Hot off the press:
Journal of Clinical Oncology, Vol 24, No 9 (March 20), 2006: pp. 1481-1482
© 2006 American Society of Clinical Oncology
DOI: 10.1200/JCO.2005.05.0286
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CORRESPONDENCE
Progesterone Receptor and Human Epidermal Growth Factor Receptor 2 Status: An Independent Influence on the Efficacy of Endocrine Therapy in Breast Cancer?
Riccardo Ponzone, Furio Maggiorotto, Claudio Robba, Luca Fuso, Piero Sismondi
Academic Department of Gynecological Oncology, Institute for Cancer Research and Treatment (IRCC) of Candiolo, University of Turin Medical School, Turin, Italy
To the Editor:
The paper by Dowsett et al1 adds convincing evidence on the relevance of progesterone receptor status in influencing the clinical outcome of early-stage breast cancer patients who undergo hormonal treatment. The authors also hypothesized that the greater benefit of anastrozole over tamoxifen in estrogen receptor–positive (ER+)/progesterone receptor–negative (PgR–) tumors might be explained, at least in part, by a greater expression of type1 growth factor receptors in this group, as recently suggested by others.2 In order to investigate this specific issue, we examined our institutional series of 972 breast cancer patients who received the following adjuvant hormonal treatments: tamoxifen (n = 725), tamoxifen with luteinizing hormone releasing hormone analogs (n = 127), and aromatase inhibitors (n = 120). Immunohistochemistry was used to assess hormone receptor status (staining of > 1% of cells was considered as positive) and HER-2 status (human epidermal growth factor receptor 2; staining of 0% to 5% was coded as 0, 6% to 15% as 1+, 16% to 39% as 2+, and 40% to 100% as 3+).
We found that ER+/PgR– versus ER+/PgR+ tumors were characterized by larger size (diameter 2 cm: 57.1% v 42.6%; P = .003), nodal involvement ( 1 positive node: 51.8% v 45.0%; P = .1), higher tumor grade (grade 2-3: 88.2% v 79.0%; P = .008), higher Ki-67 expression ( 20%: 42.9% v 28.7%; P = .001), and lower ER expression (mean percentage of cell stained: 54.9% v 70.3%; P = .000). ER+/PgR– tumors were also more likely to overexpress HER-2 than ER+/PgR + tumors (2-3+: 36.5% v 17.9%; P = .000; mean percentage of stained cells: 21.5% v 9.2%; P = .000).
At the univariate analysis of survival, lack of PgR expression (hazard ratio [HR], 1.9; 95% CI, 1.0 to 3.6; P = .03) and HER-2 overexpression (HR, 2.2; 95% CI, 1.1 to 4.1; P = .01), as well as nodal status (HR, 2.9; 95% CI, 1.5 to 5.4; P = .001), tumor diameter (HR, 2.7; 95% CI, 1.4 to 4.9; P = .001), and tumor grading (HR, 5.0; 95% CI, 1.1 to 20.9; P = .02) showed a significant association with shorter disease-free survival (DFS), even after controlling for continuous levels of ER expression. In the multivariate Cox model including all variables, lack of PgR expression (HR, 4.0; 95% CI, 1.6 to 10.0; P = .003), tumor diameter (HR, 5.2; 95% CI, 1.1 to 23.1; P = .003), and nodal status (HR, 4.4; 95% CI, 1.2 to 15.3; P = .01), but not HER-2 overexpression (P = .7), retained their prognostic significance. We then conducted a subset analysis to evaluate the prognostic value of HER-2 overexpression in the subgroups of ER+/PgR+ and ER+/PgR– tumors, but we could not find any significant association with DFS even in this subset of patients.
Our study confirms that the lack of PgR expression in ER+ breast cancer is associated with aggressive tumor features and with HER-2 overexpression. Nevertheless, in our series of patients receiving 5 years of tamoxifen as the prevalent adjuvant treatment, only PgR status and not HER-2 status was an independent predictor of the risk of recurrence. Due to the small number of patients treated with anastrozole, we could not ascertain whether PgR and/or HER-2 status provide different information between patients who receive anastrozole versus tamoxifen. Nonetheless, the predictive value of PgR expression in the whole series was stronger and not dependent on HER-2 expression; therefore, we suggest that the difference in the relative efficacy of anastrozole and tamoxifen according to PgR status in the study by Dowsett at al is unlikely due to its segregation with HER-2 status.
Authors' Disclosures of Potential Conflicts of Interest
Although all authors completed the disclosure declaration, the following authors or their immediate family members indicated a financial interest. No conflict exists for drugs or devices used in a study if they are not being evaluated as part of the investigation. For a detailed description of the disclosure categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in
Dollar Amount Codes (A) < $10,000 (B) $10,000-99,999 (C) > $100,000 (N/R) Not Required
REFERENCES
1. Dowsett M, Cuzick J, Wale C, et al: Retrospective analysis of time to recurrence in the ATAC trial according to hormone receptor status: An hypothesis-generating study. J Clin Oncol 23:7512-7517, 2005[Abstract/Free Full*Text]
2. Arpino G, Weiss H, Lee AV, et al: Estrogen receptor–positive, progesterone receptor–negative breast cancer: Association with growth factor receptor expression and tamoxifen resistance. J Natl Cancer Inst 97:1254-1261, 2005[Abstract/Free Full*Text]
Here is the abstract of the first article cited:
Retrospective Analysis of Time to Recurrence in the ATAC Trial According to Hormone Receptor Status: An Hypothesis-Generating Study
Mitch Dowsett, Jack Cuzick, Chris Wale, Tony Howell, Joan Houghton, Michael Baum
From the Royal Marsden Hospital; Cancer Research UK; University College London, London; Christie Hospital, Manchester, UK.
Address reprint requests to Mitch Dowsett, Royal Marsden Hospital London, SW3 6JJ United Kingdom; e-mail:
mitch.dowsett@icr.ac.uk
PURPOSE: Arimidex, tamoxifen alone, or in combination (ATAC) trial of anastrozole (Arimidex) versus tamoxifen or a combination of the two in 9,366 postmenopausal patients with primary breast cancer found a significant improvement in disease-free survival and time to recurrence (TTR) for anastrozole compared with tamoxifen, that was restricted to patients with hormone receptor-positive (ie, estrogen receptor–positive [ER+] and/or progesterone receptor-positive [PgR+]) disease, the target population for these therapies. We retrospectively tested the hypothesis that this benefit might differ according to PgR status.
PATIENTS AND METHODS: TTR was compared between the three treatment groups for subgroups defined by ER and PgR status using Cox's proportional hazards model, with and without adjustment for baseline variables.
RESULTS: The unadjusted hazard ratio (HR) for anastrozole versus tamoxifen for TTR was 0.74 (95% CI, 0.64 to 0.87) for women with either ER+ or PgR+ tumors. In the ER+/PgR+ subgroup (n = 3,834) the HR was 0.84 (95% CI, 0.69 to 1.02) compared with 0.43 (95% CI, 0.31 to 0.61) in the ER+/PgR-negative (PgR–) subgroup (n = 880). In the adjusted model the HRs were 0.83 and 0.45, respectively.
CONCLUSION: Time to recurrence was longer for anastrozole- than tamoxifen-treated patients in both ER+/PgR+ and ER+/PgR– subgroups, but the benefit was substantially greater in the PgR– subgroup. As this was an "exploratory" analysis, this effect should be considered as hypothesis generating and assessed prospectively in other trials comparing the adjuvant use of an aromatase inhibitor with tamoxifen.
Authors' disclosures of potential conflicts of interest are found at the end of this article.
And the second:
Go To: Home > Archive > Vol. 97, No. 17 > Arpino et al., pp. 1254-1261.
Journal of the National Cancer Institute, Vol. 97, No. 17, 1254-1261, September 7, 2005
DOI: 10.1093/jnci/dji249
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© 2005 Oxford University Press
ARTICLE
Estrogen Receptor–Positive, Progesterone Receptor–Negative Breast Cancer: Association With Growth Factor Receptor Expression and Tamoxifen Resistance
Grazia Arpino, Heidi Weiss, Adrian V. Lee, Rachel Schiff, Sabino De Placido, C. Kent Osborne, Richard M. Elledge
Affiliations of authors: Breast Center, Baylor College of Medicine and The Methodist Hospital, Houston, TX (GA, HW, AVL, RS, CKO, RME); Dipartimento di Endocrinologia e Oncologia Molecolare e Clinica, Universita di Napoli Federico II, Naples, Italy (SDP)
Correspondence to: Richard M. Elledge, MD, Breast Care Center, 6550 Fannin St., Ste. 701, Houston, TX 77030 (e-mail:
relledge@breastcenter.tmc.edu).
Background: Clinical data indicate that estrogen receptor–positive/progesterone receptor–negative (ER+/PR–) breast cancers are less sensitive to tamoxifen than are ER+/PR+ tumors. It has also been reported that tamoxifen may be less effective in tumors that overexpress either HER-2 or HER-1 (epidermal growth factor receptor) and that signaling through these receptors reduces PR expression in experimental models. We hypothesized that ER+/PR– breast tumors are more likely than ER+/PR+ breast tumors to have an aggressive phenotype, to express HER-1 and overexpress HER-2, and are less likely to benefit from tamoxifen adjuvant therapy. Methods: Clinical and biological features of 31 415 patients with ER+/PR+ tumors were compared with those of 13 404 patients with ER+/PR– tumors. Association between disease-free survival (DFS) and HER-1 and HER-2 status was analyzed in a subset of 11 399 patients receiving adjuvant tamoxifen therapy. Hazard ratios (HRs) and 95% confidence intervals (CIs) were calculated using Cox regression or Kaplan–Meier analyses, and all statistical tests were two-sided. Results: ER+/PR– tumors were more frequent in older patients, were larger in size, had a higher S-phase fraction, and were more likely to be aneuploid than ER+/PR+ tumors. Furthermore, three times as many ER+/PR– tumors as ER+/PR+ tumors expressed HER-1 (25% versus 8%; P<.001) and 50% more overexpressed HER-2 (21% versus 14%; P<.001). Among all tamoxifen-treated women, recurrence was higher among women with HER-1–expressing tumors than with HER-1–negative tumors (HR = 1.9, 95% CI = 1.0 to 3.5; P = .05); a stronger association between worse DFS and HER-2 overexpression was observed (HR = 2.3, 95% CI = 1.2 to 4.3; P = .006). However, results varied by PR status. Among tamoxifen-treated women with ER+/PR+ tumors, HER-1 or HER-2 status was not associated with worse DFS. Among women with ER+/PR– tumors, however, both HER-1 expression (HR = 2.4, 95% CI = 1.0 to 5.4; P = .036) and HER-2 overexpression (HR = 2.6, 95% CI = 1.1 to 6.0; P = .022) were associated with a higher likelihood of recurrence. Conclusions: ER+/PR– tumors express higher levels of HER-1 and HER-2 and display more aggressive features than ER+/PR+ tumors. As in laboratory models, lack of PR expression in ER+ tumors may be a surrogate marker of aberrant growth factor signaling that could contribute to the tamoxifen resistance observed in these tumors.
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