Affiliations of authors: M. A. Henderson, T. L. Harris, M. R. McKinlay, University of Melbourne, Department of Surgery, St. Vincent's Hospital, Fitzroy, Australia; J. A. Danks, J. M. Moseley, T. J. Martin (St. Vincent's Institute of Medical Research), J. L. Slavin (Department of Pathology), St. Vincent's Hospital; J. L. Hopper, Department of General Practice and Public Health, University of Melbourne.
Correspondence to: Michael A. Henderson, M.D., FRACS, Department of Surgery, St. Vincent's Hospital, 41 Victoria Parade, Fitzroy 3065, Victoria, Australia (e-mail: henderson{at}surgerysvh.unimelb.edu.au).
Metastasis of breast cancers is a common and serious clinical problem, with up to one third of women with early-stage breast cancer eventually dying of the disease. Of all patients with distant spread of the cancer, 70% have bone metastases (1,2), reflective of the observations of Paget (3) that breast cancers had a particular predilection to grow in bone. A special property required of cancer cells for growth as metastases in bone is the ability to promote bone resorption by inducing the formation and activity of osteoclasts (4). Parathyroid hormone-related protein (PTHrP) is produced by two thirds of primary breast cancers (5), promotes osteoclast formation and bone resorption, and has been implicated in site-specific metastasis of breast cancer to bone (6). The current study investigated the relationship among detection of PTHrP in primary breast cancers, development of skeletal complications, and overall survival.
From December 1, 1989, through December 31, 1994, a total of 402 consecutively accrued women with operable (stages 13) invasive primary breast cancer were followed prospectively for a median period of 67 months (range, 3120 months). Impalpable tumors detected by screening mammography accounted for 5% of the cancers. Patients with previous malignancy or preoperative therapy before open biopsy were excluded (35 patients). The timing and site of metastases and overall survival were recorded, as were routine prognostic factors. Patients were examined at least twice a year for 3 years and then annually. The study was approved by the Human Research Ethics Committee of St. Vincent's Hospital (Fitzroy, Australia), and patients provided informed consent according to institutional guidelines.
There were 367 eligible patients, and the median age at diagnosis was 60 years (range, 2792 years). The majority of these patients were postmenopausal (70%), the median tumor size was 26 mm (range, 4180 mm), and most patients were axillary lymph node negative (60%) (Table 1). PTHrP was detected by immunohistochemistry in 265 (72%) of the primary breast tumors and was associated with estrogen receptor (ER) status (odds ratio [OR] = 2.4; 95% confidence interval [CI] = 1.4 to 4.0; P<.001), progesterone receptor (PR) status (OR = 1.9; 95% CI = 1.1 to 3.2; P = .01), and presence of tumor calcification (OR = 1.6; 95% CI = 1.0 to 2.6; P = .05) but not with menopausal status, tumor size, lymph node status, tumor grade, or the presence of lymphatic/vascular invasion by tumor (7). The crude 5-year cancer-specific survival for all patients was 82% (95% CI = 78% to 86%). Prognostic factors associated with survival included American Joint Committee on Cancer stage, tumor size, lymph node status, ER status, PR status, presence of tumor calcification, absence of tumor lymphatic/vascular invasion, and tumor grade but not menopausal status. Patients with tumors containing detectable PTHrP had improved survival compared with patients with PTHrP-negative tumors (Fig. 1
, A) (8,9). The crude 5-year cancer-specific survivals were 87% (95% CI = 82% to 91%) for patients with PTHrP-positive tumors and 73% (95% CI = 63% to 81%) for those with PTHrP-negative tumors (P = .002). Cox proportional hazards modeling (10) demonstrated that positive PTHrP status was independently associated with improved survival (P = .003), as were the number of axillary lymph nodes involved (P<.001), tumor size (P<.001), and tumor grade (P = .007). After adjustment for these independently predictive prognostic factors, the hazard rate for death from breast cancer in women with a PTHrP-positive tumor was 45% (95% CI = 26% to 80%) of that in women with a PTHrP-negative tumor (P = .003) (10). All statistical tests were two-sided.
|
|
This study was carried out over a 10-year period as a prospective investigation of consecutively accrued patients. Consistent with previous reports (5,1115), approximately two thirds of primary breast tumors contained detectable PTHrP. The new finding is that PTHrP localization in female breast tumors is an independent predictor of improved survival and reduced risk of metastases, whether or not adjustment is made for the recognized prognostic factorsaxillary lymph node status, tumor size, tumor grade, and ER and PR status. These observations are contrary to our original hypothesis and indicate that PTHrP-negative cancers are associated with more metastases and less favorable survival. Thus, we conclude that PTHrP production is associated with a less invasive phenotype. A direct causal link remains to be established. Because these results were obtained before the introduction of screening mammography, the importance of PTHrP in very early breast cancer needs to be and is currently being addressed.
When the study began, we hypothesized that patients with PTHrP-positive breast cancers would be more likely to develop bone metastases. In the intervening time, experimental support has been obtained for a local role of PTHrP in bone metastasis formation (16). More frequent and larger bone metastases were found in a nude mouse model of bone metastasis when human breast cancer cells expressing PTHrP were used (1618). Concurrent treatment with bisphosphonates, which are powerful inhibitors of bone resorption, or with neutralizing antibody against PTHrP reduced both the size and the number of metastases in this model (16,17).
The present findings, however, do not exclude a central role for PTHrP in the bone metastasis process. Specific properties of the "soil," or bone microenvironment, for successful establishment of metastases and regulation of PTHrP production have been described. The role of the bone microenvironment is emphasized by studies in the nude mouse model, in which transforming growth factor- a powerful stimulator of PTHrP production (18,19) released during tumor invasion, increases local PTHrP production by breast cancer cells, thereby promoting bone resorption and facilitating tumor growth.
We conclude that women with PTHrP-positive primary breast cancers have a more favorable outcome and have fewer metastases to bone and other sites. The nature of autocrine actions of PTHrP in primary breast tumors that contribute to this favorable outcome would be of considerable interest, and attention should now be focused on how PTHrP contributes to this protective effect against invasion and metastasis. The greater frequency of bone metastases in patients with PTHrP-negative primary breast cancers remains consistent with a local role for PTHrP in the development of bone metastases because the bone microenvironment has the potential to promote tumor cell production of PTHrP.
NOTES
Supported by the National Health and Medical Research Council of Australia, by the Anti-Cancer Council of Victoria, and by the Thomaïy Breast Cancer Research Foundation.
Presented in part at the 21st Annual Meeting of the American Society for Bone and Mineral Research, St. Louis (MO), in September 1999 and at the 90th Annual Meeting of the American Association for Cancer Research, Philadelphia (PA), in March 1999.
REFERENCES
1 Coleman RE, Rubens RD. The clinical course of bone metastases from breast cancer. Br J Cancer 1987;55:616.[Medline]
2 Aaron AD, Jennings LC, Springfield DS. Local treatment of bone metastases. In: Harris JR, Lippman M, Morrow, ME, Hellman S, editors. Diseases of the breast. Philadelphia (PA): Lippincott-Raven; 1996. p. 8118.
3 Paget S. The distribution of secondary growths in cancer of the breast. Lancet 1889;1:5713.
4 Mundy GR. Mechanisms of bone metastasis. Cancer 1997;80:154656.[Medline]
5 Southby J, Kissin MW, Danks JA, Hayman JA, Moseley JM, Henderson MA, et al. Immunohistochemical localization of parathyroid hormone-related protein in human breast cancer. Cancer Res 1990;50:77106.[Abstract]
6 Powell GJ, Southby J, Danks JA, Stillwell RG, Hayman JA, Henderson MA, et al. Localization of parathyroid hormone-related protein in breast cancer metastases: increased incidence in bone compared with other sites. Cancer Res 1991;51:305961.[Abstract]
7 Mehta CR. The exact analysis of contingency tables in medical research. Cancer Treat Res 1995;75:177202.[Medline]
8 Kaplan EL, Meier P. Nonparametric estimation from incomplete observations. J Am Stat Assoc 1958;53:45781.
9 Mantel N. Evaluation of survival data and two new rank order statistics arising in its consideration. Cancer Chemother Rep 1966;50:16370.[Medline]
10 Cox DR. Regression models and life tables. J R Stat Soc 1972:34:187220.
11 Bundred NJ, Walker RA, Ratcliffe WA, Warwick J, Morrison JM, Ratcliffe JG. Parathyroid hormone-related protein and skeletal morbidity in breast cancer. Eur J Cancer 1992;28:6902.[Medline]
12 Bundred NJ, Walls J, Radcliffe WA. Parathyroid hormone-related protein, bone metastases and hypercalcaemia of malignancy. Ann R Coll Surg Engl 1996;78:3548.[Medline]
13 Liapis H, Crouch EC, Grosso LE, Kitazawa S, Wick MR. Expression of parathyroid-like protein in normal, proliferating, and neoplastic human breast tissues. Am J Pathol 1993;143:116978.[Abstract]
14 Bouizar Z, Spyratos F, Deytieux S, de Vernejoul MC, Jullienne A. Polymerase chain reaction analysis of parathyroid hormone-related protein gene expression in breast cancer patients and occurrence of bone metastases. Cancer Res 1993;53:50768.[Abstract]
15 Kissin MW, Henderson MA, Danks JA, Hayman JA, Bennett RC, Martin TJ. Parathyroid hormone related protein in breast cancers of widely varying prognosis. Eur J Surg Oncol 1993;19:13442.[Medline]
16
Guise TA, Yin JJ, Taylor SD, Kumagai Y, Dallas M, Boyce BF, et al. Evidence for a causal role of parathyroid hormone-related protein in the pathogenesis of human breast cancer-mediated osteolysis. J Clin Invest 1996;98:15449.
17 Sasaki A, Boyce BF, Story B, Wright KR, Chapman M, Boyce R, et al. Bisphosphonate risedronate reduces metastatic human breast cancer burden in bone in nude mice. Cancer Res 1995;55:35517.[Abstract]
18
Yin JJ, Selander K, Chirgwin JM, Dallas M, Grubbs BG, Wieser R, et al. TGF- signaling blockade inhibits PTHrP secretion by breast cancer cells and bone metastases development. J Clin Invest 1999;103:197206.
19
Kiriyama T, Gillespie MT, Glatz JA, Fukumoto S, Moseley JM, Martin TJ. Transforming growth factor stimulation of parathyroid hormone-related protein (PTHrP): a paracrine regulator? Mol Cell Endocrinol 1992;92:5562.
20 Sternberger LA, Hardy PH Jr, Cuculis JJ, Meyer HG. The unlabeled antibody enzyme method of immunohistochemistry: preparation and properties of soluble antigenantibody complex (horseradish peroxidase antihorseradish peroxidase) and its use in identification of spirochetes. J Histochem Cytochem 1970;18:31533.[Medline]
21 Danks JA, Ebeling PR, Hayman JA, Chou ST, Moseley JM, Dunlop J, et al. Parathyroid hormone-related protein: immunohistochemical localization in cancers and in normal skin. J Bone Miner Res 1989;4:2738.[Medline]
22 Danks JA, Ebeling PR, Hayman JA, Diefenbach-Jagger H, Collier FM, Grill V, et al. Immunohistochemical localization of parathyroid hormone-related protein in parathyroid adenoma and hyperplasia. J Pathol 1990;161:2733.[Medline]
23 American Joint Commission on Cancer. Breast. In: Beahrs OH, Henson DE, Hutter RV, Kennedy BJ, editors. Manual for staging of cancer. 4th ed. Philadelphia (PA): Lippincott; 1992. p. 14952.
24 Elston CW. Grading of invasive carcinoma of the breast. In: Page D, Anderson T, editors. Diagnostic histopathology of the breast. Edinburgh (Scotland): Churchill-Livingstone; 1987. p. 30011.
Manuscript received July 6, 2000; revised November 24, 2000; accepted November 30, 2000.
This article has been cited by other articles in HighWire Press-hosted journals:
![]() |
||||
|
Oxford University Press Privacy Policy and Legal Statement |