Heterogeneity in primary tumors and corresponding metastases: could it provide us with any hints to personalize cancer therapy?

Papers of special note have been highlighted as: ▪ of interest ▪▪ of considerable interest

Bibliography

• 1  Vogel CL, Cobleigh MA, Tripathy D et al.: Efficacy and safety of trastuzumab as a single agent in first-line treatment of HER2-overexpressing metastatic breast cancer. J. Clin. Oncol.20,719–726 (2002).
  Medline CASGoogle Scholar
• 2  Bell DW, Lynch TJ, Haserlat SM et al.: Epidermal growth factor receptor mutations and gene amplification in non-small-cell lung cancer: molecular analysis of the IDEAL/INTACT gefitinib trials. J. Clin. Oncol.23,8081–8092 (2005).
  Medline CASGoogle Scholar
• 3  Eberhard DA, Johnson BE, Amler LC et al.: Mutations in the epidermal growth factor receptor and in KRAS are predictive and prognostic indicators in patients with non-small-cell lung cancer treated with chemotherapy alone and in combination with erlotinib. J. Clin. Oncol.23,5900–5909 (2005).
  Medline CASGoogle Scholar
• 4  Bokemeyer C, Bondarenko I, Hartmann JT et al.: KRAS status and efficacy of first-line treatment of patients with metastatic colorectal cancer (mCRC) with FOLFOX with or without cetuximab: the OPUS experience. J. Clin. Oncol.26 (2008) (Abstract 4000).
  MedlineGoogle Scholar
• 5  De Roock W, Piessevaux H, De Schutter J et al.: KRAS wild-type state predicts survival and is associated to early radiological response in metastatic colorectal cancer treated with cetuximab. Ann. Oncol.19,508–515 (2008).
  Medline CASGoogle Scholar
• 6  Arnerlöv C, Emdin SO, Cajander S et al.: Intratumoral variations in DNA ploidy and S-phase fraction in human breast cancer. Anal. Cell Pathol.23,21–28 (2001).
  Medline CASGoogle Scholar
• 7  Glöckner S, Buurman H, Kleeberger W et al.: Marked intratumoral heterogeneity of c-myc and cyclinD1 but not of c-erbB2 amplification in breast cancer. Lab. Invest.82,1419–1426 (2002).
  MedlineGoogle Scholar
• 8  Benetkiewicz M, Piotrowski A, Díaz De Ståhl T et al.: Chromosome 22 array-CGH profiling of breast cancer delimited minimal common regions of genomic imbalances and revealed frequent intra-tumoral genetic heterogeneity. Int. J. Oncol.29,935–945 (2006).
  Medline CASGoogle Scholar
• 9  Hanna W, Nofech-Mozes S, Kahn HJ: Intratumoral heterogeneity of HER2/neu in breast cancer – a rare event. Breast J.13,122–129 (2007).
  Medline CASGoogle Scholar
• 10  Brunelli M, Manfrin E, Martignoni G et al.: Genotypic intratumoral heterogeneity in breast carcinoma with HER2/neu amplification: evaluation according to ASCO/CAP criteria. Am. J. Clin. Pathol.131,678–682 (2009).
  MedlineGoogle Scholar
• 11  Barry WT, Kernagis DN, Dressman HK et al.: Intratumor heterogeneity and precision of microarray-based predictors of breast cancer biology and clinical outcome. J. Clin. Oncol.28,2198–2206 (2010).
  MedlineGoogle Scholar
• 12  Chen C, Peng J, Xia H et al.: Quantum-dot-based immunofluorescent imaging of HER2 and ER provides new insights into breast cancer heterogeneity. Nanotechnology21,095101 (2010).
  MedlineGoogle Scholar
• 13  Cottu PH, Asselah J, Lae M et al.: Intratumoral heterogeneity of HER2/neu expression and its consequences for the management of advanced breast cancer. Ann. Oncol.19,595–597 (2008).
  Medline CASGoogle Scholar
• 14  Lyng MB, Laenkholm AV, Pallisgaard N et al.: Intratumor genetic heterogeneity of breast carcinomas as determined by fine needle aspiration and TaqMan low density array. Cell Oncol.29,361–372 (2007).
  Medline CASGoogle Scholar
• 15  Sayagués JM, Abad Mdel M, Melchor HB et al.: Intratumoural cytogenetic heterogeneity of sporadic colorectal carcinomas suggests several pathways to liver metastasis. J. Pathol.221,308–319 (2010).
  MedlineGoogle Scholar
• 16  Losi L, Baisse B, Bouzourene H et al.: Evolution of intratumoral genetic heterogeneity during colorectal cancer progression. Carcinogenesis26,916–922 (2005).
  Medline CASGoogle Scholar
• 17  Shen L, Toyota M, Kondo Y et al.: Integrated genetic and epigenetic analysis identifies three different subclasses of colon cancer. Proc. Natl Acad. Sci. USA104,18654–18659 (2007).
  Medline CASGoogle Scholar
• 18  Bartos JD, Stoler DL, Matsui S et al.: Genomic heterogeneity and instability in colorectal cancer: spectral karyotyping, glutathione transferase-Ml and ras. Mutat. Res.568,283–292 (2004).
  Medline CASGoogle Scholar
• 19  Half E, Broaddus R, Danenberg KD et al.: HER-2 receptor expression, localization, and activation in colorectal cancer cell lines and human tumors. Int. J. Cancer108,540–548 (2004).
  Medline CASGoogle Scholar
• 20  Garcia JM, Rodriguez R, Silva J et al.: Intratumoral heterogeneity in microsatellite alterations in BRCA1 and PTEN regions in sporadic colorectal cancer. Ann. Surg. Oncol.10,876–881 (2003).
  MedlineGoogle Scholar
• 21  Beau-Faller M, Weber JC, Schneider A et al.: Genetic heterogeneity in lung and colorectal carcinoma as revealed by microsatellite analysis in plasma or tumor tissue DNA. Cancer97,2308–2317 (2003).
  Medline CASGoogle Scholar
• 22  Whitehall VL, Wynter CV, Walsh MD et al.: Morphological and molecular heterogeneity within nonmicrosatellite instability-high colorectal cancer. Cancer Res.62,6011–6014 (2002).
  Medline CASGoogle Scholar
• 23  Lassmann S, Bauer M, Soong R et al.: Quantification of CK20 gene and protein expression in colorectal cancer by RT-PCR and immunohistochemistry reveals inter- and intratumour heterogeneity. J. Pathol.198,198–206 (2002).
  MedlineGoogle Scholar
• 24  Maekawa M, Sugano K, Ushiama M et al.: Heterogeneity of DNA methylation status analyzed by bisulfite-PCR-SSCP and correlation with clinico-pathological characteristics in colorectal cancer. Clin. Chem. Lab. Med.39,121–128 (2001).
  Medline CASGoogle Scholar
• 25  Kuwai T, Nakamura T, Kim SJ et al.: Intratumoral heterogeneity for expression of tyrosine kinase growth factor receptors in human colon cancer surgical specimens and orthotopic tumors. Am. J. Pathol.172,358–366 (2008).
  MedlineGoogle Scholar
• 26  Blackhall FH, Pintilie M, Wigle DA et al.: Stability and heterogeneity of expression profiles in lung cancer specimens harvested following surgical resection. Neoplasia6,761–767 (2004).
  MedlineGoogle Scholar
• 27  Gomez de la Cámara A, López-Encuentra A, Ferrando P et al.: Heterogeneity of prognostic profiles in non-small cell lung cancer: too many variables but a few relevant. Eur. J. Epidemiol.20,907–914 (2005).
  MedlineGoogle Scholar
• 28  Perner S, Demichelis F, Beroukhim R et al.: TMPRSS2:ERG fusion-associated deletions provide insight into the heterogeneity of prostate cancer. Cancer Res.66,8337–8341 (2006).
  Medline CASGoogle Scholar
• 29  Krause FS, Feil G, Bichler KH et al.: Heterogeneity in prostate cancer: prostate specific antigen (PSA) and DNA cytophotometry. Anticancer Res.25,1783–1785 (2005).
  MedlineGoogle Scholar
• 30  Chau CH, Figg WD: Molecular and phenotypic heterogeneity of metastatic prostate cancer. Cancer Biol. Ther.4,166–167 (2005).
  Medline CASGoogle Scholar
• 31  Walsh PC: Heterogeneity of genetic alterations in prostate cancer: evidence of the complex nature of the disease. J. Urol.168,1635–1636 (2002).
  Google Scholar
• 32  Nwosu V, Carpten J, Trent JM et al.: Heterogeneity of genetic alterations in prostate cancer: evidence of the complex nature of the disease. Hum. Mol. Genet.10,2313–2318 (2001).
  Medline CASGoogle Scholar
• 33  Cooke SL, Ng CK, Melnyk N et al.: Genomic analysis of genetic heterogeneity and evolution in high-grade serous ovarian carcinoma. Oncogene29,4905–4913 (2010).
  Medline CASGoogle Scholar
• 34  Gershenson DM: The heterogeneity of epithelial ovarian cancer: getting it right. Cancer116,1400–1402 (2010).
  MedlineGoogle Scholar
• 35  Bast RC Jr, Hennessy B, Mills GB: The biology of ovarian cancer: new opportunities for translation. Nat. Rev. Cancer9,415–428 (2009).
  Medline CASGoogle Scholar
• 36  McAlpine JN, Eisenkop SM, Spirtos NM: Tumor heterogeneity in ovarian cancer as demonstrated by in vitro chemoresistance assays. Gynecol. Oncol.110,360–364 (2008).
  Medline CASGoogle Scholar
• 37  Woloszynska-Read A, Mhawech-Fauceglia P, Yu J et al.: Intertumor and intratumor NY-ESO-1 expression heterogeneity is associated with promoter-specific and global DNA methylation status in ovarian cancer. Clin. Cancer Res.14,3283–3290 (2008).
  Medline CASGoogle Scholar
• 38  Jochumsen KM, Tan Q, Hølund B et al.: Gene expression in epithelial ovarian cancer: a study of intratumor heterogeneity. Int. J. Gynecol. Cancer17,979–985 (2007).
  Medline CASGoogle Scholar
• 39  Khalique L, Ayhan A, Weale ME et al.: Genetic intra-tumour heterogeneity in epithelial ovarian cancer and its implications for molecular diagnosis of tumours. J. Pathol.211,286–295 (2007).
  Medline CASGoogle Scholar
• 40  Pieretti M, Hopenhayn-Rich C, Khattar NH et al.: Heterogeneity of ovarian cancer: relationships among histological group, stage of disease, tumor markers, patient characteristics, and survival. Cancer Invest.20,11–23 (2002).
  MedlineGoogle Scholar
• 41  Manahan KJ, Taylor DD, Gerçel-Taylor C: Clonal heterogeneity of p53 mutations in ovarian cancer. Int. J. Oncol.19,387–394 (2001).
  Medline CASGoogle Scholar
• 42  Nakamura T, Kuwai T, Kitadai Y et al.: Zonal heterogeneity for gene expression in human pancreatic carcinoma. Cancer Res.67,7597–7604 (2007).
  Medline CASGoogle Scholar
• 43  Harada T, Okita K, Shiraishi K et al.: Interglandular cytogenetic heterogeneity detected by comparative genomic hybridization in pancreatic cancer. Cancer Res.62,835–839 (2002).
  Medline CASGoogle Scholar
• 44  Osterheld MC, Caron L, Demierre M et al.: DNA-ploidy in advanced gastric carcinoma is less heterogeneous than in early gastric cancer. Cell Oncol.26,21–29 (2004).
  Medline CASGoogle Scholar
• 45  Awata H, Hirose K, Yamaguchi A: Heterogeneity of apoptosis and proliferative activity within superficial spreading type early gastric cancer. Oncol. Rep.9,153–158 (2002).
  MedlineGoogle Scholar
• 46  Saito A, Shimoda T, Nakanishi Y et al.: Histologic heterogeneity and mucin phenotypic expression in early gastric cancer. Pathol. Int.51,165–171 (2001).
  Medline CASGoogle Scholar
• 47  Kobayashi K, Kitayama Y, Igarashi H et al.: Intratumor heterogeneity of centromere numerical abnormality in multiple primary gastric cancers: application of fluorescence in situ hybridization with intermittent microwave irradiation on paraffin-embedded tissue. Jpn. J. Cancer Res.91,1134–1341 (2000).
  Medline CASGoogle Scholar
• 48  Donahue MJ, Blakeley JO, Zhou J et al.: Evaluation of human brain tumor heterogeneity using multiple T1-based MRI signal weighting approaches. Magn. Reson. Med.59,336–344 (2008).
  MedlineGoogle Scholar
• 49  Ren ZP, Olofsson T, Qu M et al.: Molecular genetic analysis of p53 intratumoral heterogeneity in human astrocytic brain tumors. J. Neuropathol. Exp. Neurol.66,944–954 (2007).
  Medline CASGoogle Scholar
• 50  Wyss MT, Hofer S, Hefti M et al.: Spatial heterogeneity of low-grade gliomas at the capillary level: a PET study on tumor blood flow and amino acid uptake. J. Nucl. Med.48,1047–1052 (2007).
  Medline CASGoogle Scholar
• 51  Pauliah M, Saxena V, Haris M et al.: Improved T(1)-weighted dynamic contrast-enhanced MRI to probe microvascularity and heterogeneity of human glioma. Magn. Reson. Imaging25,1292–1299 (2007).
  MedlineGoogle Scholar
• 52  Andersson U, Malmer B, Bergenheim AT et al.: Heterogeneity in the expression of markers for drug resistance in brain tumors. Clin. Neuropathol.23,21–27 (2004).
  Medline CASGoogle Scholar
• 53  Walker C, du Plessis DG, Joyce KA et al.: Phenotype versus genotype in gliomas displaying inter- or intratumoral histological heterogeneity. Clin. Cancer Res.9,4841–4851 (2003).
  Medline CASGoogle Scholar
• 54  Staller P: Genetic heterogeneity and chromatin modifiers in renal clear cell carcinoma. Future Oncol.6,897–900 (2010).▪ Demonstrated the prevalence of discrepant results of HER2 status between the primary breast cancer and the distant metastases.
  CASGoogle Scholar
• 55  Gong Y, Booser DJ, Sneige N: Comparison of HER-2 status determined by fluorescence in situ hybridization in primary and metastatic breast carcinoma. Cancer103,1763–1769 (2005).
  Medline CASGoogle Scholar
• 56  Gancberg D, Di Leo A, Cardoso F et al.: Comparison of HER-2 status between primary breast cancer and corresponding distant metastatic sites. Ann. Oncol.13,1036–1043 (2002).
  Medline CASGoogle Scholar
• 57  Regitnig P, Schippinger W, Lindbauer M et al.: Change of HER-2/neu status in a subset of distant metastases from breast carcinomas. J. Pathol.203,918–926 (2004).
  Medline CASGoogle Scholar
• 58  Bozzetti C, Personeni N, Nizzoli R et al.: HER-2/neu amplification by fluorescence in situ hybridization in cytologic samples from distant metastatic sites of breast carcinoma. Cancer99,310–315 (2003).
  Medline CASGoogle Scholar
• 59  Tanner M, Järvinen P, Isola J: Amplification of HER-2/neu and topoisomerase IIα in primary and metastatic breast cancer. Cancer Res.61,5345–5348 (2001).
  Medline CASGoogle Scholar
• 60  Tapia C, Savic S, Wagner U et al.: HER2 gene status in primary breast cancers and matched distant metastases. Breast Cancer Res.9,R31 (2007).▪ Demonstrated the poor concordance between immunohistochemistry findings of pAkt and p4E-BP1 expression in primary breast cancer and metastases.
  MedlineGoogle Scholar
• 61  Akcakanat A, Sahin A, Shaye AN et al.: Comparison of Akt/mTOR signaling in primary breast tumors and matched distant metastases. Cancer112,2352–2358 (2008).▪ Comprehensive comparison of biomarker expression between patients’ primary breast carcinoma and their metastatic breast carcinomas.
  Medline CASGoogle Scholar
• 62  Wu JM, Fackler MJ, Halushka MK et al.: Heterogeneity of breast cancer metastases: comparison of therapeutic target expression and promoter methylation between primary tumors and their multifocal metastases. Clin. Cancer Res.14,1938–1946 (2008).▪ Demonstrated the heterogeneity of EGFR gene status and its downstream signaling proteins between primary colorectal cancer and its corresponding metastases.
  Medline CASGoogle Scholar
• 63  Baldus SE, Schaefer KL, Engers R et al.: Prevalence and heterogeneity of KRAS, BRAF, and PIK3CA mutations in primary colorectal adenocarcinomas and their corresponding metastases. Clin. Cancer Res.16,790–799 (2010).
  Medline CASGoogle Scholar
• 64  Molinari F, Martin V, Saletti P et al.: Differing deregulation of EGFR and downstream proteins in primary colorectal cancer and related metastatic sites may be clinically relevant. Br. J. Cancer100,1087–1094 (2009).
  Medline CASGoogle Scholar
• 65  Scartozzi M, Bearzi I, Berardi R et al.: Epidermal growth factor receptor (EGFR) status in primary colorectal tumors does not correlate with EGFR expression in related metastatic sites: implications for treatment with EGFR-targeted monoclonal antibodies. J. Clin. Oncol.22,4772–4778 (2004).
  Medline CASGoogle Scholar
• 66  Scartozzi M, Bearzi I, Berardi R et al.: Epidermal growth factor receptor (EGFR) downstream signalling pathway in primary colorectal tumours and related metastatic sites: optimising EGFR-targeted treatment options. Br. J. Cancer97,92–97 (2007).▪ Demonstrated genetic heterogeneity between primary non-small-cell lung cancer and lymph node metastases.
  Medline CASGoogle Scholar
• 67  Sasatomi E, Finkelstein SD, Woods JD et al.: Comparison of accumulated allele loss between primary tumor and lymph node metastasis in stage II non-small cell lung carcinoma: implications for the timing of lymph node metastasis and prognostic value. Cancer Res.62,2681–2689 (2002).
  Medline CASGoogle Scholar
• 68  Park S, Holmes-Tisch AJ, Cho EY et al.: Discordance of molecular biomarkers associated with epidermal growth factor receptor pathway between primary tumors and lymph node metastasis in non-small cell lung cancer. J. Thorac. Oncol.4,809–815 (2009).
  MedlineGoogle Scholar
• 69  Monaco SE, Nikiforova MN, Cieply K et al.: A comparison of EGFR and KRAS status in primary lung carcinoma and matched metastases. Hum. Pathol.41,94–102 (2010).▪▪ Retrospective study which investigated the role of PTEN loss, AKT phosphorylation and KRAS mutations in primary colorectal tumors and their corresponding metastases on the activity of cetuximab plus irinotecan.
  Medline CASGoogle Scholar
• 70  Loupakis F, Pollina L, Stasi I et al.: PTEN expression and KRAS mutations on primary tumors and metastases in the prediction of benefit from cetuximab plus irinotecan for patients with metastatic colorectal cancer. J. Clin. Oncol.27,2622–2629 (2009).
  Medline CASGoogle Scholar
• 71  Zeimet AG, Marth C: Why did p53 gene therapy fail in ovarian cancer? Lancet Oncol.4,415–422 (2003).
  Medline CASGoogle Scholar
• 72  Germano IM, Binello E: Gene therapy as an adjuvant treatment for malignant gliomas: from bench to bedside. J. Neurooncol.93,79–87 (2009).
  Medline CASGoogle Scholar
• 73  Jin K, He K, Li G et al.: Personalized cancer therapy using a patient-derived tumor tissue xenograft model: a translational field worthy of exploring further? Pers. Med.7,597–606 (2010).
  Google Scholar
• 74  Dong X, Guan J, English JC et al.: Patient-derived first generation xenografts of non-small cell lung cancers: promising tools for predicting drug responses for personalized chemotherapy. Clin. Cancer Res.16,1442–1451 (2010).
  Medline CASGoogle Scholar