Published Ahead of Print on June 2, 2014 as 10.1200/JCO.2013.49.8899 The latest version is at http://jco.ascopubs.org/cgi/doi/10.1200/JCO.2013.49.8899
JOURNAL OF CLINICAL ONCOLOGY
D I A G N O S I S
O N C O L O G Y
malignancy. Breast ultrasound demonstrated a solid 2.5-cm lesion. An excisional biopsy showed grade 2 in situ and invasive ductal carcinoma, apocrine type, with clear margins which was triple negative (ER clone 6F 11 from Novocastra and 636 from DAKO, HER2 tested by CB11 and Tab250 monoclonal antibodies; Fig 1A, hematoxylin and eosin staining). Re-excision of the tumor site with axillary node dissection revealed no evidence of residual cancer in the breast, but two out of eight lymph nodes were involved (Fig 1B), with tumor emboli in the lymphatics adjacent to the involved nodes. Both the primary tumor and the metastatic nodes (Fig 2) stained strongly and diffusely positive for AR (Leica antibody AR 2F12 at a dilution of 1/50). The patient received adjuvant chemotherapy consisting of four cycles of doxorubicin and cyclophosphamide followed by four cycles of paclitaxel 175 mg/m2 every 3 weeks. She then underwent adjuvant radiation to the breast to a total dose of 42.5 Gy in 16 fractions. In 2009, the patient had biopsy-proven disease recurrence in the right breast and contralateral axilla. Both tumor samples were morphologically similar to the original cancer and were triple negative. Subsequently she was treated with several lines of palliative chemotherapy including capecitabine (discontinued after four cycles due to coronary artery spasm despite response), low-dose cyclophosphamide and methotrexate (stable disease for 5 months), low-dose oral etoposide (disease progression after 4 months), vinorelbine (disease progression after one cycle), and gemcitabine combined with cisplatin for five cycles, to which there was a partial response. She then underwent right simple mastectomy and left axillary dissection. Pathology showed residual tumor in the right breast measuring 7 ⫻ 7 ⫻ 3 cm, grade 2, with extensive lymphovascular invasion. All resection margins were negative and greater than 1 cm. In the left axilla, three of 12 lymph nodes were involved. She remained disease and treatment free for 1 year. After disease progression, she underwent left mastectomy and excision of right chest wall skin lesions. Pathology showed grade 2 metastatic apocrine carcinoma, triple negative, AR positive (Leica antibody: 100% of the tumor cells showed nuclear staining with strong
Complete Response of Metastatic Androgen Receptor–Positive Breast Cancer to Bicalutamide: Case Report and Review of the Literature Introduction Breast cancer is a heterogeneous disease and tumors with similar clinical stage and pathology may have markedly different outcomes. Breast cancer subtypes can be identified through gene expression profiling that convey different clinical, biologic, and therapeutic implications.1 Triple-negative breast cancer (TNBC) is defined by the lack of expression of estrogen receptor (ER), progesterone receptor (PR) and human epidermal factor receptor 2 (HER2). This subtype represents 15% to 20% of all breast cancers2 and is associated with the worst outcome of all subtypes, with greater tendency to distant recurrence in general and visceral metastases in particular.3,4 Recently molecular stratification of TNBC has been described, which could have treatment implications.5,6 Approximately 10% to 32% of TNBC have androgen receptor (AR) expression.7 As AR signaling has been shown to be intact in such patients,8,9 AR blockade could be a potential endocrine treatment. Bicalutamide is a nonsteroidal antiandrogen, which competitively inhibits the binding of androgens with the AR.10 It is widely used in the treatment of locally advanced and metastatic prostate cancer either as monotherapy or combined with a gonadotropin-releasing hormone agonist.11,12 We present a case of a heavily pretreated woman with metastatic TNBC and AR expression who achieved a complete clinical response after 4 months of treatment with the AR antagonist bicalutamide. Case Report In 2002, a 55-year-old woman developed a right breast lump associated with dimpling of the skin. Mammography showed a dense fibroglandular parenchymal pattern bilaterally with no evidence of
A
I N
B
Fig 1. Journal of Clinical Oncology, Vol 32, 2014
© 2014 by American Society of Clinical Oncology
Downloaded from jco.ascopubs.org on November 17, 2015. For personal use only. No other uses without permission. Copyright © 2014 American Society of Clinical Oncology. All rights reserved.
Copyright 2014 by American Society of Clinical Oncology
1
Arce-Salinas et al
Discussion TNBC has a more aggressive clinical course than other breast cancer subtypes. These tumors do not benefit from antiestrogen therapy and no specific targeted therapy has been identified date.13,14 The development and progression of breast cancer depends on the action of steroid hormones, most notably estrogen.15,16 Although the association between androgens and breast cancer is not completely understood,17 there is evidence that androgens may increase breast cancer risk either directly, by increasing cellular growth and proliferation via the androgen receptor, or indirectly, through their aromatization to estrogens.10,18 However, there is also in vivo and in vitro evidence that androgens may protect the breast from estrogeninduced stimulation of premalignant cells, possibly by competitive blockade of the estrogen receptor, and also by inducing antiproliferative and proapoptotic effects in the cell.20,21 The expression of AR in breast cancer is common and ranges from 60% to 89%.22-28 AR expression is more common in tumors classified as Luminal A and B, in which it has been reported in 68% to 95% of specimens, followed by 40% to 56% of HER-positive tumors and 10% to 32% of triple-negative tumors.7,23,24,28 AR expression is generally more common in well-differentiated tumors and is usually associated with lower tumor burden.25 There are conflicting reports in the literature regarding the prognostic value of AR expression. Gonzalez-Angulo et al29 used reverse-phase protein arrays to measure AR levels and a mass spectroscopy-based approach to detect PIK3CA mutations in 347 breast cancer samples. Patients whose tumors expressed high levels of AR had a 5-year overall survival (OS) of 79% compared with 64% among those patients with low AR levels (P ⫽ .0004), a difference which persisted after adjustment for ER, PR, HER2, PIK3CA mutation status and treatment. Peters et al30 assessed the prognostic value of AR expression as a function of ER status for 215 breast carcinomas. For
Fig 2.
intensity) with clear margins. Molecular profiling was not done on the tissue sample. The surgery was followed by left regional nodal radiation treatment, 45 Gy in 25 fractions. However, within a few months there was unresectable disease recurrence on both right and left chest wall. In March 2012, after four cycles of eribulin, her disease progressed. There was a 3-cm lesion on the superior-medial right chest wall, and a confluent 12-cm area of disease as well as several satellite nodules on the left side (Figs 3A and 3B). There was no evidence of any other distant metastasis. Bicalutamide 150 mg orally daily was started and tolerated well, causing only grade 1 fatigue and grade 1 hot flashes (CTCAE criteria v4.03). After 4 months of treatment, the patient achieved a complete clinical response according to RECIST criteria (Figs 3C and 3D), which is ongoing 12 months after starting treatment.
A
B
C
D
Fig 3. 2
© 2014 by American Society of Clinical Oncology
JOURNAL OF CLINICAL ONCOLOGY
Downloaded from jco.ascopubs.org on November 17, 2015. For personal use only. No other uses without permission. Copyright © 2014 American Society of Clinical Oncology. All rights reserved.
Diagnosis in Oncology
patients with ER-positive tumors, AR positivity greater than 75% was associated with significantly increased OS compared with those with low AR expression (94% v 75%, P ⫽ .002). However, when ERnegative tumors were analyzed no significant difference in OS was seen according to AR expression (60% v 70%, P ⫽ .32). In a study of 413 primary breast cancers, Park et al31 found AR expression to be an independent prognostic factor for disease-free survival but not OS for both ER-positive and ER-negative tumors. In order to better understand the varying biology of triplenegative tumors, Lehmann et al,32 performed a transcriptome analysis of 21 breast cancer data sets and identified 587 TNBC cases. They found six different subgroups of TNBC, which included two basallike, two mesenchymal-like, an immunomodulatory, and a luminal subgroup, with each defined by differential gene expression, including AR targets and coactivators. The authors also did in vitro analysis of several agents and found that cells from tumors in the luminal subgroup were sensitive to bicalutamide treatment.33 Ni et al9 investigated the effect of bicalutamide on a MDA-MB453 breast cancer cell line which was AR positive, ER negative, PR negative and HER2 negative (a model for apocrine breast carcinoma) and found that bicalutamide led to reduction in expression of HER3 and p-AKT and enhanced cell death. They also demonstrated that bicalutamide could block androgen-stimulated HER2/HER3 signaling, and inhibited the growth of ER-negative/HER2-positive/ARpositive breast cancer in vivo. Recently Gucalp et al34 from the Translational Breast Cancer Research Consortium reported the results of a study in which 400 patients with metastatic TNBC were tested for AR expression, which was found in 47 (12%). In a subsequent phase II trial, 24 of these AR-positive patients were treated with bicalutamide 150 mg orally daily. Although there were no complete or partial responses, two patients had stable disease for up to 6 months and an additional five patients had stable disease for more than 6 months for a clinical benefit rate of 21%. In conclusion, TNBC includes a variety of subgroups with different outcomes and clinical behavior. For metastatic TNBC, chemotherapy is the only systemic treatment modality currently available. However, as seen by our case and the series of Gucalp et al, antiandrogen therapy with bicalutamide may provide prolonged palliative benefit with minimal toxicity for these patients. Moreover, AR expression is common in ER-positive patients and antiandrogen therapy could provide an additional effective line of hormonal therapy for such patients. Further studies are warranted.
Claudia Arce-Salinas National Cancer Institute of Mexico, Mexico City, Mexico
Maria Carmen Riesco-Martinez and Wedad Hanna Sunnybrook Odette Cancer Centre, Toronto, Ontario, Canada
Philippe Bedard Princess Margaret Hospital, Toronto, Ontario, Canada
Ellen Warner Sunnybrook Odette Cancer Centre, Toronto, Ontario, Canada
AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST
The author(s) indicated no potential conflicts of interest. www.jco.org
REFERENCES 1. Perou C, Sorlie T, Eisen MB, et al: Molecular portraits of human breast tumors. Nature 206:747-752, 2000 2. Bauer KR, Brown M, Cress RD, et al: Descriptive analysis of estrogen receptor (ER) negative, progesterone receptor (PR) negative and HER2negative invasive breast cancer, the so-called triple-negative phenotype: A population-based study from the California Cancer Registry. Cancer 109:17211728, 2007 3. Carey LA, Perou CM, Livasy CA, et al: Race, breast cancer subtypes, and survival in the Carolina Breast Cancer Study. JAMA 295:2492-2502, 2006 4. Dent R, Trudeau M, Pritchard KI, et al: Triple negative breast cancer: Clinical features and patterns of recurrence. Clin Cancer Res 13:4429-4434, 2007 5. Perou C: Molecular stratification of triple-negative breast cancers. Oncologist 16:61-70, 2011 (suppl 1) 6. Metzger-Filho O, Tutt A, de Azambuja E, et al: Dissecting the heterogeneity of triple-negative breast cancer. J Clin Oncol 30:1879-1887, 2012 7. Gucalp A, Gupta G, Patil S, et al: Androgen receptor (AR) expression in a cohort of patients with triple negative breast cancer. SABCS Symposium 2011, P4-02-04 8. Gucalp A, Traina TA: Triple negative breast cancer: Role of the androgen receptor. Cancer J 16:62-65, 2010 9. Ni M, Chen Y, Lim E, et al: Targeting androgen receptor in estrogen receptor-negative breast cancer. Cancer Cell 20:119-131, 2011 10. Wirth MP, Hakenberg OW, Froehner M: Antiandrogens in the treatment of prostate cancer. E J Urol 51:306-314, 2007 11. Anderson J: The role of antiandrogen monotherapy in the treatment of prostate cancer. BJU Int 91:455-461, 2003 12. Pilepich MV, Winter K, John MJ, et al: Phase III radiation therapy oncology group (RTOG) trial 86-10 of androgen deprivation adjuvant of definitive radiotherapy in locally advanced carcinoma of the prostate. Int J Radiat Oncol Biophys 50:1243-1252, 2001 13. Liedtke C, Kiesel L: Current issues of targeted therapy in metastatic triple-negative breast cancer. Breast Care 6:234-239, 2011 14. Hudis CA, Gianni L: Triple negative breast cancer: An unmet medical need. Oncologist 16:1-11, 2011 (suppl 1) 15. Hickey TE, Robinson LL, Carroll JS, et al: Minireview: The androgen receptor in breast tissues—Growth inhibitor, tumor suppressor, oncogene? Mol Endocrinol 26:1252-1267, 2012 16. Kotsopoulos J, Narod SA: Androgens and breast cancer. Steroids 77:1-9, 2012 17. Liao DJ, Dickson RB: Roles of androgens in the development, growth, and carcinogenesis of the mammary gland. J Steroid Biochem Mol Biol 80:175-189, 2002 18. Secreto G, Venturelli E, Meneghini E, et al: Testosterone and biological characteristics of breast cancers in postmenopausal women. Cancer Epidemiol Biomarkers Prev 18:2942-2948, 2009 19. Labrie F, Luu-The V, Labrie C, et al: Endocrine and intracrine sources of androgens in women: Inhibition of breast cancer and other roles of androgens and their precursor dehydroepiandrosterone. Endocr Rev 24:152-182, 2003 20. Dimitrakakis C, Zhou J, Wang J, et al: A physiologic role for testosterone in limiting estrogenic stimulation of the breast. Menopause 10:292-298, 2003 21. Isola JJ: Immunohistochemical demonstration of androgen receptor in breast cancer and its relationship to other prognostic factors. J Pathol 170:31-35, 1993 22. Kuenen-Boumeester V, Van der Kwast TH, van Putten WL, et al: Immunohistochemical determination of androgen receptors in relation to oestrogen and progesterone receptors in female breast cancer. Int J Cancer 52:581-584, 1992 23. Moinfar F, Okcu M, Tsybrovskyy O, et al: Androgen receptors frequently are expressed in breast carcinomas: Potential relevance to new therapeutic strategies. Cancer 98:703-711, 2003 24. Ogawa Y, Hai E, Matsumoto K, et al: Androgen receptor expression in breast cancer: Relationship with clinicopathological factors and biomarkers. Int J Clin Oncol 13:431-435, 2008 25. Gonzalez LO, Corte MD, Vazquez J, et al: Androgen receptor expression in breast cancer: Relationship with clinicopathological characteristics of the tumors, prognosis, and expression of metalloproteases and their inhibitors. BMC Cancer 8:149, 2008 26. Niemeier LA, Dabbs DJ, Beriwal S, et al: Androgen receptor in breast cancer: Expression in estrogen receptor-positive tumors and in estrogen receptor–negative tumors with apocrine differentiation. Mod Pathol 23:205212, 2010
© 2014 by American Society of Clinical Oncology
Downloaded from jco.ascopubs.org on November 17, 2015. For personal use only. No other uses without permission. Copyright © 2014 American Society of Clinical Oncology. All rights reserved.
3
Arce-Salinas et al
27. Collins LC, Cole KS, Marotti JD, et al: Androgen receptor expression in breast cancer in relation to molecular phenotype: Results from the Nurses’ Health Study. Mod Pathol 24:924-931, 2011 28. Goldberg IS: Testosterone propionate therapy in breast cancer. JAMA 188:1069-1072, 1964 29. Gonzalez-Angulo AM, Stemke-Hale K, Palla SL, et al: Androgen receptor levels and association with PIK3CA mutations and prognosis in breast cancer. Clin Cancer Res 15:2472-2478, 2009 30. Peters AA, Buchanan G, Ricciardelli C, et al: Androgen receptor inhibits estrogen receptor-alpha activity and is prognostic in breast cancer. Cancer Res 69:6131-6140, 2009 31. Park S, Koo J, Park HS, et al: Expression of androgen receptors in primary breast cancer. Ann Oncol 21:488-492, 2010
32. Lehman BD, Bauer JA, Chen X, et al: Transcriptome analysis of triple negative breast cancer identifies six distinct biological subgroups and reveals therapeutic strategies. San Antonio Breast Cancer Symposium, San Antonio, TX, December 8-12, 2010 (abstr PD01-07) 33. Lehmann BD, Bauer JA, Chen X, et al: Identification of human triplenegative breast cancer subtypes and preclinical models for selection of targeted therapies. J Clin Invest 121:2750-2767, 2011 34. Gucalp A, Tolaney SM, Isakoff SJ, et al: TBCRC 011: Targeting the androgen receptor (AR) in woman with AR⫹/ER⫺/PR⫺ metastatic breast cancer (MBC). J Clin Oncol 30:50s, 2012 (suppl; abst 1006)
DOI: 10.1200/JCO.2013.49.8899; published online ahead of print at www.jco.org on June 2, 2014
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© 2014 by American Society of Clinical Oncology
JOURNAL OF CLINICAL ONCOLOGY
Downloaded from jco.ascopubs.org on November 17, 2015. For personal use only. No other uses without permission. Copyright © 2014 American Society of Clinical Oncology. All rights reserved.
JOURNAL OF CLINICAL ONCOLOGY
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O N C O L O G Y
malignancy. Breast ultrasound demonstrated a solid 2.5-cm lesion. An excisional biopsy showed grade 2 in situ and invasive ductal carcinoma, apocrine type, with clear margins which was triple negative (ER clone 6F 11 from Novocastra and 636 from DAKO, HER2 tested by CB11 and Tab250 monoclonal antibodies; Fig 1A, hematoxylin and eosin staining). Re-excision of the tumor site with axillary node dissection revealed no evidence of residual cancer in the breast, but two out of eight lymph nodes were involved (Fig 1B), with tumor emboli in the lymphatics adjacent to the involved nodes. Both the primary tumor and the metastatic nodes (Fig 2) stained strongly and diffusely positive for AR (Leica antibody AR 2F12 at a dilution of 1/50). The patient received adjuvant chemotherapy consisting of four cycles of doxorubicin and cyclophosphamide followed by four cycles of paclitaxel 175 mg/m2 every 3 weeks. She then underwent adjuvant radiation to the breast to a total dose of 42.5 Gy in 16 fractions. In 2009, the patient had biopsy-proven disease recurrence in the right breast and contralateral axilla. Both tumor samples were morphologically similar to the original cancer and were triple negative. Subsequently she was treated with several lines of palliative chemotherapy including capecitabine (discontinued after four cycles due to coronary artery spasm despite response), low-dose cyclophosphamide and methotrexate (stable disease for 5 months), low-dose oral etoposide (disease progression after 4 months), vinorelbine (disease progression after one cycle), and gemcitabine combined with cisplatin for five cycles, to which there was a partial response. She then underwent right simple mastectomy and left axillary dissection. Pathology showed residual tumor in the right breast measuring 7 ⫻ 7 ⫻ 3 cm, grade 2, with extensive lymphovascular invasion. All resection margins were negative and greater than 1 cm. In the left axilla, three of 12 lymph nodes were involved. She remained disease and treatment free for 1 year. After disease progression, she underwent left mastectomy and excision of right chest wall skin lesions. Pathology showed grade 2 metastatic apocrine carcinoma, triple negative, AR positive (Leica antibody: 100% of the tumor cells showed nuclear staining with strong
Complete Response of Metastatic Androgen Receptor–Positive Breast Cancer to Bicalutamide: Case Report and Review of the Literature Introduction Breast cancer is a heterogeneous disease and tumors with similar clinical stage and pathology may have markedly different outcomes. Breast cancer subtypes can be identified through gene expression profiling that convey different clinical, biologic, and therapeutic implications.1 Triple-negative breast cancer (TNBC) is defined by the lack of expression of estrogen receptor (ER), progesterone receptor (PR) and human epidermal factor receptor 2 (HER2). This subtype represents 15% to 20% of all breast cancers2 and is associated with the worst outcome of all subtypes, with greater tendency to distant recurrence in general and visceral metastases in particular.3,4 Recently molecular stratification of TNBC has been described, which could have treatment implications.5,6 Approximately 10% to 32% of TNBC have androgen receptor (AR) expression.7 As AR signaling has been shown to be intact in such patients,8,9 AR blockade could be a potential endocrine treatment. Bicalutamide is a nonsteroidal antiandrogen, which competitively inhibits the binding of androgens with the AR.10 It is widely used in the treatment of locally advanced and metastatic prostate cancer either as monotherapy or combined with a gonadotropin-releasing hormone agonist.11,12 We present a case of a heavily pretreated woman with metastatic TNBC and AR expression who achieved a complete clinical response after 4 months of treatment with the AR antagonist bicalutamide. Case Report In 2002, a 55-year-old woman developed a right breast lump associated with dimpling of the skin. Mammography showed a dense fibroglandular parenchymal pattern bilaterally with no evidence of
A
I N
B
Fig 1. Journal of Clinical Oncology, Vol 32, 2014
© 2014 by American Society of Clinical Oncology
Downloaded from jco.ascopubs.org on November 17, 2015. For personal use only. No other uses without permission. Copyright © 2014 American Society of Clinical Oncology. All rights reserved.
Copyright 2014 by American Society of Clinical Oncology
1
Arce-Salinas et al
Discussion TNBC has a more aggressive clinical course than other breast cancer subtypes. These tumors do not benefit from antiestrogen therapy and no specific targeted therapy has been identified date.13,14 The development and progression of breast cancer depends on the action of steroid hormones, most notably estrogen.15,16 Although the association between androgens and breast cancer is not completely understood,17 there is evidence that androgens may increase breast cancer risk either directly, by increasing cellular growth and proliferation via the androgen receptor, or indirectly, through their aromatization to estrogens.10,18 However, there is also in vivo and in vitro evidence that androgens may protect the breast from estrogeninduced stimulation of premalignant cells, possibly by competitive blockade of the estrogen receptor, and also by inducing antiproliferative and proapoptotic effects in the cell.20,21 The expression of AR in breast cancer is common and ranges from 60% to 89%.22-28 AR expression is more common in tumors classified as Luminal A and B, in which it has been reported in 68% to 95% of specimens, followed by 40% to 56% of HER-positive tumors and 10% to 32% of triple-negative tumors.7,23,24,28 AR expression is generally more common in well-differentiated tumors and is usually associated with lower tumor burden.25 There are conflicting reports in the literature regarding the prognostic value of AR expression. Gonzalez-Angulo et al29 used reverse-phase protein arrays to measure AR levels and a mass spectroscopy-based approach to detect PIK3CA mutations in 347 breast cancer samples. Patients whose tumors expressed high levels of AR had a 5-year overall survival (OS) of 79% compared with 64% among those patients with low AR levels (P ⫽ .0004), a difference which persisted after adjustment for ER, PR, HER2, PIK3CA mutation status and treatment. Peters et al30 assessed the prognostic value of AR expression as a function of ER status for 215 breast carcinomas. For
Fig 2.
intensity) with clear margins. Molecular profiling was not done on the tissue sample. The surgery was followed by left regional nodal radiation treatment, 45 Gy in 25 fractions. However, within a few months there was unresectable disease recurrence on both right and left chest wall. In March 2012, after four cycles of eribulin, her disease progressed. There was a 3-cm lesion on the superior-medial right chest wall, and a confluent 12-cm area of disease as well as several satellite nodules on the left side (Figs 3A and 3B). There was no evidence of any other distant metastasis. Bicalutamide 150 mg orally daily was started and tolerated well, causing only grade 1 fatigue and grade 1 hot flashes (CTCAE criteria v4.03). After 4 months of treatment, the patient achieved a complete clinical response according to RECIST criteria (Figs 3C and 3D), which is ongoing 12 months after starting treatment.
A
B
C
D
Fig 3. 2
© 2014 by American Society of Clinical Oncology
JOURNAL OF CLINICAL ONCOLOGY
Downloaded from jco.ascopubs.org on November 17, 2015. For personal use only. No other uses without permission. Copyright © 2014 American Society of Clinical Oncology. All rights reserved.
Diagnosis in Oncology
patients with ER-positive tumors, AR positivity greater than 75% was associated with significantly increased OS compared with those with low AR expression (94% v 75%, P ⫽ .002). However, when ERnegative tumors were analyzed no significant difference in OS was seen according to AR expression (60% v 70%, P ⫽ .32). In a study of 413 primary breast cancers, Park et al31 found AR expression to be an independent prognostic factor for disease-free survival but not OS for both ER-positive and ER-negative tumors. In order to better understand the varying biology of triplenegative tumors, Lehmann et al,32 performed a transcriptome analysis of 21 breast cancer data sets and identified 587 TNBC cases. They found six different subgroups of TNBC, which included two basallike, two mesenchymal-like, an immunomodulatory, and a luminal subgroup, with each defined by differential gene expression, including AR targets and coactivators. The authors also did in vitro analysis of several agents and found that cells from tumors in the luminal subgroup were sensitive to bicalutamide treatment.33 Ni et al9 investigated the effect of bicalutamide on a MDA-MB453 breast cancer cell line which was AR positive, ER negative, PR negative and HER2 negative (a model for apocrine breast carcinoma) and found that bicalutamide led to reduction in expression of HER3 and p-AKT and enhanced cell death. They also demonstrated that bicalutamide could block androgen-stimulated HER2/HER3 signaling, and inhibited the growth of ER-negative/HER2-positive/ARpositive breast cancer in vivo. Recently Gucalp et al34 from the Translational Breast Cancer Research Consortium reported the results of a study in which 400 patients with metastatic TNBC were tested for AR expression, which was found in 47 (12%). In a subsequent phase II trial, 24 of these AR-positive patients were treated with bicalutamide 150 mg orally daily. Although there were no complete or partial responses, two patients had stable disease for up to 6 months and an additional five patients had stable disease for more than 6 months for a clinical benefit rate of 21%. In conclusion, TNBC includes a variety of subgroups with different outcomes and clinical behavior. For metastatic TNBC, chemotherapy is the only systemic treatment modality currently available. However, as seen by our case and the series of Gucalp et al, antiandrogen therapy with bicalutamide may provide prolonged palliative benefit with minimal toxicity for these patients. Moreover, AR expression is common in ER-positive patients and antiandrogen therapy could provide an additional effective line of hormonal therapy for such patients. Further studies are warranted.
Claudia Arce-Salinas National Cancer Institute of Mexico, Mexico City, Mexico
Maria Carmen Riesco-Martinez and Wedad Hanna Sunnybrook Odette Cancer Centre, Toronto, Ontario, Canada
Philippe Bedard Princess Margaret Hospital, Toronto, Ontario, Canada
Ellen Warner Sunnybrook Odette Cancer Centre, Toronto, Ontario, Canada
AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST
The author(s) indicated no potential conflicts of interest. www.jco.org
REFERENCES 1. Perou C, Sorlie T, Eisen MB, et al: Molecular portraits of human breast tumors. Nature 206:747-752, 2000 2. Bauer KR, Brown M, Cress RD, et al: Descriptive analysis of estrogen receptor (ER) negative, progesterone receptor (PR) negative and HER2negative invasive breast cancer, the so-called triple-negative phenotype: A population-based study from the California Cancer Registry. Cancer 109:17211728, 2007 3. Carey LA, Perou CM, Livasy CA, et al: Race, breast cancer subtypes, and survival in the Carolina Breast Cancer Study. JAMA 295:2492-2502, 2006 4. Dent R, Trudeau M, Pritchard KI, et al: Triple negative breast cancer: Clinical features and patterns of recurrence. Clin Cancer Res 13:4429-4434, 2007 5. Perou C: Molecular stratification of triple-negative breast cancers. Oncologist 16:61-70, 2011 (suppl 1) 6. Metzger-Filho O, Tutt A, de Azambuja E, et al: Dissecting the heterogeneity of triple-negative breast cancer. J Clin Oncol 30:1879-1887, 2012 7. Gucalp A, Gupta G, Patil S, et al: Androgen receptor (AR) expression in a cohort of patients with triple negative breast cancer. SABCS Symposium 2011, P4-02-04 8. Gucalp A, Traina TA: Triple negative breast cancer: Role of the androgen receptor. Cancer J 16:62-65, 2010 9. Ni M, Chen Y, Lim E, et al: Targeting androgen receptor in estrogen receptor-negative breast cancer. Cancer Cell 20:119-131, 2011 10. Wirth MP, Hakenberg OW, Froehner M: Antiandrogens in the treatment of prostate cancer. E J Urol 51:306-314, 2007 11. Anderson J: The role of antiandrogen monotherapy in the treatment of prostate cancer. BJU Int 91:455-461, 2003 12. Pilepich MV, Winter K, John MJ, et al: Phase III radiation therapy oncology group (RTOG) trial 86-10 of androgen deprivation adjuvant of definitive radiotherapy in locally advanced carcinoma of the prostate. Int J Radiat Oncol Biophys 50:1243-1252, 2001 13. Liedtke C, Kiesel L: Current issues of targeted therapy in metastatic triple-negative breast cancer. Breast Care 6:234-239, 2011 14. Hudis CA, Gianni L: Triple negative breast cancer: An unmet medical need. Oncologist 16:1-11, 2011 (suppl 1) 15. Hickey TE, Robinson LL, Carroll JS, et al: Minireview: The androgen receptor in breast tissues—Growth inhibitor, tumor suppressor, oncogene? Mol Endocrinol 26:1252-1267, 2012 16. Kotsopoulos J, Narod SA: Androgens and breast cancer. Steroids 77:1-9, 2012 17. Liao DJ, Dickson RB: Roles of androgens in the development, growth, and carcinogenesis of the mammary gland. J Steroid Biochem Mol Biol 80:175-189, 2002 18. Secreto G, Venturelli E, Meneghini E, et al: Testosterone and biological characteristics of breast cancers in postmenopausal women. Cancer Epidemiol Biomarkers Prev 18:2942-2948, 2009 19. Labrie F, Luu-The V, Labrie C, et al: Endocrine and intracrine sources of androgens in women: Inhibition of breast cancer and other roles of androgens and their precursor dehydroepiandrosterone. Endocr Rev 24:152-182, 2003 20. Dimitrakakis C, Zhou J, Wang J, et al: A physiologic role for testosterone in limiting estrogenic stimulation of the breast. Menopause 10:292-298, 2003 21. Isola JJ: Immunohistochemical demonstration of androgen receptor in breast cancer and its relationship to other prognostic factors. J Pathol 170:31-35, 1993 22. Kuenen-Boumeester V, Van der Kwast TH, van Putten WL, et al: Immunohistochemical determination of androgen receptors in relation to oestrogen and progesterone receptors in female breast cancer. Int J Cancer 52:581-584, 1992 23. Moinfar F, Okcu M, Tsybrovskyy O, et al: Androgen receptors frequently are expressed in breast carcinomas: Potential relevance to new therapeutic strategies. Cancer 98:703-711, 2003 24. Ogawa Y, Hai E, Matsumoto K, et al: Androgen receptor expression in breast cancer: Relationship with clinicopathological factors and biomarkers. Int J Clin Oncol 13:431-435, 2008 25. Gonzalez LO, Corte MD, Vazquez J, et al: Androgen receptor expression in breast cancer: Relationship with clinicopathological characteristics of the tumors, prognosis, and expression of metalloproteases and their inhibitors. BMC Cancer 8:149, 2008 26. Niemeier LA, Dabbs DJ, Beriwal S, et al: Androgen receptor in breast cancer: Expression in estrogen receptor-positive tumors and in estrogen receptor–negative tumors with apocrine differentiation. Mod Pathol 23:205212, 2010
© 2014 by American Society of Clinical Oncology
Downloaded from jco.ascopubs.org on November 17, 2015. For personal use only. No other uses without permission. Copyright © 2014 American Society of Clinical Oncology. All rights reserved.
3
Arce-Salinas et al
27. Collins LC, Cole KS, Marotti JD, et al: Androgen receptor expression in breast cancer in relation to molecular phenotype: Results from the Nurses’ Health Study. Mod Pathol 24:924-931, 2011 28. Goldberg IS: Testosterone propionate therapy in breast cancer. JAMA 188:1069-1072, 1964 29. Gonzalez-Angulo AM, Stemke-Hale K, Palla SL, et al: Androgen receptor levels and association with PIK3CA mutations and prognosis in breast cancer. Clin Cancer Res 15:2472-2478, 2009 30. Peters AA, Buchanan G, Ricciardelli C, et al: Androgen receptor inhibits estrogen receptor-alpha activity and is prognostic in breast cancer. Cancer Res 69:6131-6140, 2009 31. Park S, Koo J, Park HS, et al: Expression of androgen receptors in primary breast cancer. Ann Oncol 21:488-492, 2010
32. Lehman BD, Bauer JA, Chen X, et al: Transcriptome analysis of triple negative breast cancer identifies six distinct biological subgroups and reveals therapeutic strategies. San Antonio Breast Cancer Symposium, San Antonio, TX, December 8-12, 2010 (abstr PD01-07) 33. Lehmann BD, Bauer JA, Chen X, et al: Identification of human triplenegative breast cancer subtypes and preclinical models for selection of targeted therapies. J Clin Invest 121:2750-2767, 2011 34. Gucalp A, Tolaney SM, Isakoff SJ, et al: TBCRC 011: Targeting the androgen receptor (AR) in woman with AR⫹/ER⫺/PR⫺ metastatic breast cancer (MBC). J Clin Oncol 30:50s, 2012 (suppl; abst 1006)
DOI: 10.1200/JCO.2013.49.8899; published online ahead of print at www.jco.org on June 2, 2014
■ ■ ■
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© 2014 by American Society of Clinical Oncology
JOURNAL OF CLINICAL ONCOLOGY
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