Breast Cancer Research and Treatment 18: 165-170, 1991.
`© 1991 Kluwer Academic Publishers. Printed in the Netherlands.
`
`Report
`
`Phase II evaluation of interferon added to tamoxifen in the treatment of
`metastatic breast cancer
`
`Janet E. Macheledt, Aman U. Buzdar, Gabriel N. Hortobagyi, Debra K. Frye, Jordan U. Gutterman! and
`Frankie Ann Holmes
`From the Department of Medical Oncology (Medical Breast Service), and 1 Clinical Immunology & Biological
`Therapy, The University of Texas M.D. Anderson Cancer Center, Houston, Texas, USA
`
`Key words: breast neoplasms, tamoxifen, interferon, tumor resistance
`
`Abstract
`
`This phase II trial evaluated the clinical role of interferon (IFN) in overcoming tamoxifen (TAM) resistance
`in breast cancer. Twenty women and 1 man received recombinant alpha interferon (5 million units per meter
`squared intramuscularly, 5 times per week) plus TAM (10mg orally, twice daily) for the treatment of
`metastatic breast cancer, either after failing tamoxifen therapy or as frontline hormonal therapy.
`Of the 9 evaluable patients with disease progression after an objective response to TAM, there were no
`partial or complete responses with the addition of IFN. Ten evaluable patients received TAM plus IFN as
`frontline hormonal therapy with 2 complete and 3 partial responses for an overall response rate (RR) of 50%
`(95% confidence interval == 19-81), a 71 % RR for ER-positive patients (95% confidence interval == 29-96)
`and no responses in ER-unknown patients.
`Sixteen patients required dose reductions of IFN and 8 patients discontinued therapy due to toxicity.
`It is unlikely that the RR for TAM plus IFN is greater that than seen with TAM alone, or that the addition
`of IFN to TAM therapy can overcom~ clinical TAM resistance.
`
`Endocrine therapy plays an important role in the
`management of breast cancer [1]. Approximately
`30% of unselec!ed patients and 50 to 60% of pa(cid:173)
`tients with estrogen receptor (ER) positive tumors
`will respond to hormonal manipulations [2]. In ad(cid:173)
`dition, response rates are proportional to the level
`of ER [2], and resistance is often associated with a
`loss of the ER [3,4]. This suggests that the presence
`of a functioning ER is important for the action of
`antiestrogen drugs and up-regulation of the ER
`may retard or reverse the process of hormonal
`resistance.
`Interferons are known to have anti-tumor activ(cid:173)
`ity in vitro [5-8]. But despite early reports that
`
`leukocyte interferon produced partial responses in
`breast cancer [9, 10], the results of recent clinical
`trials using interferons as single-agent or adjuvant
`therapy for breast cancer have been disappointing
`[11, 12]. However, interferons affect a wide range
`of cellular functions and can modulate the ER in
`experimental systems. Both alpha and beta interfe(cid:173)
`ron have been reported to increase the ER activity
`in human breast cancer tissue [13] and in breast
`cancer cell lines [7, 14], although three studies have
`demonstrated either no change or a reduction in
`the ER of breast cancer cell lines incubated with
`alpha, beta, or gamma interferon [5, 6, 15]. Two in
`vivo studies have also reported conflicting results;
`
`Address for offprints: A.U. Buzdar, 1515 Holcombe, Box 78, Houston, TX 77030, USA
`
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`J E Macheledt et al.
`
`the ER and progesterone receptor (PR) status of
`skin nodules from breast cancer patients increased
`with gamma interferon [16], but no change was
`seen in the ER or PR of endometrium from preme(cid:173)
`nopausal women receiving leukocyte interferon
`[17].
`If interferon can up-regulate the ER in breast
`cancer, adding interferon to antiestrogen therapy
`might increase the response rate or duration of
`response to hormonal therapy. This study evaluat(cid:173)
`ed the clinical role of alpha interferon in over(cid:173)
`coming resistance to anti estrogen therapy in breast
`cancer.
`
`units per meter squared (mu/m2
`) intramuscularly,
`which was self-administered daily for five days each
`week. After the first 15 patients required dose re(cid:173)
`ductions of IFN, the starting dose was decreased to
`2.5 mu/m2 daily for 5 days each week. The dose of
`IFN was reduced by 50% if a patient experienced
`> grade 2 toxicity.
`Patients were evaluated at least every 6 weeks
`for evidence of a response using the criteria defined
`by the UICC [18].
`
`Patient selection and methods
`
`Table 1. Characteristics of patients treated with interferon and
`tamoxifen therapy
`
`Patients with metastatic breast cancer who were
`ER-positive or ER-unknown were eligible for the
`study. Patients had to have clearly measurable dis(cid:173)
`ease and a Zubrod performance status < 3. All
`patients signed an informed consent according to
`institutional policy. Patients were excluded from
`the study if they had received TAM in the past but
`had been off TAM for greater than 1 month, had a
`previous or concurrent primary malignancy with
`the exception of carcinoma in-situ of the cervix or
`squamous cell carcinoma of the skin, or if meta(cid:173)
`static disease involved greater than one-third of the
`liver.
`Group I included patients who were showing
`evidence of disease progression after an objective
`response to TAM therapy, and IFN was added to
`TAM therapy. In addition, some patients with no
`prior history of TAM treatment who were ER(cid:173)
`positive or ER-unknown received TAM plus IFN
`as front-line hormonal therapy (Group II).
`All patients received a history and physical ex(cid:173)
`amination. Laboratory studies included a complete
`blood count, serum chemistries, and a carcinoem(cid:173)
`bryonic antigen, and the extent of disease was doc(cid:173)
`umented by direct measurement or radiographical(cid:173)
`ly. ER and PR levels were obtained when possible.
`All patients were either continued on (Group I)
`or started on (Group II) TAM at a dose of lOmg
`orally twice daily. The initial dose of recombinant
`alpha interferon, Intron A (IFN), was 5.0 million
`
`Characteristic
`
`Sex
`
`Female
`Male
`Median age (years)
`Race
`White (including Hispanic)
`Black
`Menopausal status
`Pre or peri
`Post
`Performance status
`0
`
`2
`3
`Dominant disease
`Visceral
`Soft tissue
`Bone
`Number of disease sites
`
`2
`2:3
`Estrogen receptor
`< lO(ER -)*
`> 10(ER + )**
`Unknown
`Prior chemotherapy
`Adjuvant
`Peri-operative
`For metastatic disease
`
`* Estrogen receptor negative.
`** Estrogen receptor positive.
`
`Number (%)
`
`22
`1
`50
`
`20
`3
`
`10 (45)
`12 (55)
`
`7 (30)
`11 (48)
`3 (13)
`2 ( 8)
`
`11 (50)
`5 (23)
`6 (27)
`
`9 (41)
`9 (41)
`4 (18)
`
`1 ( 4)
`13 (59)
`8 (36)
`
`6 (27)
`2 ( 8)
`1 ( 4)
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`Phase II evaluation of interferon added to tamoxifen
`
`167
`
`Results
`
`Twenty-two women and one man with metastatic
`breast cancer were entered into this phase II study;
`23 were evaluable for toxicity and 19 were eva(cid:173)
`luable for response. Four patients were considered
`inevaluable; 2 patients discontinued IFN early due
`to toxicity, 1 patient, in retrospect, did not have
`evaluable baseline disease, and one patient contin(cid:173)
`ued TAMlIFN but did not return here for follow-up.
`Patient characteristics prior to entry into the
`study are shown in Table 1. Twenty patients were
`caucasian or hispanic and 3 were black. The age of
`the patients ranged from 27 to 76 with a median age
`of 50 years, and 78% had a Zubrod performance
`status of < 2. Ten women were pre- and 12 were
`postmenopausal.
`Of the 22 patients who had evaluable baseline
`disease, visceral disease was dominant in 50%,
`27% had primarily bone disease, and 23% had soft
`tissue involvement; 59% had more than one site of
`disease. Thirteen patients were ER-positive, 1 was
`ER-negative (ER = 9) but had responded to TAM,
`and 8 were ER-unknown; 36% had received prior
`chemotherapy.
`The major protocol toxicities (Table 2) included
`fatigue, myalgias, anorexia with weight loss, and
`
`fever. Depression or anxiety, alopecia, nausea and
`vomiting, and diarrhea were less common. Throm(cid:173)
`bocytopenia occurred in 3 patients and neutrope(cid:173)
`nia with an absolute granulocyte count < 1.0 mm3
`was seen in 3 patients receiving the full dose. A
`slight rise in serum aspartate transaminase was ob(cid:173)
`served in 5 patients, and 4-fold elevations were
`seen in 2 patients with a history of alcohol in(cid:173)
`gestion.
`The first 15 patients were started on IFN at the
`dose of 5 mu/m2
`• However, after IFN was discon(cid:173)
`tinued in 2 patients after 2 weeks and dose reduc(cid:173)
`tion was required in an additional 10 patients, the
`starting dose was reduced to 2.5 mu/m2
`• Dose andl
`or schedule reductions were also required in 4 of 8
`patients started at this level. A total of 8 of 23
`patients discontinued IFN due to toxicity after a
`median of 1 month (range 0.5 to 7.5) which was, in
`general, dose related. The dose of TAM remained
`unchanged and no unexpected toxicities occurred.
`In Group I, the median duration of responsive(cid:173)
`ness to prior TAM therapy was 13 months (range 7
`to 29 months), and there were no partial or com(cid:173)
`plete responses seen with the addition of IFN to
`TAM. One patient had a minor response and 2
`patients with stable disease at 1 month discontin(cid:173)
`ued the therapy due to toxicity.
`
`Table 2. Toxicity of tamoxifen plus interferon therapy (N* = 23)
`
`Grade
`
`0
`N (%)
`
`3 (13)
`9 (39)
`7 (30)
`5 (22)
`10 (43)
`15 (65)
`8 (35)
`15 (65)
`
`10 (43)
`
`17 (75)
`
`N(%)
`
`4 (17)
`9 (39)
`3 (13)
`6 (26)
`4 (17)
`5 (22)
`8 (35)
`3 (13)
`
`3 (13)
`5 (22)
`
`4 (17)
`
`2
`N(%)
`
`5 (22)
`5 (22)
`12 (52)
`12 (52)
`7 (30)
`2 ( 9)
`6 (26)
`4 (17)
`
`2 ( 9)
`
`0
`
`3
`N(%)
`
`11 (48)
`
`2 ( 9)
`1 ( 4)
`1 ( 4)
`1 ( 4)
`
`2( 9)
`
`1(4)
`
`4
`N(%)
`
`1(4)
`
`1(4)
`
`Fatigue/weakness
`Myalgias/arthralgias
`Anorexia/weight loss
`Fever/chills
`Depression/ anxiety
`Alopecia
`Nausea/vomiting
`Diarrhea
`Hematologic
`Thrombocytopenia
`Neutropenia
`Serum aspartate
`transaminase elevation
`
`* Number.
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`IE Macheledt et al.
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`Of the 10 evaluable patients from Group II, 2
`achieved a complete response of 10 + and 19 +
`months duration and are continuing therapy, and 3
`had a partial response for an overall response rate
`of 50% (95% confidence interval (CI) = 19-81 %).
`One patient had a minor response, 3 patients had
`stable disease, and 1 patient progressed during 1
`month of therapy. All 5 patients with objective
`responses were ER-positive, 3 of the 5 were PR(cid:173)
`positive, and there were no responses among the 3
`patients who were ER-unknown. One ER-positive
`patient had evidence of progressive liver disease
`after 1 month of TAM/IFN, but continued the ther(cid:173)
`apy elsewhere with reportedly a complete response
`lasting 22 months which could not be confirmed
`radiographically. Including this patient would in(cid:173)
`crease the response rate to 54%.
`Overall, the median time-to-progression was
`10 + months (range 7.5 to 19 +) for responders,
`and 5 months (range 3 to 12 months) for those with
`stable disease on TAM/IFN.
`
`Discussion
`
`Up-regulation of the ER might overcome resist(cid:173)
`ance to antiestrogen therapy and prolong the sur(cid:173)
`vival of patients with metastatic breast cancer. Al(cid:173)
`though interferons have been shown to modulate
`the ER status in vitro, no clinical trials to assess the
`effect of IFN on tumor responsiveness to hormonal
`therapy have been published. This study demon(cid:173)
`strated that the addition of IFN, as utilized in this
`study, does not appear to overcome TAM resist(cid:173)
`ance in patients with metastatic breast cancer. In
`Group I, only 2 patients with tumor progression on
`TAM had short-term disease stabilization with the
`addition of IFN, and both of these patients had had
`a long disease-free-interval prior to the develop(cid:173)
`ment of metastatic disease (41 and 64 months),
`suggesting that the modest benefit might only re(cid:173)
`flect the biological behavior of the tumor.
`Group II demonstrated an overall response rate
`to TAM/IFN of 50% (CI = 19 to 81%), a 71%
`response rate for ER-positive patients (CI = 29 to
`96%) and no responses in patients whose ER status
`was unknown. The published response rates to
`
`TAM for ER -positive tumors is 50 to 60%, ER - and
`PR-positive tumors is 70%, and ER-unknown tu(cid:173)
`mors is 30% [2]. Given that 4 of the 5 responding
`patients had ER levels> 50 and 3 of the 5 were PR
`positive, both of which predict for TAM sensitivity,
`it is unlikely that the response rate to TAM/IFN
`was greater than that which would have been ex(cid:173)
`pected with TAM alone (5% rejection error) [19];
`the data is insufficient to evaluate the impact of
`IFN on response duration. Although the CIs are
`wide, these results do not support the addition of
`IFN to overcome clinical TAM resistance.
`There are several possible explanations for the
`lack of therapeutic advantage to adding interferon
`to overcome TAM resistance in breast cancer.
`First, although in vitro data suggests that alpha
`interferon can increase ER activity in breast cancer
`cells, there is no similar evidence in vivo. Unfortu(cid:173)
`nately, no tissue was available to document mod(cid:173)
`ulations in the receptor status during therapy. Sec(cid:173)
`ondly, if IFN up-regulated the ER, it may not have
`been functional; hormonally insensitive breast can(cid:173)
`cer cells with abnormal receptors have recently
`been described [20]. And finally, it has been sug(cid:173)
`gested that tumors contain heterogeneous mixtures
`
`Table 3. Objective response rates to tamoxifen (TAM) plus
`interferon therapy by history of prior TAM exposure
`
`Prior TAM
`N= 10
`number
`
`No prior TAM 95% CF
`N= 13
`number (%)
`
`Complete response (CR) 0
`Partial response (PR)
`0
`Minor response
`2
`Stable disease
`Stable disease but stopped 3
`due to toxicity
`Progressive disease
`Not evaluable
`Overall response rate
`(CR+ PRJ
`Response rate for
`ER3 positive
`Response rate for
`ER unknown
`
`3
`
`0/9
`
`2
`3
`
`3
`o
`
`3
`5110 (50%)
`
`19-81
`
`517 (71%)
`
`29-96
`
`0/3
`
`1 does not include the patient with the undocumented CR.
`2 Confidence interval.
`3 Estrogen receptor.
`
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`Phase II evaluation of interferon added to tamoxifen
`
`169
`
`of cells with different sensitivities to antiprolifer(cid:173)
`ative agents [21]. Hormonally insensitive breast
`cancer cell lines can have fully functional ERs
`where the response to antiestrogen therapy would
`be unrelated to receptor status [22, 23]. In addi(cid:173)
`tion, a heterogeneous breast cancer tumor model
`in mice suggests that it is the hormone-independent
`or interferon-insensitive elements that are respons(cid:173)
`ible for therapeutic failures with these agents [24].
`In conclusion, this phase II study did not demon(cid:173)
`strate a therapeutic benefit of adding alpha in(cid:173)
`terferon to TAM therapy in order to overcome
`TAM resistance in patients with metastatic breast
`cancer who had developed resistance while on
`TAM therapy or who had never been treated with
`TAM. However, the interactions between the hor(cid:173)
`mone receptor status, antiestrogen therapy, and
`interferons are complex, and the role of interferon
`in the treatment of breast cancer remains to be
`defined.
`
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