Circulating Tumor Cells in Patients Receiving Neoadjuvant Chemotherapy: Refining the Paradigm of Prognosis and Treatment Individualization

Circulating Tumor Cells in Patients Receiving Neoadjuvant Chemotherapy: Refining the Paradigm of... Neoadjuvant chemotherapy (NAC) was originally reserved for patients with locally advanced breast cancer who required tumor downstaging in order to achieve resectability, but its use eventually expanded to include those with large, operable disease (1). NAC offers several clinical advantages relative to the loco-regional management of the disease, and by observing tumor response to NAC, valuable insight can be obtained into a patient’s tumor biology (1). Achievement of pathologic complete response (pCR) in the breast and axilla with NAC strongly correlates with excellent long-term outcomes (2,3), making pCR a short-term surrogate end point for chemotherapy efficacy (4). The strong correlation between pCR and improved outcomes implies that if NAC eliminates all invasive cancer cells from the breast and axilla, it likely eliminates micrometastatic disease sites or disseminated tumor cells. Over the past 20 years, several studies have shown that disseminated tumor cells (DTCs) in bone marrow and circulating tumor cells (CTCs) in the blood can be identified in patients with advanced disease (5–7) and in those with early-stage breast cancer (7–13) and that their presence statistically significantly correlates with adverse prognosis (6,9–11,13). In this issue of the Journal, Bidard et al. report results of a meta-analysis investigating the prognostic significance of CTCs in nonmetastatic breast cancer patients treated with NAC (14). The study provides important insights on the role of CTCs on the prognosis and prediction of response to NAC. First, the report provides some insight on the effect of the number of CTCs before NAC and before surgery on outcomes. Detecting only one CTC before NAC did not appear to confer statistically significantly worse prognosis compared with detecting no CTCs (hazard ratio [HR] for 1 vs 0 CTCs = 1.09, 95% confidence interval [CI] = 0.65 to 1.69). This raises the question of the clinical significance of detecting only one CTC. This observation may be due to low statistical power in this subset or may reflect differences in primary tumor burden between patients with one CTC vs those with more than one. It may also reflect detection of circulating epithelial cells that are noncancerous or have limited metastatic potential, as single CTCs have been occasionally found in healthy controls (6,15). Interestingly, detection of one CTC before surgery (after NAC) appears to confer more adverse prognosis on overall survival (HR for 1 vs 0 CTCs = 1.82, 95% CI = 1.16 to 2.74) and distant disease–free survival (HR for 1 vs 0 CTCs = 1.77, 95% CI = 1.19 to 2.56). This observation, if confirmed by others, could indicate that the inability of NAC to clear all CTCs confers adverse prognosis independent of the number of CTCs. Further support for this hypothesis is provided by the observation that hazard ratios for adverse outcome increased progressively with higher numbers of CTCs when assessed before NAC, but not to the same degree when assessed before surgery. In the report by Bidard et al., CTC count before surgery (after NAC) was statistically significantly lower vs before NAC (15.1% vs 25.1%). This is in line with other reports on CTC counts before vs after adjuvant or neoadjuvant chemotherapy (11,16–20), although the magnitude of the decrease varies and, in some, CTC detection rate was similar before vs after adjuvant chemotherapy (10). This variation may be because some patients with detectable CTCs before adjuvant or neoadjuvant chemotherapy have no detectable CTCs afterwards while others without detectable CTCs before adjuvant or neoadjuvant chemotherapy are found to have detectable CTCs afterwards (16–20). Thus, the overall change in the rate of CTC positivity after adjuvant or neoadjuvant chemotherapy can vary based on the magnitude of each of these two opposing effects. From an outcome standpoint, patients who clear their CTCs with adjuvant or neoadjuvant chemotherapy have a good prognosis, and those who have detectable CTCs after adjuvant or neoadjuvant chemotherapy (either persistent or newly detected) have a poor prognosis (16–21). Perhaps the most interesting aspect of evaluating CTCs in patients treated with NAC is the potential to correlate the presence and eventual elimination of CTCs with pCR and their respective effect on outcomes. The studies by Bidard and several others have clearly shown that the presence of CTCs before NAC does not correlate with the probability of achieving pCR (17,19,21). This finding is not surprising given that the presence of CTCs outside the loco-regional confines of early breast cancer is unlikely to capture additional tumor biology above and beyond what is determined by primary tumor characteristics (such as estrogen receptor, progesterone receptor, human epidermal growth factor receptor 2 neu, grade, and proliferation), which correlate with the probability of achieving pCR. The question of whether CTC counts either before or after NAC affect outcomes of patients who achieve pCR is undoubtedly an important one because it may have therapeutic implications for potential treatment escalation or de-escalation after NAC. Bidard et al. do not directly address the prognostic impact of CTCs after NAC in patients with pCR. However, they report that adding baseline CTC counts (before NAC) to statistical models including clinico-pathologic data and pCR increased post-NAC survival prognostication. Similar findings were reported from a smaller randomized phase II trial of NAC in patients with large operable/locally advanced breast cancer, in which CTC detection before and/or after NAC remained an independent prognostic factor in multivariable analysis that included pCR (19). In another single-arm neoadjuvant trial in patients with inflammatory breast cancer, baseline CTC counts further improved the prognosis of patients with pCR. Although patients with pCR had a three-year DFS of 80%, patients with pCR and no baseline CTCs had a three-year DFS of 95% (21). Thus, in that study, combining pCR and baseline CTC counts identified a subgroup of inflammatory breast cancer patients with excellent survival. The study by Bidard et al. provides further insight into the existing evidence on the potential role of CTCs in patients treated with NAC. The study further refines the paradigm of using NAC to individualize prognosis and potentially tailor the therapeutic approach by adding information provided by CTC status. Additional studies in large cohorts of patients are clearly needed to further elucidate the complex relationship between pCR and baseline/post-NAC CTC counts and phenotypic characterization on prognosis and prediction of treatment response. The development and clinical evaluation of more sensitive assays of cell-free nucleic acid detection could help to further refine this evolving paradigm. Notes Affiliation of author: University of Florida Health Cancer Center, Orlando Health, Orlando, FL. The author has no conflicts of interest to disclose. References 1 Mamounas EP. Neoadjuvant therapy for early-stage breast cancer: A model for individualizing outcomes and tailoring locoregional and systemic therapy. Oncology (Williston Park).  2015; 29( 11): 839– 840, 846. Google Scholar PubMed  2 Cortazar P, Zhang L, Untch Met al.  , Pathological complete response and long-term clinical benefit in breast cancer: The CTNeoBC pooled analysis. Lancet.  2014; 384( 9938): 164– 172. Google Scholar CrossRef Search ADS PubMed  3 Rastogi P, Anderson SJ, Bear HDet al.  , Preoperative chemotherapy: Updates of National Surgical Adjuvant Breast and Bowel Project Protocols B-18 and B-27. J Clin Oncol.  2008; 26( 5): 778– 785. Google Scholar CrossRef Search ADS PubMed  4 Prowell TM, Pazdur R. Pathological complete response and accelerated drug approval in early breast cancer. N Engl J Med.  2012; 366( 26): 2438– 2441. Google Scholar CrossRef Search ADS PubMed  5 Cristofanilli M, Budd GT, Ellis MJet al.  , Circulating tumor cells, disease progression, and survival in metastatic breast cancer. N Engl J Med.  2004; 351( 8):781-7–1. 6 Bidard FC, Peeters DJ, Fehm Tet al.  , Clinical validity of circulating tumour cells in patients with metastatic breast cancer: A pooled analysis of individual patient data. Lancet Oncol.  2014; 15( 4): 406– 414. Google Scholar CrossRef Search ADS PubMed  7 Zhang L, Riethdorf S, Wu Get al.  , Meta-analysis of the prognostic value of circulating tumor cells in breast cancer. Clin Cancer Res.  2012; 18( 20): 5701– 5710. Google Scholar CrossRef Search ADS PubMed  8 Diel IJ, Solomayer EF, Costa SDet al.  , Reduction in new metastases in breast cancer with adjuvant clodronate treatment. N Engl J Med.  1998; 339( 6): 357– 363. Google Scholar CrossRef Search ADS PubMed  9 Bidard FC, Kirova YM, Vincent-Salomon Aet al.  , Disseminated tumor cells and the risk of locoregional recurrence in nonmetastatic breast cancer. Ann Oncol.  2009; 20( 11): 1836– 1841. Google Scholar CrossRef Search ADS PubMed  10 Rack B, Schindlbeck C, Jückstock Jet al.  , Circulating tumor cells predict survival in early average-to-high risk breast cancer patients. J Natl Cancer Inst.  2014; 106( 5):dju066. 11 Schramm A, Schochter F, Friedl TWPet al.  , Prevalence of circulating tumor cells after adjuvant chemotherapy with or without anthracyclines in patients with HER2-negative, hormone receptor-positive early breast cancer. Clin Breast Cancer.  2017; 17( 4): 279– 285. Google Scholar CrossRef Search ADS PubMed  12 Bidard FC, Mathiot C, Delaloge Set al.  , Single circulating tumor cell detection and overall survival in nonmetastatic breast cancer. Ann Oncol.  2010; 21( 4): 729– 733. Google Scholar CrossRef Search ADS PubMed  13 Braun S, Vogl FD, Naume Bet al.  , A pooled analysis of bone marrow micrometastasis in breast cancer. N Engl J Med.  2005; 353( 8): 793– 802. Google Scholar CrossRef Search ADS PubMed  14 Bidard FC, Michiels S, Riethdorf Set al.  , Circulating tumor cells in breast cancer patients treated by neoadjuvant chemotherapy: a meta-analysis. J Natl Cancer Inst . 2018; 110( 6):djy018. 15 Allard WJ, Matera J, Miller MCet al.  , Tumor cells circulate in the peripheral blood of all major carcinomas but not in healthy subjects or patients with nonmalignant diseases. Clin Cancer Res.  2004; 10( 20): 6897– 6904. Google Scholar CrossRef Search ADS PubMed  16 Pachmann K, Dengler R, Lobodasch Ket al.  , An increase in cell number at completion of therapy may develop as an indicator of early relapse: Quantification of circulating epithelial tumor cells (CETC) for monitoring of adjuvant therapy in breast cancer. J Cancer Res Clin Oncol.  2008; 134( 1): 59– 65. Google Scholar CrossRef Search ADS PubMed  17 Riethdorf S, Muller V, Zhang Let al.  , Detection and HER2 expression of circulating tumor cells: Prospective monitoring in breast cancer patients treated in the neoadjuvant GeparQuattro trial. Clin Cancer Res.  2010; 16( 9): 2634– 2645. Google Scholar CrossRef Search ADS PubMed  18 Xenidis N, Ignatiadis M, Apostolaki Set al.  , Cytokeratin-19 mRNA-positive circulating tumor cells after adjuvant chemotherapy in patients with early breast cancer. J Clin Oncol.  2009; 27( 13): 2177– 2184. Google Scholar CrossRef Search ADS PubMed  19 Pierga JY, Bidard FC, Mathiot Cet al.  , Circulating tumor cell detection predicts early metastatic relapse after neoadjuvant chemotherapy in large operable and locally advanced breast cancer in a phase II randomized trial. Clin Cancer Res.  2008; 14( 21): 7004– 7010. Google Scholar CrossRef Search ADS PubMed  20 Serrano MJ, Rovira PS, Martinez-Zubiaurre I, Rodriguez MD, Fernandez M, Lorente JA. Dynamics of circulating tumor cells in early breast cancer under neoadjuvant therapy. Exp Ther Med.  2012; 4( 1): 43– 48. Google Scholar CrossRef Search ADS PubMed  21 Pierga JY, Petit T, Levy Cet al.  , Pathological response and circulating tumor cell count identifies treated HER2+ inflammatory breast cancer patients with excellent prognosis: BEVERLY-2 survival data. Clin Cancer Res.  2015; 21( 6): 1298– 1304. Google Scholar CrossRef Search ADS PubMed  © The Author(s) 2018. Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.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) http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png JNCI: Journal of the National Cancer Institute Oxford University Press

Circulating Tumor Cells in Patients Receiving Neoadjuvant Chemotherapy: Refining the Paradigm of Prognosis and Treatment Individualization

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Abstract

Neoadjuvant chemotherapy (NAC) was originally reserved for patients with locally advanced breast cancer who required tumor downstaging in order to achieve resectability, but its use eventually expanded to include those with large, operable disease (1). NAC offers several clinical advantages relative to the loco-regional management of the disease, and by observing tumor response to NAC, valuable insight can be obtained into a patient’s tumor biology (1). Achievement of pathologic complete response (pCR) in the breast and axilla with NAC strongly correlates with excellent long-term outcomes (2,3), making pCR a short-term surrogate end point for chemotherapy efficacy (4). The strong correlation between pCR and improved outcomes implies that if NAC eliminates all invasive cancer cells from the breast and axilla, it likely eliminates micrometastatic disease sites or disseminated tumor cells. Over the past 20 years, several studies have shown that disseminated tumor cells (DTCs) in bone marrow and circulating tumor cells (CTCs) in the blood can be identified in patients with advanced disease (5–7) and in those with early-stage breast cancer (7–13) and that their presence statistically significantly correlates with adverse prognosis (6,9–11,13). In this issue of the Journal, Bidard et al. report results of a meta-analysis investigating the prognostic significance of CTCs in nonmetastatic breast cancer patients treated with NAC (14). The study provides important insights on the role of CTCs on the prognosis and prediction of response to NAC. First, the report provides some insight on the effect of the number of CTCs before NAC and before surgery on outcomes. Detecting only one CTC before NAC did not appear to confer statistically significantly worse prognosis compared with detecting no CTCs (hazard ratio [HR] for 1 vs 0 CTCs = 1.09, 95% confidence interval [CI] = 0.65 to 1.69). This raises the question of the clinical significance of detecting only one CTC. This observation may be due to low statistical power in this subset or may reflect differences in primary tumor burden between patients with one CTC vs those with more than one. It may also reflect detection of circulating epithelial cells that are noncancerous or have limited metastatic potential, as single CTCs have been occasionally found in healthy controls (6,15). Interestingly, detection of one CTC before surgery (after NAC) appears to confer more adverse prognosis on overall survival (HR for 1 vs 0 CTCs = 1.82, 95% CI = 1.16 to 2.74) and distant disease–free survival (HR for 1 vs 0 CTCs = 1.77, 95% CI = 1.19 to 2.56). This observation, if confirmed by others, could indicate that the inability of NAC to clear all CTCs confers adverse prognosis independent of the number of CTCs. Further support for this hypothesis is provided by the observation that hazard ratios for adverse outcome increased progressively with higher numbers of CTCs when assessed before NAC, but not to the same degree when assessed before surgery. In the report by Bidard et al., CTC count before surgery (after NAC) was statistically significantly lower vs before NAC (15.1% vs 25.1%). This is in line with other reports on CTC counts before vs after adjuvant or neoadjuvant chemotherapy (11,16–20), although the magnitude of the decrease varies and, in some, CTC detection rate was similar before vs after adjuvant chemotherapy (10). This variation may be because some patients with detectable CTCs before adjuvant or neoadjuvant chemotherapy have no detectable CTCs afterwards while others without detectable CTCs before adjuvant or neoadjuvant chemotherapy are found to have detectable CTCs afterwards (16–20). Thus, the overall change in the rate of CTC positivity after adjuvant or neoadjuvant chemotherapy can vary based on the magnitude of each of these two opposing effects. From an outcome standpoint, patients who clear their CTCs with adjuvant or neoadjuvant chemotherapy have a good prognosis, and those who have detectable CTCs after adjuvant or neoadjuvant chemotherapy (either persistent or newly detected) have a poor prognosis (16–21). Perhaps the most interesting aspect of evaluating CTCs in patients treated with NAC is the potential to correlate the presence and eventual elimination of CTCs with pCR and their respective effect on outcomes. The studies by Bidard and several others have clearly shown that the presence of CTCs before NAC does not correlate with the probability of achieving pCR (17,19,21). This finding is not surprising given that the presence of CTCs outside the loco-regional confines of early breast cancer is unlikely to capture additional tumor biology above and beyond what is determined by primary tumor characteristics (such as estrogen receptor, progesterone receptor, human epidermal growth factor receptor 2 neu, grade, and proliferation), which correlate with the probability of achieving pCR. The question of whether CTC counts either before or after NAC affect outcomes of patients who achieve pCR is undoubtedly an important one because it may have therapeutic implications for potential treatment escalation or de-escalation after NAC. Bidard et al. do not directly address the prognostic impact of CTCs after NAC in patients with pCR. However, they report that adding baseline CTC counts (before NAC) to statistical models including clinico-pathologic data and pCR increased post-NAC survival prognostication. Similar findings were reported from a smaller randomized phase II trial of NAC in patients with large operable/locally advanced breast cancer, in which CTC detection before and/or after NAC remained an independent prognostic factor in multivariable analysis that included pCR (19). In another single-arm neoadjuvant trial in patients with inflammatory breast cancer, baseline CTC counts further improved the prognosis of patients with pCR. Although patients with pCR had a three-year DFS of 80%, patients with pCR and no baseline CTCs had a three-year DFS of 95% (21). Thus, in that study, combining pCR and baseline CTC counts identified a subgroup of inflammatory breast cancer patients with excellent survival. The study by Bidard et al. provides further insight into the existing evidence on the potential role of CTCs in patients treated with NAC. The study further refines the paradigm of using NAC to individualize prognosis and potentially tailor the therapeutic approach by adding information provided by CTC status. Additional studies in large cohorts of patients are clearly needed to further elucidate the complex relationship between pCR and baseline/post-NAC CTC counts and phenotypic characterization on prognosis and prediction of treatment response. The development and clinical evaluation of more sensitive assays of cell-free nucleic acid detection could help to further refine this evolving paradigm. Notes Affiliation of author: University of Florida Health Cancer Center, Orlando Health, Orlando, FL. The author has no conflicts of interest to disclose. References 1 Mamounas EP. Neoadjuvant therapy for early-stage breast cancer: A model for individualizing outcomes and tailoring locoregional and systemic therapy. Oncology (Williston Park).  2015; 29( 11): 839– 840, 846. Google Scholar PubMed  2 Cortazar P, Zhang L, Untch Met al.  , Pathological complete response and long-term clinical benefit in breast cancer: The CTNeoBC pooled analysis. Lancet.  2014; 384( 9938): 164– 172. Google Scholar CrossRef Search ADS PubMed  3 Rastogi P, Anderson SJ, Bear HDet al.  , Preoperative chemotherapy: Updates of National Surgical Adjuvant Breast and Bowel Project Protocols B-18 and B-27. J Clin Oncol.  2008; 26( 5): 778– 785. Google Scholar CrossRef Search ADS PubMed  4 Prowell TM, Pazdur R. Pathological complete response and accelerated drug approval in early breast cancer. N Engl J Med.  2012; 366( 26): 2438– 2441. Google Scholar CrossRef Search ADS PubMed  5 Cristofanilli M, Budd GT, Ellis MJet al.  , Circulating tumor cells, disease progression, and survival in metastatic breast cancer. N Engl J Med.  2004; 351( 8):781-7–1. 6 Bidard FC, Peeters DJ, Fehm Tet al.  , Clinical validity of circulating tumour cells in patients with metastatic breast cancer: A pooled analysis of individual patient data. Lancet Oncol.  2014; 15( 4): 406– 414. Google Scholar CrossRef Search ADS PubMed  7 Zhang L, Riethdorf S, Wu Get al.  , Meta-analysis of the prognostic value of circulating tumor cells in breast cancer. Clin Cancer Res.  2012; 18( 20): 5701– 5710. Google Scholar CrossRef Search ADS PubMed  8 Diel IJ, Solomayer EF, Costa SDet al.  , Reduction in new metastases in breast cancer with adjuvant clodronate treatment. N Engl J Med.  1998; 339( 6): 357– 363. Google Scholar CrossRef Search ADS PubMed  9 Bidard FC, Kirova YM, Vincent-Salomon Aet al.  , Disseminated tumor cells and the risk of locoregional recurrence in nonmetastatic breast cancer. Ann Oncol.  2009; 20( 11): 1836– 1841. Google Scholar CrossRef Search ADS PubMed  10 Rack B, Schindlbeck C, Jückstock Jet al.  , Circulating tumor cells predict survival in early average-to-high risk breast cancer patients. J Natl Cancer Inst.  2014; 106( 5):dju066. 11 Schramm A, Schochter F, Friedl TWPet al.  , Prevalence of circulating tumor cells after adjuvant chemotherapy with or without anthracyclines in patients with HER2-negative, hormone receptor-positive early breast cancer. Clin Breast Cancer.  2017; 17( 4): 279– 285. Google Scholar CrossRef Search ADS PubMed  12 Bidard FC, Mathiot C, Delaloge Set al.  , Single circulating tumor cell detection and overall survival in nonmetastatic breast cancer. Ann Oncol.  2010; 21( 4): 729– 733. Google Scholar CrossRef Search ADS PubMed  13 Braun S, Vogl FD, Naume Bet al.  , A pooled analysis of bone marrow micrometastasis in breast cancer. N Engl J Med.  2005; 353( 8): 793– 802. Google Scholar CrossRef Search ADS PubMed  14 Bidard FC, Michiels S, Riethdorf Set al.  , Circulating tumor cells in breast cancer patients treated by neoadjuvant chemotherapy: a meta-analysis. J Natl Cancer Inst . 2018; 110( 6):djy018. 15 Allard WJ, Matera J, Miller MCet al.  , Tumor cells circulate in the peripheral blood of all major carcinomas but not in healthy subjects or patients with nonmalignant diseases. Clin Cancer Res.  2004; 10( 20): 6897– 6904. Google Scholar CrossRef Search ADS PubMed  16 Pachmann K, Dengler R, Lobodasch Ket al.  , An increase in cell number at completion of therapy may develop as an indicator of early relapse: Quantification of circulating epithelial tumor cells (CETC) for monitoring of adjuvant therapy in breast cancer. J Cancer Res Clin Oncol.  2008; 134( 1): 59– 65. Google Scholar CrossRef Search ADS PubMed  17 Riethdorf S, Muller V, Zhang Let al.  , Detection and HER2 expression of circulating tumor cells: Prospective monitoring in breast cancer patients treated in the neoadjuvant GeparQuattro trial. Clin Cancer Res.  2010; 16( 9): 2634– 2645. Google Scholar CrossRef Search ADS PubMed  18 Xenidis N, Ignatiadis M, Apostolaki Set al.  , Cytokeratin-19 mRNA-positive circulating tumor cells after adjuvant chemotherapy in patients with early breast cancer. J Clin Oncol.  2009; 27( 13): 2177– 2184. Google Scholar CrossRef Search ADS PubMed  19 Pierga JY, Bidard FC, Mathiot Cet al.  , Circulating tumor cell detection predicts early metastatic relapse after neoadjuvant chemotherapy in large operable and locally advanced breast cancer in a phase II randomized trial. Clin Cancer Res.  2008; 14( 21): 7004– 7010. Google Scholar CrossRef Search ADS PubMed  20 Serrano MJ, Rovira PS, Martinez-Zubiaurre I, Rodriguez MD, Fernandez M, Lorente JA. Dynamics of circulating tumor cells in early breast cancer under neoadjuvant therapy. Exp Ther Med.  2012; 4( 1): 43– 48. Google Scholar CrossRef Search ADS PubMed  21 Pierga JY, Petit T, Levy Cet al.  , Pathological response and circulating tumor cell count identifies treated HER2+ inflammatory breast cancer patients with excellent prognosis: BEVERLY-2 survival data. Clin Cancer Res.  2015; 21( 6): 1298– 1304. Google Scholar CrossRef Search ADS PubMed  © The Author(s) 2018. Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.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)

Journal

JNCI: Journal of the National Cancer InstituteOxford University Press

Published: Apr 11, 2018

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