Clinical Usefulness of the Histoculture Drug Response Assay for Breast Cancer

  • Robert M. Hoffman
  • Hirokazu Tanino
Part of the Methods in Molecular Biology book series (MIMB, volume 1760)


The histoculture drug response assay (HDRA) was used to compare drug sensitivity of recurrent and primary breast cancer in vitro as well as in the clinic. The HDRA utilizes 3-dimensional culture of human tumors on Gelfoam®. The evaluation rate was 98.8%. The HDRA mean inhibition rate of primary tumors vs. recurrent tumors was, respectively, 57.9% and 38.6% for doxorubicin (DOX); 59.9% and 42.8% for mitomycin C (MMC); 49.0% and 33.4% for 5-fluorouracil (5-FU); and 34.5% and 16.0% for cisplatinum (CDDP). The recurrent cases were pretreated clinically with CAF (cyclophosphamide [CTX], DOX, and 5-FU), CEF (CTX, epirubicin [EPN], and 5-FU), or CMF (CTX, methotrexate [MTX], and 5-FU). 64.7% of the recurrent cases were resistant to all four agents tested compared to 27% of the primary cases. Only 5.9% of the recurrent cases were sensitive to three or more agents as opposed to 18% of the primary cases. The correlation of the HDRA results to clinical outcome in another breast-cancer study was 80.0% with 15 cases evaluated consisting of five true positives, three false positives, seven true negatives, and no false negatives. HDRA was also performed on surgical specimens of primary tumor and axillary lymph node metastasis from each of 30 breast cancer patients. The lymph-node metastases were more resistant than the primary tumor for DOX, 5-FU, and MMC, but not for CDDP. The data suggest that both primary tumor and metastases from individual patients should be tested in the HDRA to enhance clinical efficacy of chemotherapy. There also was a lack of correlation with breast cancer subtype and drug response in the HDRA, further suggesting the importance of individualized treatment for breast cancer patients afforded by the HDRA.

Key words

Gelfoam® histoculture, Metastasis HDRA Breast cancer, Primary tumor 


  1. 1.
    Sorlie Τ, Perou CM, Tibshirani R, Aas T, Geisler S, Johnsen H, Hastie T, Eisen MB, Van de Rijin M, Jeffrey SS, Thorsen T, Quist H, Matese JC, Brown PO, Botstein D, Lonning PE, Borresen-Dale AL (2001) Gene expression pattern of breast carcinomas distinguish tumor subclasses with clinical implications. Proc Natl Acad Sci U S A 98:10869–10874 Google Scholar
  2. 2.
    Robson M, Im SA, Senkus E, Xu B, Domchek SM, Masuda N, Delaloge S, Li W, Tung N, Armstrong A, Wu W, Goessl C, Runswick S, Conte P (2017) Olaparib for metastatic breast cancer in patients with a germline BRCA mutation. N Engl J Med 377:523–533Google Scholar
  3. 3.
    Hoffman, R.M. Histocultures and their use. In: Encyclopedia of Life Sciences. John Wiley and Sons, Ltd.: Chichester, 2010, Published Online. DOI: 10.1002/9780470015902.a0002573.pub2Google Scholar
  4. 4.
    Furukawa T, Kubota T, Tanino H, Oura S, Yuasa S, Murate H, Morita K, Kozakai K, Yano T, Hoffman RM (2000) Chemosensitivity of breast cancer lymph node metastasis compared to the primary tumor from individual patients tested in the histoculture drug response assay. Anticancer Res 20:3657–3658 Google Scholar
  5. 5.
    Tanino H, Oura S, Hoffman RM, Kubota T, Furukawa T, Arimoto J, Yoshimasu T, Hirai I, Bessho T, Suzuma T, Sakurai T, Naito Y (2001) Acquisition of multidrug resistance in recurrent breast cancer demonstrated by the histoculture drug response assay. Anticancer Res 21:4083–4086 Google Scholar
  6. 6.
    Kim JB, Stein R, O’ Hare MJ (2004) Three-dimensional in vitro tissue culture models of breast cancer- a review. Breast Cancer Res Treat 85:281–291CrossRefPubMedGoogle Scholar
  7. 7.
    Hoffman RM (1993) In vitro assays for chemotherapy sensitivity. Crit Rev Oncol Hematol 15:99–111CrossRefPubMedGoogle Scholar
  8. 8.
    Kim KY, Chung BW, Yang I, Kim MB, Hoffman RM (2014) Independence of cytotoxic drug sensitivity profiles and receptor subtype of invasive ductal breast carcinoma demonstrated by the histoculture drug response assay (HDRA). Anticancer Res 34:7197–7201PubMedGoogle Scholar
  9. 9.
    Shinden Y, Kijima Y, Hirata M, Arima H, Nakajyo A, Tanoue K, Maemura K, Natsugoe S (2016) Clinical significance of the histoculture drug response assay in breast cancer. Anticancer Res 36:6173–6178CrossRefPubMedGoogle Scholar
  10. 10.
    Nakada S, Aoki D, Ohie S, Horiuchi M, Suzuki N, Kanasugi M, Susumu N, Udagawa Y, Nozawa S (2005) Chemosensitivity testing of ovarian cancer using the histoculture drug response assay: sensitivity to cisplatin and clinical response. Int J Gynecol Cancer 15:445–452CrossRefPubMedGoogle Scholar
  11. 11.
    Jung PS, Kim DY, Kim MB, Lee SW, Kim JH, Kim YM, Kim YT, Hoffman RM, Nam JH (2013) Progression-free survival is accurately predicted in patients treated with chemotherapy for epithelial ovarian cancer by the histoculture drug response assay in a prospective correlative clinical trial at a single institution. Anticancer Res 33:1029–1034PubMedGoogle Scholar
  12. 12.
    Bhatia S, Frangioni JV, Hoffman RM, Iafrate AJ, Polyak K (2012) The challenges posed by cancer heterogeneity. Nat Biotechnol 30:604–610Google Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  1. 1.AntiCancer Inc.San DiegoUSA
  2. 2.Department of SurgeryUniversity of CaliforniaSan DiegoUSA
  3. 3.Department of Breast SurgeryKobe University HospitalKobeJapan

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