Purpose: A major clinical problem in the treatment of breast cancer is the inherent and acquired resistance to antiestrogen therapy.
In this study, we sought to determine whether antiprogestin ...treatment, used as a monotherapy or in combination with antiestrogen
therapy, induced growth arrest and active cell death in antiestrogen-resistant breast cancer cells.
Experimental Design: MCF-7 sublines were established from independent clonal isolations performed in the absence of drug selection and tested
for their response to the antiestrogens 4-hydroxytamoxifen (4-OHT) and ICI 182,780 (fulvestrant), and the antiprogestin mifepristone
(MIF). The cytostatic (growth arrest) effects of the hormones were assessed with proliferation assays, cell counting, flow
cytometry, and a determination of the phosphorylation status of the retinoblastoma protein. The cytotoxic (apoptotic) effects
were analyzed by assessing increases in caspase activity and cleavage of poly(ADP-ribose) polymerase.
Results: All of the clonally derived MCF-7 sublines expressed estrogen receptor and progesterone receptor but showed a wide range
of antiestrogen sensitivity, including resistance to physiological levels of 4-OHT. Importantly, all of the clones were sensitive
to the antiprogestin MIF, whether used as a monotherapy or in combination with 4-OHT. MIF induced retinoblastoma activation,
G 1 arrest, and apoptosis preceded by caspase activation.
Conclusions: We demonstrate that: ( a ) estrogen receptor + progesterone receptor + , 4-OHT-resistant clonal variants can be isolated from an MCF-7 cell line in the absence of antiestrogen selection; and ( b ) MIF and MIF plus 4-OHT combination therapy induces growth arrest and active cell death of the antiestrogen-resistant breast
cancer cells. These preclinical findings show potential for a combined hormonal regimen of an antiestrogen and an antiprogestin
to combat the emergence of antiestrogen-resistant breast cancer cells and, ultimately, improve the therapeutic index of antiestrogen
therapy.
Mifepristone (MIF) is an antiprogestin with potent anti-glucocorticoid and anti-androgen activity. MIF also appears to have anti-tumor activity independent of its ability to bind to nuclear ...receptors. In this study, we tested the ability of MIF to inhibit the growth of ER and PR negative breast cancer cells. In addition, because high-dose anti-estrogen treatment has been shown to inhibit ER and PR negative breast cancer cells, we compared the anti-proliferative activity of MIF to that of the anti-estrogen 4-hydroxytamoxifen (TAM) or combination hormonal therapy (MIF + TAM). MIF and TAM therapy induced a significant time- and dose-dependent growth inhibition and, ultimately, induced cell death in MDA-231 cells as evidenced by increased DNA fragmentation, cytochrome c release from the mitochondria, and the activation of caspase-3. The anti-proliferative activity of TAM plus MIF combination treatment was at least additive as compared to either monotherapy. The earliest indicator of TAM and MIF cytostatic and cytotoxic action on MDA-231 cells was a significant (p<0.05) induction of TGFbeta1 secretion into the growth medium within 4 h of treatment. Secreted TGFbeta1 levels at 24 and 48 h were significantly higher in the TAM plus MIF treatment group as compared to cells treated with TAM or MIF alone. TGFbeta1 neutralizing antibody or addition of mannose-6-phosphate (M6P), a reagent also used to inhibit TGFbeta1, significantly attenuated the TAM and/or MIF-induced cell growth inhibition and cell death. In summary, our results indicate that MIF used in combination with TAM can effectively kill estrogen-insensitive human breast cancer cells. Our study further implies that agents that effectively increase TGFbeta1 levels in ER negative breast cancer cells may be one treatment approach for hormone-independent breast cancers.
Abstract
Background: Androgen Receptor (AR) signaling is a new target present in and under evaluation in all breast cancer subtypes. AR expression is noted in 70%-90% of primary breast tumors, up to ...75% of all breast cancer metastases and is associated with resistance to endocrine therapy. Orteronel, an oral, selective, nonsteroidal inhibitor of androgen synthesis, is being developed as an endocrine therapy for hormone-sensitive cancers. In preclinical studies, orteronel suppresses sex hormone levels in blood and hormone-dependent malignant tissue. This study will evaluate the safety and efficacy of orteronel in the treatment of AR+ MBC.
Study Objectives: This phase II trial is designed to determine the response rate and disease control rate (CR+PR+SD at 6 mo) following treatment with orteronel in pts with AR+ MBC. Two groups will be evaluated: Cohort 1 will include pts with AR+, triple negative (TN) (ER-/PR-/HER2-) MBC, and Cohort 2 will include pts with AR+, ER+ and/or PR+ MBC (may be HER2+ or HER2-). Secondary objectives include evaluation of PFS and OS, safety and tolerability, as well as evaluation of changes in serum levels of total and free testosterone, sex hormone binding globulins (SHBG), adrenocorticotropic hormone (ACTH), dehydroepiandrosterone sulfate (DHEA-S), cortisol and estradiol during orteronel treatment. As an exploratory objective, archived tumor tissue will be analyzed for the presence of phosphatidylinositol 3-kinase (PIK3CA) mutations and loss of phosphatase and tensin homolog (PTEN).
Eligibility: Pts ≥18 years with AR+ (≥10% staining by immunohistochemistry) MBC, either TN or ER+ and/or PR+, are eligible. TNBC pts must have had 1-3 prior chemotherapy regimens in the advanced setting and ER+ and/or PR+ pts must have had 1-3 prior hormonal therapies and ≥1 chemotherapy regimen in the advanced setting. HER2+ pts must have received ≥2 lines of HER2-directed therapies. Additional eligibility criteria include: ECOG PS 0-2; adequate bone marrow and organ function, including left ventricular ejection fraction of ≥50%.
Trial Design: Six pts will be enrolled and treated with orteronel in the lead-in phase to confirm safety and tolerability. In the absence of any safety concerns, subsequent pts will be enrolled to either Cohort 1 or Cohort 2 (described above). Cohort 1 will contain 31 pts with AR+ TNBC and Cohort 2 will contain 55 pts with AR+ ER+ and/or PR+ MBC. All pts will receive 300 mg orteronel PO BID over a 4 week cycle. Pts will be evaluated with CT scans every 2 cycles and treatment will continue until disease progression or unacceptable toxicity. Response rate and disease control rate will be presented as the point estimate along with 95% confidence interals calculated using both asymptotic normal approximation and exact binomial methods. Simon’s two-stage design will be applied using alpha=0.10 and power=0.80 for each cohort. Blood samples will be collected at baseline, on Cycle 2 Day 1, Cycle 4 Day 1, and at the end of treatment to evaluate serum total and free testosterone, SHBG, ACTH, DHEA-S, cortisol, and estradiol levels. Archival tumor samples will be collected for exploratory PTEN and PIK3CA biomarker evaluations. This trial is currently enrolling and has a total accrual goal of 86 pts.
Citation Format: Denise A Yardley, Suzanne F Jones, Nancy W Peacock, Mythili Shastry, Robyn R Young, Andre M Kallab, Howard A Burris III. A phase II study with orteronel as monotherapy in patients with androgen receptor (AR) expressing metastatic breast cancer (MBC) abstract. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr OT2-1-07.
Anal melanoma is a devastating malignancy easily confused with benign hemorrhoids. Physician unfamiliarity with this bleeding rectal lesion can lead to delays in diagnosis and therapy. Four cases of ...anal melanoma, all initially mistaken for hemorrhoids, have been documented in the past 4 years at our institution. Despite surgical intervention and chemoimmunotherapy, each patient succumbed to widely metastatic disease. Average survival was 15.2 months. The clinical, pathologic, surgical, and oncologic features of anal melanoma are reviewed to enhance physician recognition of this unusual anorectal disorder.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
Tumor lysis syndrome, resulting from the abrupt release of intracellular ions into the blood stream due to sudden tumor cell death, is a serious complication of chemotherapy treatment. This syndrome ...occurs more frequently in hematologic malignancies and lymphomas. Its incidence in solid tumors is rare, but has a high mortality rate owing to the lack of prophylactic therapy to prevent this complication. We report a case of tumor lysis syndrome accompanied by death in a patient with extensive stage small cell lung cancer who was treated with cisplatin and etoposide, and review the risk factors associated with the syndrome in solid tumor patients who are likely to respond to chemotherapy.
Many sarcomas are of intermediate nature, with aggressive local behavior and low-to-moderate tendency to metastasize. A low-grade fibromyxoid sarcoma had abnormal glucose uptake in the principal ...tumor and contralateral lung metastases with pleural involvement demonstrated with F-18 FDG positron emission tomography (PET). A high-grade malignant hemangiopericytoma had abnormal glucose uptake in the principal tumor and a metastasis in an ipsilateral paratracheal lymph node, but was falsely negative in a small adjacent intraparenchymal lung metastasis. F-18 FDG PET could be useful in rare soft tissue sarcomas to demonstrate sites of possible metastasis and direct biopsy, but is of uncertain negative predictive value with small tumor deposits.
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