score is likely to be favorable, particularly if other patient characteristics suggest that risks of treatment are likely to outweigh benefit. The decline in chemotherapy use from 2013 to 2015 also coincided with changes in Medicare Part B reimbursement mandated by budget sequestration, which went into effect in March of 2013. This legislation cut payments by 2%, yielding a reduction in the margins that oncology practices generate from the “buy and bill” model of chemotherapy delivery. Whether this change in reimbursement directly altered provider behavior is not clear, but there has been a shift in chemotherapy administration from smaller practices to hospitals, where physicians may derive less financial incentive to prescribe chemotherapy (16). Although there were no major changes in adjuvant chemotherapy guidelines during the study period, a National Comprehensive Care Network database study demonstrated excellent outcomes for patients with small ER+/HER2- tumors not treated with chemotherapy with distant recurrence-free survival rates of 98% (T1a) and 96% (T1b) (17). These data suggest that most patients with small ER+ tumors should not receive chemotherapy and may have also led to a decline in chemotherapy use. Genomic expression assays may ultimately have an even greater impact on the management of young women with ER+ breast cancer, a population that faces the long-term consequences of treatment toxicities. Due to the small proportion of young women in NSABP B14 and B20 and the increased risk of recurrence in very young women (18), many oncologists have been uneasy trusting a favorable genomic assay in a young patient with node-negative disease. Predictive evidence of the RS in node-positive patients remains limited to postmenopausal women (9). Nonetheless, it is likely that the RS assay and other genomics predictors reflect disease biology that is independent of age. It is known that young women with ER+ disease do indeed have outcomes inferior to their older counterparts (19), but there is reason to believe that this disparity may relate to the adequacy of endocrine therapy in young women. Recent data from the SOFT trial clearly indicate that many young women can be effectively managed with endocrine therapy alone (20–22). In spite of our increasing ability to identify patients with more indolent tumors and excellent outcomes, de-escalation of treatment remains a challenge. While the Kurian study (10) demonstrated that the proportion of oncologists who recommended chemotherapy in the “less favorable” scenario dropped from 91.3% to 56.4% after the low RS was revealed, limiting chemotherapy use in real time is far more vexing than when one sits in front of the computer monitor. It is both understandable and easier for most oncologists to err on the side of overtreatment than undertreatment. As clinicians, we fear omitting a therapy that could be life saving, but benefits and toxicities must be balanced. Clinical trials such as TAILORx and RxPONDER will likely identify patient populations that can safely forego chemotherapy. For those who do still receive chemotherapy, recent data support limiting anthracyclines to women with higher-risk features, thus reducing long-term complications (23). De-escalation of therapy is not a concept that is confined to ER-positive and HER2-negative disease. In the setting of HER2-positive and triple-negative disease, several agents—capecitabine, platinum, pertuzumab, and neratinib—have been used to escalate the intensity of treatment (24–27). Although these approaches represent advances, the benefits for an individual are often marginal. Whether we are focusing on traditional chemotherapy or targeted approaches, we must strive to integrate prognostic biomarkers such as pathologic complete response and develop new prognostic and predictive biomarkers. Our goal is to provide the adjuvant treatment that allows each patient to remain cancer free and, at the same time, avoid unnecessary toxicity. Kurian and colleagues (10) demonstrate substantial progress in the de-escalation of treatment for patients with stage I–II ER+ disease over a span of only two years. We hope and anticipate that such trends will continue and expand to other subgroups of patients. Note The authors have no conflicts of interest. References 1 Jagsi R , Hawley ST , Abrahamse P et al. , Impact of adjuvant chemotherapy on long-term employment of survivors of early-stage breast cancer . Cancer. 2014 ; 120 12 : 1854 – 1862 . http://dx.doi.org/10.1002/cncr.28607 Google Scholar CrossRef Search ADS PubMed 2 Kroenke CH , Rosner B , Chen WY , Kawachi I , Colditz GA , Holmes MD. Functional impact of breast cancer by age at diagnosis . J Clin Oncol. 2004 ; 22 10 : 1849 – 1856 . Google Scholar CrossRef Search ADS PubMed 3 DeSantis CE , Ma J , Goding Sauer A , Newman LA , Jemal A. Breast cancer statistics, 2017, racial disparity in mortality by state . CA Cancer J Clin. 2017 ; 67 6 : 439 – 448 . Google Scholar CrossRef Search ADS PubMed 4 Berry DA , Cronin KA , Plevritis SK et al. , Effect of screening and adjuvant therapy on mortality from breast cancer . N Engl J Med. 2005 ; 353 17 : 1784 – 1792 . http://dx.doi.org/10.1056/NEJMoa050518 Google Scholar CrossRef Search ADS PubMed 5 Fan C , Oh DS , Wessels L et al. , Concordance among gene-expression-based predictors for breast cancer . N Engl J Med. 2006 ; 355 6 : 560 – 569 . http://dx.doi.org/10.1056/NEJMoa052933 Google Scholar CrossRef Search ADS PubMed 6 Cardoso F , Van't Veer LJ , Bogaerts J et al. , 70-gene signature as an aid to treatment decisions in early-stage breast cancer . N Engl J Med. 2016 ; 375 8 : 717 – 729 . http://dx.doi.org/10.1056/NEJMoa1602253 Google Scholar CrossRef Search ADS PubMed 7 Paik S , Shak S , Tang G et al. , A multigene assay to predict recurrence of tamoxifen-treated, node-negative breast cancer . N Engl J Med. 2004 ; 351 : 2817 – 2826 . http://dx.doi.org/10.1056/NEJMoa041588 Google Scholar CrossRef Search ADS PubMed 8 Paik S , Tang G , Shak S et al. , Gene expression and benefit of chemotherapy in women with node-negative, estrogen receptor-positive breast cancer . J Clin Oncol. 2006 ; 24 23 : 3726 – 3734 . http://dx.doi.org/10.1200/JCO.2005.04.7985 Google Scholar CrossRef Search ADS PubMed 9 Albain SK , Barlow WE , Shak S et al. , Prognostic and predictive value of the 21-gene recurrence score assay in postmenopausal women with node-positive, oestrogen-receptor-positive breast cancer on chemotherapy: A retrospective analysis of a randomised trial . Lancet Oncol. 2010 ; 11 : 55 – 65 . http://dx.doi.org/10.1016/S1470-2045(09)70314-6 Google Scholar CrossRef Search ADS PubMed 10 Kurian AW , Bondarenko I , Jagsi R et al. , Recent trends in chemotherapy use and oncologists' treatment recommendations for early-stage breast cancer . J Natl Cancer Inst. 2018 ; 110 5 : 493 – 500 . 11 Hassett MJ , Silver SM , Hughes ME et al. , Adoption of gene expression profile testing and association with use of chemotherapy among women with breast cancer . J Clin Oncol. 2012 ; 30 18 : 2218 – 2226 . http://dx.doi.org/10.1200/JCO.2011.38.5740 Google Scholar CrossRef Search ADS PubMed 12 Sparano JA , Gray RJ , Makower DF et al. , Prospective validation of a 21-gene expression assay in breast cancer . N Engl J Med. 2015 ; 373 21 : 2005 – 2014 . http://dx.doi.org/10.1056/NEJMoa1510764 Google Scholar CrossRef Search ADS PubMed 13 Slevin ML , Stubbs L , Plant HJ et al. , Attitudes to chemotherapy: Comparing views of patietns with cancer with those of doctors, nurses, and general public . BMJ. 1990 ; 300 6737 : 1458 – 1460 . http://dx.doi.org/10.1136/bmj.300.6737.1458 Google Scholar CrossRef Search ADS PubMed 14 Lindley C , Vasa S , Sawyer WT , Winer EP. Quality of life and preferences for treatment following systemic adjuvant therapy for early-stage breast cancer . J Clin Oncol. 1998 ; 16 4 : 1380 – 1387 . http://dx.doi.org/10.1200/JCO.19188.8.131.520 Google Scholar CrossRef Search ADS PubMed 15 Simes RJ , Coates AS. Patient preferences for adjuvant chemotherapy of early breast cancer: How much benefit is needed? J Natl Cancer Inst Monogr. 2001 ; 30 : 146 – 152 . Google Scholar CrossRef Search ADS 16 Polite B , Conti RM , Ward JC. Reform of the buy-and-bill system for outpatient chemotherapy care is inevitable: Perspectives from an economist, a realpolitik, and an oncologist . Am Soc Clin Oncol Educ Book. 2015 : e75 – e80 . 17 Vaz-Luis I , Ottesen RA , Hughes ME et al. , Outcomes by tumor subtype and treatment pattern in women with small, node-negative breast cancer: A multi-institutional study . J Clin Oncol. 2014 ; 32 20 : 2142 – 2215 . http://dx.doi.org/10.1200/JCO.2013.53.1608 Google Scholar CrossRef Search ADS PubMed 18 Han W , Kim SW , Park IA et al. , Young age: An independent risk factor for disease-free survival in women with operable breast cancer . BMC Cancer. 2004 ; 4 : 82 . http://dx.doi.org/10.1186/1471-2407-4-82 Google Scholar CrossRef Search ADS PubMed 19 Partridge AH , Hughes ME , Warner ET et al. , Subtype-dependent relationship between young age at diagnosis and breast cancer survival . J Clin Oncol. 2016 ; 34 27 : 3308 – 3314 . http://dx.doi.org/10.1200/JCO.2015.65.8013 Google Scholar CrossRef Search ADS PubMed 20 Gnant M , Mlineritsch B , Schippinger W et al. , Endocrine therapy plus zoledronic acid in premenopausal breast cancer . N Engl J Med. 2009 ; 360 7 : 679 – 691 . http://dx.doi.org/10.1056/NEJMoa0806285 Google Scholar CrossRef Search ADS PubMed 21 Pagani O , Regan MM , Walley BA et al. , Adjuvant exemestane with ovarian suppression in premenopausal breast cancer . N Engl J Med. 2014 ; 371 2 : 107 – 118 . http://dx.doi.org/10.1056/NEJMoa1404037 Google Scholar CrossRef Search ADS PubMed 22 Francis PA , Regan MM , Fleming GF et al. , Adjuvant ovarian suppression in premenopausal breast cancer . N Engl J Med. 2015 ; 372 5 : 436 – 446 . http://dx.doi.org/10.1056/NEJMoa1412379 Google Scholar CrossRef Search ADS PubMed 23 Blum JL , Flynn PJ , Yothers G et al. , Anthracyclines in early breast cancer: The ABC Trials-USOR 06-690, NSABP B-46-I/USOR 07132, and NSABP B-49 (NRG Oncology) . J Clin Oncol. 2017 ; 35 23 : 2647 – 2655 . http://dx.doi.org/10.1200/JCO.2016.71.4147 Google Scholar CrossRef Search ADS PubMed 24 Masuda N , Lee SJ , Ohtani S et al. , Adjuvant capecitabine for breast cancer after preoperative chemotherapy . N Engl J Med. 2017 ; 376 22 : 2147 – 2159 . http://dx.doi.org/10.1056/NEJMoa1612645 Google Scholar CrossRef Search ADS PubMed 25 Sikov WM , Berry DA , Perou CM et al. , Impact of the addition of carboplatin and/or bevacizumab to neoadjuvant once-per-week paclitaxel followed by dose-dense doxorubicin and cyclophosphamide on pathologic complete response rates in stage II to III triple-negative breast cancer: CALGB 40603 (Alliance) . J Clin Oncol. 2015 ; 33 1 : 13 – 21 . http://dx.doi.org/10.1200/JCO.2014.57.0572 Google Scholar CrossRef Search ADS PubMed 26 von Minckwitz G , Procter M , de Azambuja E et al. , Adjuvant pertuzumab and trastuzumab in early HER2-positive breast cancer . N Engl J Med. 2017 ; 377 2 : 122 – 131 . http://dx.doi.org/10.1056/NEJMoa1703643 Google Scholar CrossRef Search ADS PubMed 27 Chan A , Delaloge S , Holmes FA et al. , Neratinib after trastuzumab-based adjuvant therapy in patients with HER2-positive breast cancer (ExteNET): A multicentre, randomised, double-blind, placebo-controlled, phase 3 trial . Lancet Oncol. 2016 ; 17 3 : 367 – 377 . http://dx.doi.org/10.1016/S1470-2045(15)00551-3 Google Scholar CrossRef Search ADS PubMed © The Author 2017. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: email@example.com. This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (https://academic.oup.com/journals/pages/about_us/legal/notices)
JNCI: Journal of the National Cancer Institute – Oxford University Press
Published: Dec 11, 2017
It’s your single place to instantly
discover and read the research
that matters to you.
Enjoy affordable access to
over 18 million articles from more than
15,000 peer-reviewed journals.
All for just $49/month
Query the DeepDyve database, plus search all of PubMed and Google Scholar seamlessly
Save any article or search result from DeepDyve, PubMed, and Google Scholar... all in one place.
Get unlimited, online access to over 18 million full-text articles from more than 15,000 scientific journals.
Read from thousands of the leading scholarly journals from SpringerNature, Elsevier, Wiley-Blackwell, Oxford University Press and more.
All the latest content is available, no embargo periods.
“Hi guys, I cannot tell you how much I love this resource. Incredible. I really believe you've hit the nail on the head with this site in regards to solving the research-purchase issue.”Daniel C.
“Whoa! It’s like Spotify but for academic articles.”@Phil_Robichaud
“I must say, @deepdyve is a fabulous solution to the independent researcher's problem of #access to #information.”@deepthiw
“My last article couldn't be possible without the platform @deepdyve that makes journal papers cheaper.”@JoseServera