The Breast (I997) 6. l86kl89
`© 1997 Pearson Professional Lld
`
`ORIGINAL ARTICLE
`
`Duration of remission to ICI 182,780 compared to megestrol acetate in tamoxifen
`resistant breast cancer
`
`J. F. R. Robertson, A. Howell*, D. J. De Friend*, R. W. Blarney and P. Walton’
`
`Department of Surgery, City Hospital, Nottingham, *CRC Department, Medical Oncology, Christie Hospital, Manchester,
`lleneca Pharmaceuticals, Macclesfield, UK
`
`S U M M A R Y. Recently we reported that treatment with the specific (pure) antioestrogen, ICI 182,780, in 19 patients with
`advanced breast cancer resistant to tamoxifen resulted in a high response rate and a long median duration of remission (> 22
`months). In order to assess the relative value of ICI 182,780 in this clinical situation we have compared its activity with that
`of megestrol acetate, the standard second-line endocrine therapy in a group of similarly selected patients.
`Each ICI 182,780 treated patient was matched with three patients who received megestrol acetate (n = 57). Both groups
`were previously treated with tamoxifen. Patients were matched for age, site of metastases, prior tamoxifen therapy (for
`adjuvant or advanced disease) and therapeutic response to tamoxifen where given for advanced disease and therapeutic
`response to second-line therapy (i.e. ICI 182,780 or megestrol acetate). The duration of remission (PR or SD) was signifi-
`cantly longer for patients treated with ICI 182,780 compared to megestrol acetate (26 months and 14 months respectively,
`P = 0.04). These findings support further clinical comparison between ICI 182,780 and established endocrine agents.
`
`INTRODUCTION
`
`The antioestrogen, tamoxifen, has become established as
`the initial endocrine therapy of choice in postmenopausal
`patients with advanced breast cancer. In some patients the
`cancer shows primary resistance whilst in the remainder,
`although initially responsive, the cancer eventually develops
`acquired resistance to tamoxifen. The choices for further
`endocrine manipulation most commonly are either a synthe-
`tic progestin (e.g. megestrol acetate, medroxy-progesterone
`acetate) or an aromatase inhibitor (e.g. aminoglutethimide,
`4-hydroxy androstenedione, anastrozole or letrozole).
`We have recently reported a phase II study of the new
`specific antioestrogen ICI 182,780 used as second-line
`endocrine therapy in 19 patients with tamoxifen-resistant
`advanced breast cancer.” Rather surprisingly for a second
`antioestrogen, not only did most patients respond but the
`median duration of remission (>22 months) was longer
`than expected for a second-line endocrine agent such as
`megestrol acetate3 or aminoglutethimide.“
`The Notingham Breast Unit previously reported on a
`large series of patients with advanced breast cancer treated
`with megestrol acetate. Interestingly, in patients who had
`
`Address correspondence to: J. F. R. Robertson, Department of Surgery,
`City Hospital, Nottingham NG5 IPB, UK
`
`186
`
`shown disease remission (stable disease or objective
`response) on tamoxifen, 62% subsequently showed a remis-
`sion to megestrol acetate — a figure similar to that reported
`for ICI 182,780. However, the median duration of remission
`in patients treated with megestrol acetate was only 15
`months} We therefore decided to compare the duration of
`remission to ICI 182,780 versus megestrol acetate in
`matched tamoxifen-resistant patients. For this comparative
`study we identified patients from the Nottingham and
`Manchester units treated with megestrol acetate as second-
`line endocrine therapy after tamoxifen and selected a group
`of patients with similar clinical characteristics to those
`reported in our recent phase II study of ICI 182,780.
`
`PATIENTS AND METHODS
`
`A detailed description of 19 patients treated with ICI
`182,780 has been published.” All were postmenopausal,
`less than 81 years and had advanced histologically proven
`breast cancer. The patients were selected as having endo-
`crine responsive tumours based on their previous treatment
`with tamoxifen:
`
`(1) If they had been treated with tamoxifen as adjuvant
`therapy for more than 2 years before disease relapse;
`or
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`(2) If they had been treated with tamoxifen for advanced
`disease and had shown a complete or partial
`remission, or static disease by International Union
`Against Cancer (UICC) criteriag for at least 6
`months” and subsequently progressed.
`
`For each of the 19 patients treated with ICI 182,780 we
`matched three control patients who had received megestrol
`acetate. Patients were matched on the basis of age, site of
`disease, response to prior tamoxifen therapy and response to
`second-line therapy (i.e. ICI 182,780 or megestrol acetate)
`(Table). It was not possible to match for oestrogen receptor
`(ER) or progesterone receptor status owing to lack of data
`concerning tumour hormone receptor content on a large
`number of the historical control group of patients.
`The matching appeared to be satisfactory on all criteria
`(Table). Matching for the main sites of disease (i.e. bone,
`lung and viscera) was perfect while for age of patient (1 5
`years) it was good. Matching for prior therapeutic response
`was perfect
`in 10 patients who received tamoxifen for
`advanced disease. The matched patients who received
`megestrol acetate were treated initially with megestrol
`acetate up to 12 years ago. The routine use of tamoxifen
`as an adjuvant therapy prior to this time was not standard
`therapy. Matching the nine ICI 182,780 treated patients who
`more recently received tamoxifen as adjuvant therapy with
`a similar group of megestrol acetate treated patients proved
`more difficult. In order to weigh the matching in favour of
`the megestrol acetate treated group we matched megestrol
`acetate treated patients whose tumours had shown disease
`remission on tamoxifen for advanced disease (i.e. endocrine
`sensitive) as controls for the ICI 182,780 treated patients
`who received tamoxifen as adjuvant therapy:
`it
`is more
`difficult to be certain that a tumour is responsive to adjuvant
`therapy. The overall rate of disease remission (objective
`
`Table Matching megestrol acetate treated patients with ICI 182.780
`treated patients
`
`ICI 182.780 Megestrol acetate
`(n = 19)
`(n = 57)
`
`Site of metastases matched
`
`Age (1- 5 years)
`(x 10 years)
`(> 10 years)
`Prior tamoxifen therapy
`Advanced disease
`— therapeutic remission matched
`Adjuvant therapy — matched
`
`Secondaline therapy
`Therapeutic remission (OR + SD)
`Progressive disease
`
`19
`
`13
`3
`3
`
`10
`9
`
`13
`6
`
`57
`
`39
`9
`9
`
`30
`1017*
`
`36
`21
`
`*1t was not possible to match megestrol acetate treated patients for prior
`adjuvant tamoxifen therapy (11 = 17). We matched for tamoxifen therapy
`in advanced disease where patients had shown disease remission
`(objective response [n = 13] and static disease [n = 4].
`
`Duration of remission to specific antioestrogen
`
`187
`
`response + static disease) to second-line therapy was 13 out
`of 19 (69%) for the ICI 182,780 treated patients compared
`to 36 out of 57 (63%) for megestrol acetate treated patients.
`The ICI 182,780 and the megestrol acetate treated
`patients were followed up regularly at similar intervals in
`the same outpatient clinics in each of the two centres
`(Nottingham and Manchester).
`
`STATISTICS
`
`Duration of remission and overall survival between the
`
`two groups was compared using the Lee-Desu statistic ~ a
`modification of Gehan’s generalized Wilcoxon test. The
`analysis was carried out using SPSS for Windows (SPSS
`UK Ltd).
`
`RESULTS
`
`The disease stabilization rate (objective response + static
`disease) was 13 out of 19 (69%) for ICI 182,780 and 36
`out of 57 (63%) for megestrol acetate. The duration of
`remission was significantly longer in the group of patients
`treated with ICI 182,780 (26 months) compared to mege-
`strol acetate (14 months) (Fig. 1, P: 0.04). The survival
`curves diverge in a similar pattern to the duration of remis-
`sion but as yet there is no significant difference in survivial
`between these two groups, although it should be emphasised
`that the number of patients in each group is small (Fig. 2).
`Ten of the ICI 182,780 treated patients have gone on
`to receive megestrol
`acetate
`as
`third-line
`endocrine
`therapy. None showed an objective response. Nine patients
`progressed within 6 months of starting megestrol acetate
`and the remaining patient had static disease at 6 months.
`
`DISCUSSION
`
`The development of specific antioestrogens has resulted in
`a new class of endocrine agents for the treatment of breast
`cancer. Experimental work using either the lead compound
`ICI 164,384, or ICI 182,780, which has greater affinity for
`the ER, suggested that these compounds were more potent
`than tamoxifen at inhibiting oestradiol stimulation of hor-
`mone responsive breast cancer cell 1ines.‘°‘” It was recently
`reported that for endocrine naive MCF-7 xenografts grown
`in nude mice the time to progression using ICI 182,780 was
`double that obtained with tamoxifen (200 and 104 days
`respectively)” Other studies have also shown that even
`where breast cancer cell
`lines have developed acquired
`resistant to tamoxifen they may still be sensitive to the pure
`antioestrogens.”
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`Comparison of duration of remission (Fig. 1) suggested that
`ICI 182,780 may maintain breast tumours in remission for
`significantly longer than megestrol acetate. The majority of
`randomized clinical
`studies have reported therapeutic
`equivalence of tamoxifen and megestrol acetate as first—line
`endocrine therapy'“"’8 suggesting indirectly that ICI 182,780
`may be a therapeutic advance over not only megestrol
`acetate but also current antioestrogenic agents. The only
`direct comparison on remission times between the pure
`antioestrogens and tamoxifen is the experimental data from
`breast cancer xenograft studies. Remission durations in
`mice treated with ICI 182,780 were more than twice as long
`as mice treated with tamoxifen.” It is of great interest that
`in both the experimental and the clinical studies the dura-
`tion of remission to ICI 182,780 has been twice that seen
`with currently available endocrine agents (tamoxifen and
`megestrol acetate respectively). Since the first prospective
`randomized clinical trial comparing ICI 182,780 with an
`established endocrine agent has yet to start it will be at
`least 5 years before a comparison can be made of duration
`of remission. The matched comparison presented in this
`paper may therefore be an important early identification
`of a potential clinical benefit of ICI 182,780 over other
`endocrine agents.
`10 patients who developed acquired
`None of the
`resistance to ICI 182,780 subsequently showed an objective
`response to metestrol acetate as third-line therapy. This par-
`ticular group of patients did have endocrine sensitive
`tumours (to first and second-line antioestrogen therapies).
`Therefore, while the number of patients (n = 10) was small
`a proportion might have been expected to show an objective
`response to a third-line endocrine agent. Clearly the con-
`fidence limits must be large with such a small number
`of patients but this early finding raises the hypothesis as
`to whether acquired resistance to ICI 182,780 may be
`equivalent to developing an endocrine resistant phenotype.
`This finding also needs to be addressed in a larger study.
`
`References
`
`1. Howell A, DeFriend D, Robertson J, Blarney R, Walton P. Response
`to a specific anti-oestrogen (ICI 182,780) in tamoxifen resistant
`breast cancer. Lancet 1995; 345: 29-30.
`2. Howell A, DeFriend D, Robertson J F R et al. Pharmacokinetics,
`pharmacological and antitumour effects of the specific antioestrogen
`ICI 182,780 in women with advanced breast cancer. Br J Cancer
`1996; 74: 300-308.
`3. Robertson J F R, Williams M R, Todd J, Nicholson R 1, Morgan
`D A L, Blarney R W. Factors predicting the response of patients
`with advanced breast cancer to endocrine (Megace) therapy. Eur J
`Cancer Clin Oncol 1989; 25: 469-475.
`4. Smith I E, Harris A L, Morgan M et al. Tamoxifen versus
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`
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`188
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`The Breast
`
`100
`90
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`42
`fi
`a.
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`70
`60
`50
`40
`so
`20
`n=36
`—.—MA
`10
`-u-|C|182,7B0 n=13
`—-1
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`.———u—-
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`0. wjr-—-1 ——
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`6 912151B212421303336
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`months
`
`Fig. 1 DoR in patients achieving OR or SD on MA or ICI 182,780.
`MA = megestrol aoetate, DoR = duration of remission, OR = objective
`response, SD = static disease.
`
`100
`90
`80
`70
`60
`50
`40
`30
`10
`10
`0
`
`“I.
`
`survival -.— MA
`
`nIGG
`4401182, 750 n=13
`y— 1
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`3
`6
`9
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`ll
`
`I
`12
`
`.
`15
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`1
`18
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`21
`
`l
`24
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`1
`17
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`1
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`
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`
`Fig. 2 Survival of patients achieving OR or SD on MA or ICI 182,780.
`MA = megestrol acetate, OR = objective response, SD = static disease.
`
`An initial phase I study using ICI 182,780 reported
`biological evidence of antioestrogenic effects on endocrine
`naive human breast cancers in vivo even after only 7 days
`treatment. Furthermore, in contrast to tamoxifen, there was
`no evidence of agonist activity.” A subsequent phase II
`study showed that ICI 182,780 produces responses in
`patients with tamoxifen resistant breast cancer.‘ These
`clinical studies matched the preclinical experimental data
`and confirmed that ICI 182,780 appeared to act as a specific
`antioestrogen without agonistic activity and while human
`breast cancers might develop tamoxifen resistance this
`should not be equated to resistance to pure antioestrogens.
`These results with ICI 182,780 in tamoxifen resistant breast
`cancer are in contrast to other new antioestrogens, such as
`toremifene and idoxifene.”
`In patients with tamoxifen resistant breast cancer it will
`require a randomized study to determine whether
`the
`response rate is significantly different for ICI 182',78O
`compared to other endocrine agents as second-line therapy.
`Nevertheless, by matching the megestrol acetate treated
`controls closely to the ICI 182,780 treated patient we have
`obtained two groups with similar characteristics in relation
`to the patient (age), the disease (site of metastases), pre-
`vious
`endocrine
`therapy
`(tamoxifen)
`and endocrine
`sensitivity (response to first and second-line therapies).
`
`

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