Tumor response after withdrawal of endocrine therapy for advanced breast cancer with estrogens and androgens is well described. There have been few reports of withdrawal responses (WRs) after cessation of treatment with the newer antiestrogens and progestogens. We assessed WR in women after cessation of adjuvant therapy at first relapse, and after progression on first, second or third line endocrine therapy for advanced disease. One of seven patients (14%) responded after cessation of tamoxifen adjuvant therapy at relapse. Sixty-five of 72 patients were evaluable for WR after cessation of tamoxifen as first line therapy for advanced disease. There were five partial responses (8%) and 14 (22%) 'no change' with a median duration of WR of 10 months (range 3-40 months). WR were seen mainly in soft tissue disease but there were two responses in lung and two in bone. Four of 21 (19%) patients had a WR after cessation of norethisterone acetate (3) and tamoxifen (1), all used as second line therapy. WR are therefore demonstrable after cessation of tamoxifen and norethisterone acetate with durations of response similar to those found with additive therapy. Assessment of WR may represent a way of prolonging the overall response duration in patients with relatively indolent metastatic breast cancer, particularly in soft tissues.
"Clinical and laboratory studies have identified possible mechanisms for the acquired resistance to SERMs, and tamoxifen. Acquired resistance to SERMs is unique as the tumors are SERM stimulated for growth (Howell et al. 1992). The first laboratory model (Gottardis and Jordan 1988; Gottardis et al. 1988; Gottardis et al. 1990) of transplantable tamoxifen resistant cells demonstrated that 1) tamoxifen or estrogen can cause tumors to grow, 2) tumors require a liganded receptor to grow, 3) an aromatase inhibitors (estrogen deprivation) or a pure antiestrogen that causes ER degradation would be useful second line agents, 4) there was cross resistance with other SERMs (O'Regan et al. 2002). "
"There is significant and sustained CB (60%) on "withdrawal" from tamoxifen even in heavily pre-treated patients in our study. Previous studies have explained development of resistance to tamoxifen itself due to clonal selection of breast cancer cells that grow in the presence of tamoxifen [4,6]. An in vitro study of cells derived from tumors of post-menopausal patients which progressed on tamoxifen showed growth enhanced by addition of tamoxifen  suggesting domination of agonistic activity on long-term tamoxifen therapy. "
[Show abstract][Hide abstract] ABSTRACT: It has been shown in in-vitro experiments that "withdrawal" of tamoxifen inhibits growth of tumor cells. However, evidence is scarce when this is extrapolated into clinical context. We report our experience to verify the clinical relevance of "withdrawal therapy".
Breast cancer patients since 1998 who fulfilled the following criteria were selected from the departmental database and the case-notes were retrospectively reviewed: (1) estrogen receptor positive, operable primary breast cancer in elderly (age > 70 years), locally advanced or metastatic breast cancer; (2) disease deemed suitable for treatment by hormonal manipulation; (3) disease assessable by UICC criteria; (4) received "withdrawal" from a prior endocrine agent as a form of therapy; (5) on "withdrawal therapy" for ≥ 6 months unless they progressed prior.
Seventeen patients with median age of 84.3 (53.7-92.5) had "withdrawal therapy" as second to tenth line of treatment following prior endocrine therapy using tamoxifen (n = 10), an aromatase inhibitor (n = 5), megestrol acetate (n = 1) or fulvestrant (n = 1). Ten patients (58.8%) had clinical benefit (CB) (complete response/partial response/stable disease ≥ 6 months) with a median duration of Clinical Benefit (DoCB) of 10+ (7-27) months. Two patients remain on "withdrawal therapy" at the time of analysis.
"Withdrawal therapy" appears to produce sustained CB in a significant proportion of patients. This applies not only to "withdrawal" from tamoxifen, but also from other categories of endocrine agents. "Withdrawal" from endocrine therapy is, therefore, a viable intercalating option between endocrine agents to minimise resistance and provide additional line of therapy. It should be considered as part of the sequencing of endocrine therapy.
World Journal of Surgical Oncology 09/2011; 9(1):101. DOI:10.1186/1477-7819-9-101 · 1.41 Impact Factor
"However, its effectiveness wanes with time, and after 2–5 years of treatment, most ER+ tumours become refractory to Tam (Early Breast Cancer Trialists' Collaborative Group, 1992; Jordan, 1999a). Also, there are some ER+ breast cancers that are unresponsive to Tam at first presentation (Jensen and DeSombre, 1996), and there are others that, after chronic treatment with Tam, actually become growth-stimulated by Tam (Canney et al, 1987; Gottardis and Jordan, 1988; Howell et al, 1992). There are no good tests to differentiate between these phenotypes, and it is possible that seeds of each phenotype are present when breast cancer is first diagnosed. "
[Show abstract][Hide abstract] ABSTRACT: Tamoxifen (Tam) is effective for the treatment and prevention of breast cancer. However, it has toxic drawbacks and has limited-duration utility because, over time, human tumours become refractory to Tam. Recently, a new nontoxic peptide, alpha-fetoprotein-derived peptide (AFPep) has been proposed for the treatment and prevention of breast cancer. The purpose of this paper is to determine whether combining AFPep with Tam would increase efficacy and reduce toxicity in experimental models of breast cancer. Low doses of AFPep and Tam were more effective in combination than either agent alone against breast cancer growth in cell culture, in tumour-xenografted mice, and in carcinogen-exposed rats. alpha-Fetoprotein-derived peptide interfered with Tam-induced uterine hyperplasia in immature mice, and showed no toxic effects. Unlike Tam, AFPep did not inhibit binding of oestradiol (E(2)) to oestrogen receptor (ER). Thus, these two agents utilise different mechanisms to interfere with ER functionality, yet work cooperatively to reduce breast cancer growth and alleviate Tam's troubling toxicity of uterine hyperplasia and appear to be a rational combination for the treatment of ER-positive breast cancer.
British Journal of Cancer 09/2007; 97(3):327-33. DOI:10.1038/sj.bjc.6603882 · 4.84 Impact Factor
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