Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress
Clinical Collections
Advances in Alzheimer’s

At a glance: The ONWARDS insulin icodec trials

A round-up of the ONWARDS phase 3 clinical trials evaluating the novel weekly insulin icodec in people with diabetes.
ADVANCED SEARCH
Log in
Top
Breast Cancer Research and Treatment
Published in: Breast Cancer Research and Treatment 1/2019

Open Access 01-02-2019 | Editorial

Outcome for triple negative breast cancer in a retrospective cohort with an emphasis on response to platinum-based neoadjuvant therapy

Authors: Elaine M. Walsh, Aliaa Shalaby, Mark O’Loughlin, Nessa Keane, Mark J Webber, Michael J. Kerin, Maccon M. Keane, Sharon A. Glynn, Grace M. Callagy

Published in: Breast Cancer Research and Treatment | Issue 1/2019

Login to get access

Abstract

Purpose

The rate of pathological complete response (pCR) for patients with triple negative breast cancer (TNBC) is increased when carboplatin is added to neo-adjuvant chemotherapy (NACT). However, while phase III trial data showing a survival benefit are awaited, carboplatin is not yet standard-of-care for TNBC. The aim of this study was to examine the rate of pCR and the outcome for those treated with carboplatin and to examine the predictors of response to therapy.

Methods

The retrospective series comprised 333 consecutive patients with TNBC (median follow-up time, 43 months). Adjuvant chemotherapy was given to 51% (n = 168) of patients and 29% (n = 97) received anthracycline–taxane NACT with carboplatin given to 9% (n = 31) of patients.

Results

Overall, 25% (n = 78) of patients experienced a breast cancer recurrence and 22% (n = 68) died from disease. A pCR breast and pCR breast/axilla was more common in those who received carboplatin (n = 18, 58% and n = 17, 55%, respectively) compared those who did not (n = 23, 36% and n = 18, 28%, respectively) (p = 0.041 and p = 0.011, respectively). By multivariable analysis, carboplatin and high tumor grade were independent predictors of pCR breast/axilla (ORnon-pCR = 0.17; 95% CI 0.06–0.54; p = 0.002; and ORnon-pCR = 0.05, 95% CI 0.01–0.27; p < 0.001, respectively). pCR breast/axilla was an independent predictor of DFS (HRnon-pCR=6.23; 95% CI 1.36–28.50; p = 0.018), metastasis-free survival (HRnon-pCR = 5.08; 95% CI 1.09–23.65; p = 0.038) and BCSS (HRnon-pCR = 8.52; 95% CI 1.09–66.64; p = 0.041).

Conclusion

Carboplatin therapy and high tumor grade are associated with a significant increase in the rate of pCR, which is an independent predictor of outcome. These data support the use of carboplatin in NACT for TNBC, while results from phase III studies are awaited.
Appendix
Available only for authorised users
Literature
1.
Dent R, Trudeau M, Pritchard KI, Hanna WM, Kahn HK, Sawka CA et al (2007) Triple-negative breast cancer: clinical features and patterns of recurrence. Clin Cancer Res 13(15):4429–4434PubMedCrossRef
2.
Liedtke C, Mazouni C, Hess KR, André F, Tordai A, Mejia JA et al (2008) Response to neoadjuvant therapy and long-term survival in patients with triple-negative breast cancer. J Clin Oncol 26(8):1275–1281PubMedCrossRef
3.
Foulkes WD, Smith IE, Reis-Filho JS (2010) Triple-negative breast cancer. N Engl J Med 363(20):1938–1948PubMedCrossRef
4.
Cheang MCU, Voduc D, Bajdik C, Leung S, McKinney S, Chia SK et al (2008) Basal-like breast cancer defined by five biomarkers has superior prognostic value than triple-negative phenotype. Clin Cancer Res 14(5):1368–1376PubMedCrossRef
5.
Hernandez-Aya LF, Chavez-MacGregor M, Lei X, Meric-Bernstam F, Buchholz TA, Hsu L et al (2011) Nodal status and clinical outcomes in a large cohort of patients with triple-negative breast cancer. J Clin Oncol 29(19):2628–2634PubMedPubMedCentralCrossRef
6.
Sørlie T, Perou CM, Tibshirani R, Aas T, Geisler S, Johnsen H et al (2001) Gene expression patterns of breast carcinomas distinguish tumor subclasses with clinical implications. Proc Natl Acad Sci USA 98(19):10869–10874PubMedCrossRefPubMedCentral
7.
Kennecke H, Yerushalmi R, Woods R, Cheang MCU, Voduc D, Speers CH et al (2010) Metastatic behavior of breast cancer subtypes. J Clin Oncol 28(20):3271–3277PubMedCrossRef
8.
Thike AA, Iqbal J, Cheok PY, Chong APY, Tse GM-K, Tan B et al (2010) Triple negative breast cancer: outcome correlation with immunohistochemical detection of basal markers. Am J Surg Pathol 34(7):956–964PubMedCrossRef
9.
Dent R, Hanna WM, Trudeau M, Rawlinson E, Sun P, Narod SA (2009) Pattern of metastatic spread in triple-negative breast cancer. Breast Cancer Res Treat 115(2):423–428PubMedCrossRef
10.
11.
Badve S, Dabbs DJ, Schnitt SJ, Baehner FL, Decker T, Eusebi V et al (2011) Basal-like and triple-negative breast cancers: a critical review with an emphasis on the implications for pathologists and oncologists. Mod Pathol 24(2):157–167PubMedCrossRef
12.
Sikov WM, Berry DA, Perou CM, Singh B, Cirrincione CT, Tolaney SM et al (2015) 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 (A). J Clin Oncol 33(1):13–21PubMedCrossRef
13.
Von Minckwitz G, Schneeweiss A, Loibl S, Salat C, Denkert C, Rezai M et al (2014) Neoadjuvant carboplatin in patients with triple-negative and HER2-positive early breast cancer (GeparSixto; GBG 66): a randomised phase 2 trial. Lancet Oncol 15(7):747–756CrossRef
14.
Carey LA, Dees EC, Sawyer L, Gatti L, Moore DT, Collichio F et al (2007) The triple negative paradox: primary tumor chemosensitivity of breast cancer subtypes. Clin Cancer Res 13(8):2329–2334PubMedCrossRef
15.
Cortazar P, Zhang L, Untch M, Mehta K, Costantino JP, Wolmark N et al (2014) Pathological complete response and long-term clinical benefit in breast cancer: the CTNeoBC pooled analysis. Lancet 384(9938):164–172PubMedCrossRef
16.
Lehmann BD, Jovanović B, Chen X, Estrada MV, Johnson KN, Shyr Y et al (2016) Refinement of triple-negative breast cancer molecular subtypes: implications for neoadjuvant chemotherapy selection. PLoS ONE 11(6):e0157368PubMedPubMedCentralCrossRef
17.
Lehmann BD, Bauer JA, Chen X, Sanders ME, Chakravarthy AB, Shyr Y et al (2011) Identification of human triple-negative breast cancer subtypes and preclinical models for selection of targeted therapies. J Clin Invest 121(7):2750–2767PubMedPubMedCentralCrossRef
18.
Lehmann BD, Pietenpol JA (2014) Identification and use of biomarkers in treatment strategies for triple-negative breast cancer subtypes. J Pathol 232(2):142–150PubMedPubMedCentralCrossRef
19.
Burstein MD, Tsimelzon A, Poage GM, Covington KR, Contreras A, Fuqua SAW et al (2015) Comprehensive genomic analysis identifies novel subtypes and targets of triple-negative breast cancer. Clin Cancer Res 21(7):1688–1698PubMedCrossRef
20.
Koboldt DC, Fulton RS, McLellan MD, Schmidt H, Kalicki-Veizer J, McMichael JF et al (2012) Comprehensive molecular portraits of human breast tumours. Nature 490(7418):61–70CrossRef
21.
Shah SP, Roth A, Goya R, Oloumi A, Ha G, Zhao Y et al (2012) The clonal and mutational evolution spectrum of primary triple-negative breast cancers. Nature 486(7403):395–399PubMedCrossRef
22.
Turner N, Tutt A, Ashworth A (2004) Hallmarks of “BRCAness” in sporadic cancers. Nat Rev Cancer 4(10):814–819PubMedCrossRef
23.
Lips EH, Mulder L, Oonk A, Van Der Kolk LE, Hogervorst FBL, Imholz ALT et al (2013) Triple-negative breast cancer: BRCAness and concordance of clinical features with BRCA1-mutation carriers. Br J Cancer 108(10):2172–2177PubMedPubMedCentralCrossRef
24.
Tutt A, Ellis P, Kilburn L, Gilett C, Pinder S, Abraham J et al (2014) The Tnt Trial: a randomised phase Iii trial of Carboplatin (C) Compared with Docetaxel (D) for patients with metastatic or recurrent locally advanced triple negative or Brca1/2 breast cancer (Cruk/07/012) Abstr S3-01. In: San Antonio Breast Cancer Symposium. San Antonio, TX
25.
Rugo HS, Olopade OI, DeMichele A, Yau C, Van’t Veer LJ, Buxton MB et al (2016) Adaptive randomization of veliparib-carboplatin treatment in breast cancer. N Engl J Med 375(1):23–34PubMedPubMedCentralCrossRef
26.
Ando M, Yamauchi H, Aogi K, Shimizu S, Iwata H, Masuda N et al (2014) Randomized phase II study of weekly paclitaxel with and without carboplatin followed by cyclophosphamide/epirubicin/5-fluorouracil as neoadjuvant chemotherapy for stage II/IIIA breast cancer without HER2 overexpression. Breast Cancer Res Treat 145(2):401–409PubMedCrossRef
27.
Chang HR, Glaspy J, Allison MA, Kass FC, Elashoff R, Chung DU et al (2010) Differential response of triple-negative breast cancer to a docetaxel and carboplatin-based neoadjuvant treatment. Cancer 116(18):4227–4237PubMedCrossRef
28.
Guarneri V, Dieci MV, Bisagni G, Boni C, Cagossi K, Puglisi F et al (2015) Preoperative carboplatin–paclitaxel–bevacizumab in triple-negative breast cancer: final results of the phase II Ca.Pa.Be study. Ann Surg Oncol 22(9):2881–2887PubMedCrossRef
29.
Fan Y, Xu BH, Yuan P, Ma F, Wang JY, Ding XY et al (2013) Docetaxel-cisplatin might be superior to docetaxel-capecitabine in the first-line treatment of metastatic triple-negative breast cancer. Ann Oncol 24(5):1219–1225PubMedCrossRef
30.
Abramson VG, Lehmann BD, Ballinger TJ, Pietenpol JA (2015) Subtyping of triple-negative breast cancer: implications for therapy. Cancer 121(1):8–16PubMedCrossRef
31.
Stover DG, Winer EP (2015) Tailoring adjuvant chemotherapy regimens for patients with triple negative breast cancer. Breast 24:S132–S135PubMedCrossRef
32.
Harvey JM, Clark GM, Osborne CK, Allred DC (1999) Estrogen receptor status by immunohistochemistry is superior to the ligand-binding assay for predicting response to adjuvant endocrine therapy in breast cancer. J Clin Oncol 17(5):1474PubMedCrossRef
33.
Elston CW, Ellis IO (1991) Pathological prognostic factors in breast cancer. The value of histological grade in breast cancer: experience from a large study with long-term follow-up. Histopathology 19:403–410PubMedCrossRef
34.
Ellis I, Al-Sam S, Anderson N, Carder P, Deb R, Girling A et al (2016) Pathology reporting of breast disease in surgical excision specimens incorporating the dataset for histological reporting of breast cancer. The Royal College of Pathologists, London
35.
36.
Wittekind C, Sobin L, Gospodarowicz M (2009) TNM classification of malignant tumours, 7th ed. Wiley, Hoboken
37.
Provenzano E, Bossuyt V, Viale G, Cameron D, Badve S, Denkert C et al (2015) Standardization of pathologic evaluation and reporting of postneoadjuvant specimens in clinical trials of breast cancer: recommendations from an international working group. Mod Pathol 28(9):1185–1201PubMedCrossRef
38.
Hammond ME, Hayes DF, Dowsett M, Allred DC, Hagerty KL, Badve S et al (2010) American Society of Clinical Oncology/College of American Pathologists guideline recommendations for immunohistochemical testing of estrogen and progesterone receptors in breast cancer (unabridged version). Arch Pathol Lab Med 134(7):48–72
39.
Wolff AC, Hammond MEH, Hicks DG, Dowsett M, McShane LM, Allison KH et al (2013) Recommendations for human epidermal growth factor receptor 2 testing in breast. J Clin Oncol 31(31):3997–4013PubMedCrossRef
40.
Fisher B, Brown A, Mamounas E, Wieand S, Robidoux A, Margolese RG et al (1997) Effect of preoperative chemotherapy on local-regional disease in women with operable breast cancer: findings from National Surgical Adjuvant Breast and Bowel Project B-18. J Clin Oncol 15(7):2483–2493PubMedCrossRef
41.
Bonadonna G, Valagussa P, Brambilla C, Ferrari L, Moliterni A, Terenziani M et al (1998) Primary chemotherapy in operable breast cancer: eight-year experience at the Milan Cancer Institute. J Clin Oncol 16(1):93–100PubMedCrossRef
42.
Fisher B, Bryant J, Wolmark N, Mamounas E, Brown A, Fisher ER et al (1998) Effect of preoperative chemotherapy on the outcome of women with operable breast cancer. J Clin Oncol 16(8):2672–2685PubMedCrossRef
43.
Bear HD, Anderson S, Brown A, Smith R, Mamounas EP, Fisher B et al (2003) The effect on tumor response of adding sequential preoperative docetaxel to preoperative doxorubicin and cyclophosphamide: preliminary results from national surgical adjuvant breast and bowel project protocol B-27. J Clin Oncol 21(22):4165–4174PubMedCrossRef
44.
Berruti A, Amoroso V, Gallo F, Bertaglia V, Simoncini E, Pedersini R et al (2014) Pathologic complete response as a potential surrogate for the clinical outcome in patients with breast cancer after neoadjuvant therapy: a meta-regression of 29 randomized prospective studies. J Clin Oncol 32(34):3883–3891PubMedCrossRef
45.
Rastogi P, Anderson SJ, Bear HD, Geyer CE, Kahlenberg MS, Robidoux A et al (2008) Preoperative chemotherapy: updates of national surgical adjuvant breast and bowel project protocols B-18 and B-27. J Clin Oncol 26(5):778–785PubMedCrossRef
46.
Hatzis C, Symmans WF, Zhang Y, Gould RE, Moulder SL, Hunt KK et al (2016) Relationship between complete pathologic response to neoadjuvant chemotherapy and survival in triple-negative breast cancer. Clin Cancer Res 22(1):26–33PubMedCrossRef
47.
48.
Alba E, Chacon JI, Lluch A, Anton A, Estevez L, Cirauqui B et al (2012) A randomized phase II trial of platinum salts in basal-like breast cancer patients in the neoadjuvant setting. Results from the GEICAM/2006-03, multicenter study. Breast Cancer Res Treat 136(2):487–493PubMedCrossRef
49.
50.
Vasey PA, Jayson GC, Gordon A, Gabra H, Coleman R, Atkinson R et al (2004) Phase III randomized trial of docetaxel-carboplatin versus paclitaxel-carboplatin as first-line chemotherpy for ovarian carcinoma. J Natl Cancer Inst 96(22):1682–1691PubMedCrossRef
51.
Perez EA, Hillman DW, Stella PJ, Krook JE, Hartmann LC, Fitch TR et al (2000) A phase II study of paclitaxel plus carboplatin as first-line chemotherapy for women with metastatic breast carcinoma. Cancer 88(1):124–131PubMedCrossRef
52.
Perez EA, Suman VJ, Fitch TR, Mailliard JA, Ingle JN, Cole JT et al (2005) A phase II trial of docetaxel and carboplatin as first-line chemotherapy for metastatic breast cancer: NCCTG study N9932. Oncology 69(2):117–121PubMedCrossRef
53.
Sharma P, López-Tarruella S, García-Saenz JA, Ward C, Connor CS, Gómez HL et al (2017) Efficacy of Neoadjuvant carboplatin plus docetaxel in triple-negative breast cancer: combined analysis of two cohorts. Clin Cancer Res 23(3):649–657PubMedCrossRef
54.
Zhao S, Ma D, Xiao Y, Jiang Y-Z, Shao Z-M (2018) Clinicopathologic features and prognoses of different histologic types of triple-negative breast cancer: a large population-based analysis. Eur J Surg Oncol 44(4):420–428PubMedCrossRef
55.
Liao H-Y, Zhang W-W, Sun J-Y, Li F-Y, He Z-Y, Wu S-G (2017) The clinicopathological features and survival outcomes of different histological subtypes in triple-negative breast cancer. J Cancer 9(2):296–303CrossRef
56.
Mills MN, Yang GQ, Oliver DE, Liveringhouse CL, Ahmed KA, Orman AG et al (2018) Histologic heterogeneity of triple negative breast cancer: a National Cancer Centre Database analysis. Eur J Cancer [Internet] 98:48–58CrossRef
57.
Urru SAM, Gallus S, Bosetti C, Moi T, Medda R, Sollai E et al (2018) Clinical and pathological factors influencing survival in a large cohort of triple-negative breast cancer patients. BMC Cancer 18(1):56PubMedPubMedCentralCrossRef
58.
Masuda H, Baggerly KA, Wang Y, Zhang Y, Gonzalez-Angulo AM, Meric-Bernstam F et al (2013) Differential response to neoadjuvant chemotherapy among 7 triple-negative breast cancer molecular subtypes. Clin Cancer Res 19(19):5533–5540PubMedCrossRef
59.
Nielsen TO, Hsu FD, Jensen K, Cheang M, Karaca G, Hu Z et al (2004) Immunohistochemical and clinical characterization of the basal-like subtype of invasive breast carcinoma. Clin Cancer Res 10(16):5367–5374PubMedCrossRef
60.
Rakha EA, El-Sayed ME, Green AR, Lee AHS, Robertson JF, Ellis IO (2007) Prognostic markers in triple-negative breast cancer. Cancer 109(1):25–32PubMedCrossRef
61.
Foulkes WD, Grainge MJ, Rakha EA, Green AR, Ellis IO (2009) Tumor size is an unreliable predictor of prognosis in basal-like breast cancers and does not correlate closely with lymph node status. Breast Cancer Res Treat 117(1):199–204PubMedCrossRef
62.
Abdulkarim BS, Cuartero J, Hanson J, Deschênes J, Lesniak D, Sabri S (2011) Increased risk of locoregional recurrence for women with T1-2N0 triple-negative breast cancer treated with modified radical mastectomy without adjuvant radiation therapy compared with breast-conserving therapy. J Clin Oncol 29(21):2852–2858PubMedPubMedCentralCrossRef
63.
Adkins FC, Gonzalez-Angulo AM, Lei X, Hernandez-Aya LF, Mittendorf EA, Litton JK et al (2011) Triple-negative breast cancer is not a contraindication for breast conservation. Ann Surg Oncol 18(11):3164–3173PubMedPubMedCentralCrossRef
64.
Voduc KD, Cheang MCU, Tyldesley S, Gelmon K, Nielsen TO, Kennecke H (2010) Breast cancer subtypes and the risk of local and regional relapse. J Clin Oncol 28(10):1684–1691PubMedCrossRef
65.
Cameron D, Brown J, Dent R, Jackisch C, Mackey J, Pivot X et al (2013) Adjuvant bevacizumab-containing therapy in triple-negative breast cancer (BEATRICE): primary results of a randomised, phase 3 trial. Lancet Oncol 14(10):933–942PubMedCrossRef
66.
Gerber B, Loibl S, Eidtmann H, Rezai M, Fasching PA, Tesch H et al (2013) Neoadjuvant bevacizumab and anthracycline-taxane-based chemotherapy in 678 triple-negative primary breast cancers; results from the geparquinto study (GBG 44). Ann Oncol 24(12):2978–2984PubMedCrossRef
67.
Bear HD, Tang G, Rastogi P, Geyer CE, Liu Q, Robidoux A et al (2015) Neoadjuvant plus adjuvant bevacizumab in early breast cancer (NSABP B-40 [NRG Oncology]): secondary outcomes of a phase 3, randomised controlled trial. Lancet Oncol 16(9):1037–1048PubMedPubMedCentralCrossRef
68.
Sataloff DM, Mason BA, Prestipino AJ, Seinige UL, Lieber CP, Baloch Z (1995) Pathologic response to induction chemotherapy in locally advanced carcinoma of the breast: a determinant of outcome. J Am Coll Surg 180(3):297–304PubMed
69.
Symmans WF, Peintinger F, Hatzis C, Rajan R, Kuerer H, Valero V et al (2007) Measurement of residual breast cancer burden to predict survival after neoadjuvant chemotherapy. J Clin Oncol 25(28):4414–4422PubMedCrossRef
70.
Symmans WF, Wei C, Gould R, Yu X, Zhang Y, Liu M et al (2017) Long-term prognostic risk after neoadjuvant chemotherapy associated with residual cancer burden and breast cancer subtype. J Clin Oncol 35(10):1049–1060PubMedPubMedCentralCrossRef
71.
Peintinger F, Sinn B, Hatzis C, Albarracin C, Downs-Kelly E, Morkowski J et al (2015) Reproducibility of residual cancer burden for prognostic assessment of breast cancer after neoadjuvant chemotherapy. Mod Pathol 28(7):913–920PubMedPubMedCentralCrossRef
72.
Iwamoto T, Booser D, Valero V, Murray JL, Koenig K, Esteva FJ et al (2012) Estrogen receptor (ER) mRNA and ER-related gene expression in breast cancers that are 1–10% ER-positive by immunohistochemistry. J Clin Oncol 30(7):729–734PubMedCrossRef
73.
Sheffield BS, Kos Z, Asleh-Aburaya K, Wang XQ, Leung S, Gao D et al (2016) Molecular subtype profiling of invasive breast cancers weakly positive for estrogen receptor. Breast Cancer Res Treat 155(3):483–490PubMedCrossRef
74.
Liedtke C, Rody A (2015) New treatment strategies for patients with triple-negative breast cancer. Curr Opin Obstet Gynecol 27(1):77–84PubMedCrossRef
Metadata
Title
Outcome for triple negative breast cancer in a retrospective cohort with an emphasis on response to platinum-based neoadjuvant therapy
Authors
Elaine M. Walsh
Aliaa Shalaby
Mark O’Loughlin
Nessa Keane
Mark J Webber
Michael J. Kerin
Maccon M. Keane
Sharon A. Glynn
Grace M. Callagy
Publication date
01-02-2019
Publisher
Springer US
Published in
Breast Cancer Research and Treatment / Issue 1/2019
Print ISSN: 0167-6806
Electronic ISSN: 1573-7217
DOI
https://doi.org/10.1007/s10549-018-5066-6

Other articles of this Issue 1/2019

Breast Cancer Research and Treatment 1/2019 Go to the issue

Review

Anthracycline and taxane-based chemotherapy versus docetaxel and cyclophosphamide in the adjuvant treatment of HER2-negative breast cancer patients: a systematic review and meta-analysis of randomized controlled trials

Epidemiology

A nationwide study of breast cancer, depression, and multimorbidity among hospitalized women and men in the United States

Preclinical study

Identification, clinical-pathological characteristics and treatment outcomes of patients with metastatic breast cancer and somatic human epidermal growth factor receptor 2 (ERBB2) mutations

Clinical Trial

A real-world study of cardiac events in > 3700 patients with HER2-positive early breast cancer treated with trastuzumab: final analysis of the OHERA study

Preclinical study

Glutamate dehydrogenase (GLUD1) expression in breast cancer

Epidemiology

Time-varying risks of second events following a DCIS diagnosis in the population-based Vermont DCIS cohort
Webinar | 19-02-2024 | 17:30 (CET)

Keynote webinar | Spotlight on antibody–drug conjugates in cancer

Watch now

Antibody–drug conjugates (ADCs) are novel agents that have shown promise across multiple tumor types. Explore the current landscape of ADCs in breast and lung cancer with our experts, and gain insights into the mechanism of action, key clinical trials data, existing challenges, and future directions.

Dr. Véronique Diéras
Prof. Fabrice Barlesi
Developed by: Springer Medicine
Image Credits