Journal Article
. 1976 Feb;294(8).
doi: 10.1056/NEJM197602192940801.

Combination chemotherapy as an adjuvant treatment in operable breast cancer

G Bonadonna  E Brusamolino  P Valagussa  A Rossi  L Brugnatelli  C Brambilla  M De Lena  G Tancini  E Bajetta  R Musumeci  U Veronesi  
  • PMID: 1246307
  •     223 citations

Abstract

Prolonged cyclic combination chemotherapy with cyclophosphamide, methotrexate and fluorouracil was evaluated as adjuvant treatment to radical mastectomy in primary breast cancer with positive axillary lymph nodes. After 27 months of study, treatment occurred in 24 per cent of 179 control patients and in 5.3 per cent of 207 women given combination chemotherapy (P less than 10(-6)), the advantage appearing statistically significant in all subgroups of patients. Patients with four or more positive axillary nodes had a higher per cent of relapses than those with fewer nodes. The initial new clinical manifestations occurred in distant sites in 81.5 per cent of relapsed patients. Long-term chemotherapy produced an acceptable toxicity, thus allowing the administration of a high percentage of drug dosage. These results should be considered with caution, since, at present, the effect of this therapy on survival and possible long-term side effects remain unknown.

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Eur J Cancer, 2007 Dec 11; 44(1). PMID: 18068350    Free PMC article.
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General surgery: adjuvant chemotherapy of breast cancer.
F C Sparks.
West J Med, 1977 May 01; 126(5). PMID: 18747931    Free PMC article.
Recent advances in systemic therapy: advances in adjuvant systemic chemotherapy of early breast cancer.
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Breast Cancer Res, 2009 Apr 07; 11(2). PMID: 19344489    Free PMC article.
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Concurrent chemoradiotherapy in adjuvant treatment of breast cancer.
Nabil Ismaili, Nawfel Mellas, +13 authors, Hassan Errihani.
Radiat Oncol, 2009 Apr 09; 4. PMID: 19351405    Free PMC article.
Classifying breast cancer surgery: a novel, complexity-based system for oncological, oncoplastic and reconstructive procedures, and proof of principle by analysis of 1225 operations in 1166 patients.
Jürgen Hoffmann, Diethelm Wallwiener.
BMC Cancer, 2009 Apr 10; 9. PMID: 19356240    Free PMC article.
Nitric oxide synthase variants and disease-free survival among treated and untreated breast cancer patients in a Southwest Oncology Group clinical trial.
Ji-Yeob Choi, William E Barlow, +14 authors, Christine B Ambrosone.
Clin Cancer Res, 2009 Aug 13; 15(16). PMID: 19671875    Free PMC article.
State of the art of neoadjuvant chemotherapy in breast cancer: rationale, results and recent developments.
Arnd Honig, Lorenz Rieger, +3 authors, Erich-Franz Solomayer.
Ger Med Sci, 2005 Jan 01; 3. PMID: 19675725    Free PMC article.
Chemotherapy for early-stage breast cancer: a brief history.
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Br J Cancer, 2009 Sep 17; 101 Suppl 1. PMID: 19756003    Free PMC article.
Radiation impact in breast cancer.
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Breast Cancer Res, 2010 Jan 20; 11 Suppl 3. PMID: 20030865    Free PMC article.
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Chemotherapy: dose-dense treatment for triple-negative breast cancer.
Eitan Amir, Alberto Ocana, +2 authors, Bostjan Seruga.
Nat Rev Clin Oncol, 2010 Feb 02; 7(2). PMID: 20118978
Manganese superoxide dismutase polymorphism, treatment-related toxicity and disease-free survival in SWOG 8897 clinical trial for breast cancer.
Song Yao, William E Barlow, +15 authors, Christine B Ambrosone.
Breast Cancer Res Treat, 2010 Mar 24; 124(2). PMID: 20309628    Free PMC article.
Adjuvant radiotherapy and chemotherapy in breast cancer: 30 year follow-up of survival.
Colin S McArdle, Donald C McMillan, Nicola Greenlaw, David S Morrison.
BMC Cancer, 2010 Aug 03; 10. PMID: 20673353    Free PMC article.
Anthracycline and concurrent radiotherapy as adjuvant treatment of operable breast cancer: a retrospective cohort study in a single institution.
Nabil Ismaili, Sanaa Elmajjaoui, +10 authors, Hassan Errihani.
BMC Res Notes, 2010 Oct 06; 3. PMID: 20920323    Free PMC article.
Optimizing dose-dense regimens for early-stage breast cancer.
Patrick G Morris, Clifford A Hudis.
Nat Rev Clin Oncol, 2010 Dec 01; 7(12). PMID: 21116238
Dose dense cyclophosphamide, methotrexate, fluorouracil is feasible at 14-day intervals: a pilot study of every-14-day dosing as adjuvant therapy for breast cancer.
Pamela Drullinsky, Steven M Sugarman, +15 authors, Clifford Hudis.
Clin Breast Cancer, 2010 Dec 15; 10(6). PMID: 21147686    Free PMC article.
Gene polymorphisms in cyclophosphamide metabolism pathway,treatment-related toxicity, and disease-free survival in SWOG 8897 clinical trial for breast cancer.
Song Yao, William E Barlow, +15 authors, Christine B Ambrosone.
Clin Cancer Res, 2010 Dec 21; 16(24). PMID: 21169260    Free PMC article.
Are current development programs realising the full potential of new agents?
Per Eystein Lønning.
Breast Cancer Res, 2011 Jan 05; 12 Suppl 4. PMID: 21172086    Free PMC article.
Drug therapy of cancer.
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Eur J Clin Pharmacol, 2011 Feb 22; 67(5). PMID: 21336995
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Increased sensitivity to apoptosis induced by methotrexate is mediated by JNK.
Charles F Spurlock, Zachary T Aune, +6 authors, Thomas M Aune.
Arthritis Rheum, 2011 May 28; 63(9). PMID: 21618198    Free PMC article.
Real-world experience with adjuvant fec-d chemotherapy in four Ontario regional cancer centres.
Y Madarnas, S F Dent, +5 authors, T Vandenberg.
Curr Oncol, 2011 Jun 10; 18(3). PMID: 21655158    Free PMC article.
Methotrexate increases expression of cell cycle checkpoint genes via JNK activation.
Charles F Spurlock, John T Tossberg, +2 authors, Thomas M Aune.
Arthritis Rheum, 2011 Dec 21; 64(6). PMID: 22183962    Free PMC article.
Two hundred years of cancer research.
Vincent T DeVita, Steven A Rosenberg.
N Engl J Med, 2012 Jun 01; 366(23). PMID: 22646510    Free PMC article.
SULT1A1 rs9282861 polymorphism-a potential modifier of efficacy of the systemic adjuvant therapy in breast cancer?
Maria Tengström, Arto Mannermaa, +2 authors, Vesa Kataja.
BMC Cancer, 2012 Jun 20; 12. PMID: 22708928    Free PMC article.
Past, present, and future of radiotherapy for the benefit of patients.
Juliette Thariat, Jean-Michel Hannoun-Levi, +2 authors, Jean-Pierre Gérard.
Nat Rev Clin Oncol, 2012 Nov 28; 10(1). PMID: 23183635
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From Transplant to Tablets: A paradigm shift in Oncology.
Ikram A Burney, Mansour S Al-Moundhri.
Sultan Qaboos Univ Med J, 2013 Jan 01; 12(4). PMID: 23275834    Free PMC article.
Tumour-microenvironment interactions: role of tumour stroma and proteins produced by cancer-associated fibroblasts in chemotherapy response.
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Cell Oncol (Dordr), 2013 Mar 16; 36(2). PMID: 23494412
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Pneumocystis pneumonia during Postoperative Adjuvant Chemotherapy for Breast Cancer.
Tsuyoshi Shinohara, Makito Yasui, +2 authors, Kiyofumi Yamagishi.
Case Rep Oncol Med, 2013 Jun 14; 2013. PMID: 23762693    Free PMC article.
Is it time for a new paradigm for systemic cancer treatment? Lessons from a century of cancer chemotherapy.
Sarah Crawford.
Front Pharmacol, 2013 Jun 28; 4. PMID: 23805101    Free PMC article.
Statistics for surgeons - understanding survival analysis.
Girdhar Gopal Agarwal.
Indian J Surg Oncol, 2013 Sep 03; 3(3). PMID: 23997508    Free PMC article.
Benefit risk assessment and update on the use of docetaxel in the management of breast cancer.
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Cancer Manag Res, 2013 Oct 22; 5. PMID: 24143122    Free PMC article.
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Ocular surface and tear film abnormalities in women under adjuvant chemotherapy for breast cancer with the 5-Fluorouracil, Epirubicin and Cyclophosphamide (FEC) regimen.
A Karamitsos, V Kokkas, +4 authors, K Boboridis.
Hippokratia, 2014 Jan 01; 17(2). PMID: 24376315    Free PMC article.
Tamoxifen as the first targeted long-term adjuvant therapy for breast cancer.
V Craig Jordan.
Endocr Relat Cancer, 2014 Mar 25; 21(3). PMID: 24659478    Free PMC article.
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Second malignancies after breast cancer: The impact of adjuvant therapy.
Chunhui Dong, Ling Chen.
Mol Clin Oncol, 2014 Apr 29; 2(3). PMID: 24772296    Free PMC article.
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Past, present, and future challenges in breast cancer treatment.
George W Sledge, Eleftherios P Mamounas, +3 authors, Antonio C Wolff.
J Clin Oncol, 2014 Jun 04; 32(19). PMID: 24888802    Free PMC article.
Chemotherapy in early breast cancer: when, how and which one?
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Breast Care (Basel), 2014 Sep 02; 9(3). PMID: 25177256    Free PMC article.
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Comparative benefit from small tumour size and adjuvant chemotherapy: clues for explaining breast cancer mortality decline.
Romano Demicheli, Federico Ambrogi.
BMC Cancer, 2014 Sep 25; 14. PMID: 25249290    Free PMC article.
Advances in adjuvant systemic therapy for non-small-cell lung cancer.
David Leong, Rajat Rai, +2 authors, Desmond Yip.
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Current treatment of early breast cancer: adjuvant and neoadjuvant therapy.
Elizabeth Miller, Hee Jin Lee, +3 authors, Bora Lim.
F1000Res, 2014 Nov 18; 3. PMID: 25400908    Free PMC article.
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Binghe Xu, Andrew Seidman, Stephen Chan.
Oncologist, 2015 Jan 16; 20(1). PMID: 25589501    Free PMC article.
Surgical issues in patients with breast cancer receiving neoadjuvant chemotherapy.
Tari A King, Monica Morrow.
Nat Rev Clin Oncol, 2015 Apr 09; 12(6). PMID: 25850554
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Adjuvant Metronomic CMF in a Contemporary Breast Cancer Cohort: What's Old Is New.
Eunpi Cho, Ann K Schwemm, +7 authors, Vijayakrishna K Gadi.
Clin Breast Cancer, 2015 May 31; 15(5). PMID: 26025883    Free PMC article.
Adjuvant Therapy Reduces Rate of Dissemination but Shortens Survival Thereafter.
Michael K Fink, Ulrich R Kleeberg, Stefan Bartels.
Oncologist, 2015 Jun 13; 20(7). PMID: 26069279    Free PMC article.
Ophthalmic Metastasis of Breast Cancer and Ocular Side Effects from Breast Cancer Treatment and Management: Mini Review.
Ilias Georgalas, Theodore Paraskevopoulos, +4 authors, Dimitris Papaconstantinou.
Biomed Res Int, 2015 Jun 17; 2015. PMID: 26078956    Free PMC article.
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Progress in adjuvant chemotherapy for breast cancer: an overview.
Jesus Anampa, Della Makower, Joseph A Sparano.
BMC Med, 2015 Aug 19; 13. PMID: 26278220    Free PMC article.
Highly Cited. Review.
A streamlined search technology for identification of synergistic drug combinations.
Andrea Weiss, Robert H Berndsen, +5 authors, Patrycja Nowak-Sliwinska.
Sci Rep, 2015 Sep 30; 5. PMID: 26416286    Free PMC article.
Recent advances of cocktail chemotherapy by combination drug delivery systems.
Quanyin Hu, Wujin Sun, Chao Wang, Zhen Gu.
Adv Drug Deliv Rev, 2015 Nov 08; 98. PMID: 26546751    Free PMC article.
Highly Cited. Review.
Exploring circulating micro-RNA in the neoadjuvant treatment of breast cancer.
Máire-Caitlín Casey, Karl J Sweeney, James Andrew Lawrence Brown, Michael J Kerin.
Int J Cancer, 2016 Jan 13; 139(1). PMID: 26756433    Free PMC article.
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The fruits of long endeavors - 200 years of oncology.
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Met and its ligand HGF are associated with clinical outcome in breast cancer.
Cynthia Veenstra, Gizeh Pérez-Tenorio, +5 authors, Olle Stål.
Oncotarget, 2016 May 14; 7(24). PMID: 27175600    Free PMC article.
Real-world adjuvant TAC or FEC-D for HER2-negative node-positive breast cancer in women less than 50 years of age.
S Lupichuk, D Tilley, X Kostaras, A A Joy.
Curr Oncol, 2016 Jun 23; 23(3). PMID: 27330344    Free PMC article.
Systemic Therapy for Early-Stage Breast Cancer: What the Plastic Surgeon Should Know.
Chad M Teven, Daniel B Schmid, +2 authors, Michael A Howard.
Eplasty, 2017 Mar 16; 17. PMID: 28293332    Free PMC article.
Biocompatible astaxanthin as a novel marine-oriented agent for dual chemo-photothermal therapy.
Van Phuc Nguyen, Sung Won Kim, +5 authors, Hyun Wook Kang.
PLoS One, 2017 Apr 04; 12(4). PMID: 28369126    Free PMC article.
Adjuvant Therapy for High Risk Localized Kidney Cancer: Emerging Evidence and Future Clinical Trials.
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J Urol, 2017 May 10; 199(1). PMID: 28479237    Free PMC article.
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Neoadjuvant chemotherapy induces breast cancer metastasis through a TMEM-mediated mechanism.
George S Karagiannis, Jessica M Pastoriza, +13 authors, Maja H Oktay.
Sci Transl Med, 2017 Jul 07; 9(397). PMID: 28679654    Free PMC article.
Highly Cited.
Assessing the Clinical Benefit of Systemic Adjuvant Therapies for Early Breast Cancer.
Volker Möbus, Susanne Hell, Marcus Schmidt.
Geburtshilfe Frauenheilkd, 2017 Nov 03; 77(10). PMID: 29093601    Free PMC article.
Efficacy and Safety of Cyclophosphamide Treatment in Severe Juvenile Dermatomyositis Shown by Marginal Structural Modeling.
Claire T Deakin, Raquel Campanilho-Marques, +5 authors, Juvenile Dermatomyositis Research Group.
Arthritis Rheumatol, 2018 Jan 18; 70(5). PMID: 29342499    Free PMC article.
Is invasion a necessary step for metastases in breast cancer?
Steven A Narod, Victoria Sopik.
Breast Cancer Res Treat, 2018 Jan 22; 169(1). PMID: 29353366    Free PMC article.
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Precision Medicine with Imprecise Therapy: Computational Modeling for Chemotherapy in Breast Cancer.
Matthew T McKenna, Jared A Weis, +2 authors, Thomas E Yankeelov.
Transl Oncol, 2018 Apr 21; 11(3). PMID: 29674173    Free PMC article.
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Practical consensus recommendations on ovarian suppression in early breast cancer (adjuvant).
M Singhal, T P Sahoo, +8 authors, Purvish M Parikh.
South Asian J Cancer, 2018 May 04; 7(2). PMID: 29721484    Free PMC article.
Anthracycline Use for Early Stage Breast Cancer in the Modern Era: a Review.
Sakshi Jasra, Jesus Anampa.
Curr Treat Options Oncol, 2018 May 13; 19(6). PMID: 29752560
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Drug-Triggered Self-Assembly of Linear Polymer into Nanoparticles for Simultaneous Delivery of Hydrophobic and Hydrophilic Drugs in Breast Cancer Cells.
Sandeep Palvai, Libi Anandi, +4 authors, Sudipta Basu.
ACS Omega, 2018 Jul 20; 2(12). PMID: 30023590    Free PMC article.
The Prosigna gene expression assay and responsiveness to adjuvant cyclophosphamide-based chemotherapy in premenopausal high-risk patients with breast cancer.
Maj-Britt Jensen, Anne-Vibeke Lænkholm, +7 authors, Bent Ejlertsen.
Breast Cancer Res, 2018 Jul 29; 20(1). PMID: 30053900    Free PMC article.
Adjuvant Anthracyclines in Breast Cancer: What Is Their Role?
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Oncologist, 2018 Aug 19; 23(10). PMID: 30120159    Free PMC article.
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Prognostic Significance of Adjuvant Chemotherapy Induced Amenorrhea in Luminal A and B Subtypes.
Çetin Ordu, Kezban Nur Pilancı, +14 authors, Vahit Özmen.
Eur J Breast Health, 2018 Aug 21; 14(3). PMID: 30123884    Free PMC article.
Chemotherapy-Exacerbated Breast Cancer Metastasis: A Paradox Explainable by Dysregulated Adaptive-Response.
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A nanodroplet cell processing platform facilitating drug synergy evaluations for anti-cancer treatments.
Ching-Te Kuo, Jong-Yueh Wang, +7 authors, Hsinyu Lee.
Sci Rep, 2019 Jul 14; 9(1). PMID: 31300742    Free PMC article.
Doxorubicin Is Key for the Cardiotoxicity of FAC (5-Fluorouracil + Adriamycin + Cyclophosphamide) Combination in Differentiated H9c2 Cells.
Maria Pereira-Oliveira, Ana Reis-Mendes, +3 authors, Vera Marisa Costa.
Biomolecules, 2019 Jan 13; 9(1). PMID: 30634681    Free PMC article.
Drug Combinations in Breast Cancer Therapy.
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Pharm Nanotechnol, 2019 Jan 23; 7(1). PMID: 30666921    Free PMC article.
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Drug repurposing for breast cancer therapy: Old weapon for new battle.
Sadhna Aggarwal, Sumit Singh Verma, Sumit Aggarwal, Subash Chandra Gupta.
Semin Cancer Biol, 2019 Sep 25; 68. PMID: 31550502    Free PMC article.
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The Impact of Adding Taxanes to Anthracyclines on Women with Breast Cancer Receiving Adjuvant Chemotherapy.
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Cureus, 2020 Apr 08; 12(2). PMID: 32257663    Free PMC article.
Cancer Vaccines and Oncolytic Viruses Exert Profoundly Lower Side Effects in Cancer Patients than Other Systemic Therapies: A Comparative Analysis.
Volker Schirrmacher.
Biomedicines, 2020 Mar 20; 8(3). PMID: 32188078    Free PMC article.
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Late effects of adjuvant chemotherapy adumbrate dormancy complexity in breast cancer.
Romano Demicheli, Christine Desmedt, +3 authors, Elia Biganzoli.
Breast, 2020 May 20; 52. PMID: 32428688    Free PMC article.
Ameliorative Effect of Gallic Acid on Methotrexate-Induced Hepatotoxicity and Nephrotoxicity in Rat.
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Comparative study of adjuvant chemotherapeutic efficacy of docetaxel plus cyclophosphamide and doxorubicin plus cyclophosphamide in female breast cancer.
Muhammad Adeel, Muhammad Asif, +3 authors, Muhammad Khalid.
Cancer Manag Res, 2019 Jan 31; 11. PMID: 30697066    Free PMC article.
Pharmacological Treatment of Chemotherapy-Induced Neuropathic Pain: PPARγ Agonists as a Promising Tool.
Nara Lins Meira Quintão, José Roberto Santin, +3 authors, Robson Costa.
Front Neurosci, 2019 Sep 27; 13. PMID: 31555078    Free PMC article.
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Does the Sequence of Anthracycline and Taxane Matter? The NeoSAMBA Trial.
José Bines, Isabele A Small, +9 authors, Martin Bonamino.
Oncologist, 2020 Jun 02; 25(9). PMID: 32476183    Free PMC article.
Do we still need breast cancer screening in the era of targeted therapies and precision medicine?
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Insights Imaging, 2020 Sep 26; 11(1). PMID: 32975658    Free PMC article.
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Side effects of adjuvant chemotherapy and their impact on outcome in elderly breast cancer patients: a cohort study.
Valentina Zanuso, Vittorio Fregoni, Lorenzo Gervaso.
Future Sci OA, 2020 Nov 26; 6(9). PMID: 33235809    Free PMC article.
Clinical target sequencing for precision medicine of breast cancer.
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Int J Clin Oncol, 2019 Jan 04; 24(2). PMID: 30604156
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Current Status and Future Prospects of Clinically Exploiting Cancer-specific Metabolism-Why Is Tumor Metabolism Not More Extensively Translated into Clinical Targets and Biomarkers?
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Int J Mol Sci, 2019 Mar 22; 20(6). PMID: 30893889    Free PMC article.
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The effects of PTPN2 loss on cell signalling and clinical outcome in relation to breast cancer subtype.
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J Cancer Res Clin Oncol, 2019 Apr 27; 145(7). PMID: 31025094    Free PMC article.
Antitumor activity and efficacy of shorter versus longer duration of anthracycline-taxane neoadjuvant chemotherapy in stage II-III HER2-negative breast cancer: a 10-year, retrospective analysis.
Riccardo Lobefaro, Emma Zattarin, +15 authors, Giuseppe Capri.
Ther Adv Med Oncol, 2020 Dec 19; 12. PMID: 33335565    Free PMC article.
Current Stimuli-Responsive Mesoporous Silica Nanoparticles for Cancer Therapy.
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Methotrexate enhances antigen presentation and maturation of tumour antigen-loaded dendritic cells through NLRP3 inflammasome activation: a strategy for dendritic cell-based cancer vaccine.
Gao-Na Shi, Min Hu, +5 authors, Tiantai Zhang.
Ther Adv Med Oncol, 2021 Feb 23; 13. PMID: 33613696    Free PMC article.
Drug Combination in Cancer Treatment-From Cocktails to Conjugated Combinations.
Yosi Gilad, Gary Gellerman, David M Lonard, Bert W O'Malley.
Cancers (Basel), 2021 Feb 11; 13(4). PMID: 33562300    Free PMC article.
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Implications of Breast Cancer Chemotherapy-Induced Inflammation on the Gut, Liver, and Central Nervous System.
Taurean Brown, DeLawrence Sykes, Antiño R Allen.
Biomedicines, 2021 Mar 07; 9(2). PMID: 33668580    Free PMC article.
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A view on drug resistance in cancer.
Neil Vasan, José Baselga, David M Hyman.
Nature, 2019 Nov 15; 575(7782). PMID: 31723286    Free PMC article.
Highly Cited. Review.
Reconsidering the Meaning of Curing Primary Breast Cancer as a Systemic Disease.
Ryungsa Kim, Takanori Kin.
Front Oncol, 2021 Apr 06; 11. PMID: 33816282    Free PMC article.
Signaling Pathways in Cancer: Therapeutic Targets, Combinatorial Treatments, and New Developments.
Hon Yan Kelvin Yip, Antonella Papa.
Cells, 2021 Apr 04; 10(3). PMID: 33809714    Free PMC article.
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