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 who fulfilled the following criteria were selected from the departmental database and the case-notes were retrospectively reviewed: Seventeen patients with median age of Two patients remain on "withdrawal therapy" at the time of analysis.
This applies not only to "withdrawal" from tamoxifen, but also from other categories of endocrine agents. It should be considered as part of the sequencing of endocrine therapy. Estrogen receptor ER positive breast cancers after a period of response to anti-estrogens develop resistance and clinically the disease progresses.
Besides the predominant role of alternative signalling pathways, domination of partial agonistic activity of tamoxifen over its antagonist activity has been implicated for acquired resistance [ 1 ]. Regression of tumor on cessation of tamoxifen therapy and the resultant clinical benefit CB have been reported in several case-reports and series [ 2 - 6 ]. In-vitro experiments have also shown that "withdrawal" of tamoxifen inhibits growth of tumor cells [ 7 ], tamoxifen remaining in body after discontinuation.
We report clinical relevance of "withdrawal therapy" from tamoxifen and other hormonal agents in patients heavily pre-treated with endocrine therapy. Case-notes of the breast cancer patients treated in the Nottingham breast unit since fulfilling the following criteria were studied retrospectively:.
Duration of CB DoCB is the duration of therapy in months only in patients who have derived CB and including patient still on treatment. Duration of treatment DoT is the duration of therapy in months of all patients regardless of the type of response and including patient still on treatment. Two patients were still on follow-up at analysis.
Drugs prior to withdrawal were mostly several lines of endocrine agents tamoxifen, aromatase inhibitors, AIs- letrozole and exemestane, fulvestrant, megestrol acetate but some tamoxifen remaining in body after discontinuation radio and chemotherapy as necessary.
Tamoxifen may continue to provide antagonistic activity on ER nuclear signalling activity but may act as an agonist on the ER membrane signalling activity which could explain the loss of continuing CB to some patients on long-term tamoxifen therapy [ 1 ]. 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 [ 46 ]. An in vitro study of cells derived from tumors of post-menopausal patients which progressed on tamoxifen showed growth enhanced by addition of tamoxifen [ 11 ] suggesting domination of agonistic activity on long-term tamoxifen therapy.
In an in-vivo study [ 12 ], athymic tamoxifen remaining in body after discontinuation were transplanted with ER positive tumor cells and then exposed to tamoxifen or placebo. The tumors regressed initially over 4 months but started to grow towards the end of the study 8 months on long-term exposure to tamoxifen and placebo.
Tumors from both groups were re-transplanted into athymic mice. Tumors which grew in the presence of tamoxifen grew either on exposure to estrogen or on exposure to further tamoxifen. In clinical setting, therefore, cessation of further growth would be expected on withdrawal of tamoxifen therapy at development of resistance to tamoxifen. Our case-series and previously reported case series confirm this finding in clinical setting.
The lack of response in the remaining patients on withdrawal of tamoxifen could partly be explained by the growth promoting action of natural estrogen in the body as seen in the above in-vivo study [ 12 ]. Therefore, if "withdrawal therapy" from tamoxifen does not provide any clinically beneficial response, an AI or fulvestrant may be the subsequent endocrine agents of choice to negate the effects of persisting estrogen. This tactic of manipulating hormonal environment of the tumor provides a viable intercalating option between endocrine agents without possible side-effects.
No further endocrine therapy was instituted as they already had multiple lines of other therapies. On routine clinical follow-up, incidental responses were seen in these patients. It is difficult to explain incidental responses to withdrawal from categories of endocrine agents other than tamoxifen or an AI.
It could be due to paradoxical action of natural tamoxifen remaining in body after discontinuation rebounding after "withdrawal" of anti-estrogens without agonist activity [ 113 ]. In an in-vitro study in MCF-7 cells by Masamura et al [ 14 ] long-term estrogen deprivation akin to usage of anti-estrogens in the form of AIs clinically led these cells to develop estrogen hypersensitivity. In a long-term estrogen deprived tamoxifen remaining in body after discontinuation resistant breast cancer cell model MCF This is again possible due to activation of cross-talk mechanisms and domination of mitogen-activated protein kinase or growth factors [ 1 ].
The above in-vitro concept is being explored further in clinical settings. The rationale for this study is that long-term estrogen deprivation by an AI reduces the sensitivity of the tumour cells to therapy tamoxifen remaining in body after discontinuation interruptions to therapy allows resurgence of estrogenic stimulation leading to restoration of sensitivity to letrozole on its reintroduction.
In locally advanced and advanced breast cancer, ideally, inhibitors of the alternative pathways would be the subsequent logical therapy following resistance to other endocrine agents. However, if the patient is unfit to receive any further anti-estrogen therapy then it is very likely that they would not be suitable for further growth factor inhibitors or indeed chemotherapeutic agents. In this circumstance, withdrawal of therapy may be the only feasible option or alternating regime of endocrine therapy and withdrawal therapy as is being tested in the adjuvant setting in the SOLE trial, tamoxifen remaining in body after discontinuation.
Our data therefore provides some clinical evidence and emphasises the relevance of withdrawal therapy. The concept is being tested in large randomised trials in adjuvant settings. However, tamoxifen remaining in body after discontinuation, larger datasets and results of ongoing adjuvant trials are needed to provide confirmatory evidence for or against the concept and feasibility of withdrawal therapy in locally advanced and metastatic tamoxifen remaining in body after discontinuation cancer.
KLC conceived this study. AA collected data, performed analysis, drafted, revised and finalised the manuscript. All authors read and approved the final manuscript.
National Center for Biotechnology InformationU. World J Surg Oncol. Published online Sep 9. Received Apr 2; Accepted Sep 9. This article has been cited by other articles in PMC. Abstract Background It has been shown in in-vitro experiments that "withdrawal" of tamoxifen inhibits growth of tumor cells.
Methods Breast cancer patients since who fulfilled the following criteria were alcoholism pancreatic cancer from the departmental database and the case-notes were retrospectively reviewed: Results Seventeen patients with median age of Conclusion "Withdrawal therapy" appears to produce sustained CB in a significant proportion of patients.
Background Estrogen receptor ER positive breast cancers after a period of response to anti-estrogens develop resistance and clinically the disease progresses. Methods Case-notes of the breast cancer patients treated in the Nottingham breast unit since fulfilling the following criteria were studied retrospectively: Table 1 Patient and Tumour characteristics.
Open in a separate window. Table 2 Disease distribution and Clinical results. Discussion Tamoxifen may continue to provide antagonistic activity on ER nuclear signalling activity but may act as an agonist on the ER membrane signalling activity which could explain the loss of continuing CB to some patients on long-term tamoxifen therapy [ 1 ]. Conclusions Our data therefore provides some clinical evidence and emphasises the relevance of withdrawal therapy.
Conflict of interests The authors declare that they have no competing interests. Tamoxifen-induced tumor stimulation and withdrawal response, tamoxifen remaining in body after discontinuation. Response of metastatic breast cancer to tamoxifen withdrawal: Clinical significance of tamoxifen withdrawal response. Report of a case. Response after withdrawal of tamoxifen and progestogens in advanced breast cancer.
Reversal of tamoxifen resistant breast cancer by low dose estrogen therapy. J Steroid Biochem Mol Biol. Automated quantitation of immunocytochemically localized estrogen receptors in human breast cancer.
Assessment of response to treatment in advanced breast cancer. Assessment of response to therapy in advanced breast cancer: In vitro growth promotion of human mammary carcinoma cells by steroid hormones, tamoxifen, tamoxifen remaining in body after discontinuation, and prolactin, tamoxifen remaining in body after discontinuation.