Current Status of High-Dose Progestins in Breast Cancer
`
`Jeffrey S. Abrams, Howard Parnes, and Joseph Aisner
`
`Progestins at standard doses have compared favorably
`with tamoxifen for the front-line treatment of women
`with metastatic breast cancer. Attempts to further en-
`hance the role of progestins have centered on dosage
`escalation, based on European data suggesting a dose-
`response effect. A phase l/Il pilot trial at the University
`of Maryland demonstrated that doses of megestrol ac-
`etate up to 1,600 mg/d were well tolerated for prolonged
`periods. Responses were seen in patients whose disease
`was refractory to both standard doses of megestrol ac-
`etate and to tamoxifen. Different mechanisms of pro-
`gestin action on breast tumors are theorized at the higher
`doses, which could account for the dose-response effect.
`Two large mum-institutional dose comparison trials of
`megestrol acetate in metastatic breast cancer have been
`undertaken in the United States. The Piedmont Oncology
`Association recently reported a significant benefit for
`megestrol acetate 800 mg/d compared with the standard
`160 mg/d in terms of response and disease-free and
`overall survival. The largest trial is currently ongoing in
`the Cancer and Leukemia Group 8. They are comparing
`800 and 1,600 mg/d with standard doses. and results
`from this study are eagerly anticipated.
`© 1990 by WB. Saunders Company.
`
`YNTHETIC PROGESTINS have a well-es-
`
`tablished role in the palliation of metastatic
`breast cancer. The two most widely tested pro-
`gestins, megestrol acetate (Megace, Bristol-Myers,
`Evansville, IN) and medroxyprogesterone ace-
`tate, have demonstrated overall response rates of
`about 30% in unselected patients,"3 a rate similar
`to that associated with other commonly used
`hormonal
`therapies.
`In addition, several ran-
`domized trials have shown that megestrol acetate
`and the antiestrogen tamoxifen induce compa-
`rable response rates in untreated patients with
`metastatic disease, with no differences in response
`duration or survival.“‘7 Although the side effects
`of both megestrol acetate and tamoxifen are mild,
`close scrutiny of their toxicity profiles reveals sig-
`nificant differences: weight gain and increased
`appetite are the most common side effects of me-
`gestrol acetate, while tamoxifen more frequently
`
`From the Division ofMedieal Oncology. Department of
`Medicine. University of Maryland Cancer Center. Baltimore.
`Address reprint requests to Jeffrey S. Abrams. MD. Assistant
`Professor ofMedicine and Oncology. University ofMaryland
`Cancer Center. 22 South Greene St. Baltimore, MD 2 I 20] .
`(C) 1990 by W. B. Saunders. Company.
`0093- 7 754/90/1 706— 9008505. 00/0
`
`causes tumor flare, vaginal bleeding, and hot
`flashes.2
`
`Unlike tamoxifen. progestins have not yet been
`adequately tested in the adjuvant setting. They
`have, therefore, generally been reserved for use
`in patients whose disease has relapsed on adju-
`vant tamoxifen therapy and who have non—life-
`threatening disease. For those women whose dis-
`ease progresses after tamoxifen. progestins are the
`treatment of choice when further hormonal ther-
`
`apy is indicated. Progestins may be preferable to
`tamoxifen as first-line therapy in women with
`metastatic disease who are underweight or an-
`orexic. The proven effectiveness of the progestins
`in advanced breast cancer has encouraged efforts
`to further exploit these drugs by increasing their
`dosage.
`
`HlGH-DOSE PROGESTIN THERAPY
`
`Although very low doses of progestins have
`been effective in some patients,8 European studies
`conducted in the early 19805 indicated an im-
`proved response rate with increased doses of
`medroxyprogesterone acetate.9 These single-arm
`trials provided the impetus for further exploration
`of the dose-response question of progestin therapy
`in breast cancer. The Swiss Group for Clinical
`Research conducted the largest randomized trial
`evaluating this issue”): they compared medroxy-
`progesterone acetate 1,000 mg intramuscularly
`(IM) givcn Monday through Friday for 4 con-
`secutive weeks with 500 mg IM given twice
`weekly for 4 weeks. Responding patients were
`maintained on 500 mg IM once weekly until
`progression. In that trial, 30 of 91 (31%) patients
`on the high-dose arm responded compared with
`14 of 93 (15%) on the low-dose arm (P = .004).
`There were no differences between the two
`
`groups, however, in median duration of response,
`time to progression, or survival. Although other
`randomized trials did not confirm such a differ-
`
`ence in response according to dose. all of those
`trials had small numbers of patients and the
`dosage differentials were never more than two-
`fold.l "'3
`
`Interestingly, despite its better gastrointestinal
`absorption and bioavailability, megestrol acetate
`
`68
`
`Seminars in Oncology, Vol 17, No 6, Suppl 9 (December). 1990: pp 68-72
`
`AstraZeneca Exhibit 2149 p. 1
`InnoPharma Licensing LLC V. AstraZeneca AB IPR2017-00900
`Fresenius-Kabi USA LLC V. AstraZeneca AB IPR2017-01913
`
`

`

`HIGH-DOSE PROGESTINS lN BREAST CANCER
`
`69
`
`was not tested as extensively as medroxyproges-
`terone acetate in Europe.” Standard doses of
`megestrol acetate (160 mg/d) have been found to
`result in blood levels five to ten times higher than
`those seen with high doses of medroxyprogester-
`one acetate given either orally or lM.’5 and it has
`been estimated that 160 mg of oral megestrol ac-
`etate is equivalent to 1.000 mg of oral medroxy-
`progesterone acetate. Peak plasma levels of me-
`gestrol acetate occur 2 to 3 hours after a single
`oral dose, and the serum half-life is 15 to 20
`hours.”
`
`Alexieva-Figusch et a1” were among the first
`to study increased doses of megestrol acetate in
`patients with breast cancer. They administered
`consecutive 6-week treatments of 90. 180. and
`270 mg megestrol acetate in random sequence to
`l8 patients. Ten of the 18 patients responded,
`but plasma accumulation of megestrol acetate
`rendered the dose-response effect
`inevaluable.
`These researchers did note, however. that me-
`gestrol acetate at doses of l 80 and 270 mg/d. but
`not at 90 mg/d, produced complete suppression
`of the hypothalamic-pituitary—adrenal axis, and
`only the highest dose significantly increased basal
`insulin levels. This selective pharmacologic hy-
`pophysectomy leading to complete suppression
`of adrenal steroid secretion (including secretion
`of estradiol) also has been noted with medroxy-
`progesterone acetate'8 and may represent an im-
`portant mechanism of action of the progestins.
`As early as 1983. a pilot study was conducted to
`evaluate even higher doses of megestrol acetate
`(800 mg/d), but no definite conclusions were
`reached.'6 However. results of a recent.
`large,
`randomized study appear to indicate an advan-
`tage for higher doses (800 mg/d) compared with
`standard-dose treatment.’9 This has renewed in-
`
`terest in the mechanism of action of high-dose
`progestins.
`
`Potential Mechanisms Q/‘Actirm
`
`Precise explanations of the way in which pro-
`gestins combat breast cancer remain elusive, but
`it is likely that several mechanisms are involved
`(Table 1). It also is probable that the predominant
`effect of these semisynthetic progesterone deriv-
`atives varies with the drug dose. Several investi-
`gators have hypothesized that low doses may de-
`crease the concentration of the estrogen receptor,
`thereby diminishing the ability oftumor cells to
`
`Table 1 . Potential Mechanisms of Progestin Activity
`in Breast Cancer
`
`Endocrinologic effects
`Suppression of adrenal production of estradiol and
`androstenedione
`Interference with steroid hormone receptors (estrogen,
`progesterone, androgen, and glucocorticord)
`Direct cytotoxicity
`Suppression of growth in hormone-sensrtwe cell lines
`Regulation of autocrine growth factors
`Stimulatory or inhibitory effects on production of growth
`factors (TGF-a, TGF-p’. EGF, IGF~1)
`Regulation of growth factor receptors
`
`Abbreviations: TGF. transforming growth factor; EGF, epidermal
`growth factor; IGF, insulin growth factor.
`
`respond to endogenous estrogen20 while higher
`doses are capable of blocking adrenal production
`of sex hormonesI7 and also may cause direct cy-
`totoxicity.“ This provides a rationale for the ef-
`fectiveness of higher doses of progestins in pa-
`tients whose disease has progressed on lower
`doses.
`
`Using two human breast tumor lines. one sen-
`sitive to hormones (MCF-7) and the other resis-
`tant (MBA-231), Allegra and Kieferz' demon-
`strated in vitro that progesterone and megestrol
`acetate caused direct cytotoxicity and were ca-
`pable of inhibiting the mitogenic effects of estra-
`diol in the hormone-sensitive tumor cell line. No
`effect was seen in the hormone-resistant cell line.
`The concentration of progestin used was 10‘5
`mol/L, which is attainable in plasma. Lower
`doses ( 10‘“ to 10‘” mol/L) were ineffective. while
`higher concentrations of these agents were found
`to be “nonspecifically cytotoxic."
`Using oral doses of medroxyprogesterone ac-
`etate ranging from 500 to 1.500 mg/d, Blossey et
`al '8 showed that differential endocrinologic effects
`in women with metastatic breast cancer depended
`on the dose. Medroxyprogesterone acetate doses
`of 1,000 mg/d or greater were necessary to com-
`pletely suppress endogenous cortisol secretion.
`with a concomitant decrease in follicle-stimulat-
`
`ing hormone. luteinizing hormone. and estradiol.
`It is also instructive that megestrol acetate has
`been substituted successfully for prednisone in
`combination with aminoglutethimide treat-
`ment.22 The weak corticoid effects of high-dose
`progestins, their ability to compete for the glu-
`cocorticoid receptor.“ and their suppression of
`adrenal steroid production in postmenopausal
`
`AstraZeneca Exhibit 2149 p. 2
`
`

`

`70
`
`ABRAMS. PARNES, AND AISNER
`
`time followed by an asymptotic increase in weight
`to a maximal weight gain?5 This side effect has
`been turned to advantage in patients suffering
`from cancer cachexia, as described by Aisner et
`al elsewhere in this issue (pp 2-7). Additional side
`
`effects included hyperglycemia and hypertension.
`which occurred in 16% and 12% of patients, re-
`spectively. Insulin, oral hypoglycemic agents, and
`antihypenensive drugs were occasionally needed
`to counteract these effects; however, all patients
`so affected had baseline hypertension or glucose
`intolerance before starting therapy. and most
`were being treated for these problems before en-
`tering the study.
`The overall response rate, including complete
`response (CR) and partial response (PR), was 32%
`in patients with measurable tumor; responses.
`including CRs, were seen at each dose level (Table
`2). Responses were fairly equivalent in patients
`with predominantly soft tissue, bone. or visceral
`tumors, with the exception of those with hepatic
`metastases (Table 3): all five patients with liver
`disease progressed rapidly on this study. This
`finding is similar to results noted by others with
`conventional megestrol acetate doses.“
`In 27 of these study patients. disease progres-
`sion had previously occurred during treatment
`with standard doses of megestrol acetate, includ-
`ing 9 patients whose tumors demonstrated pri-
`mary refractoriness to conventional doses of the
`hormone. A 15% response rate (1 CR. 3 PR5) was
`noted with high-dose megestrol acetate. and 10
`patients (37%) had stable disease lasting a median
`of 5.4 months (range, 3 to l 1.5). Two ofthe ob-
`jective responses occurred in women whose tu-
`mors had previously not responded to standard
`megestrol acetate doses. In addition, 2 of 14 pa—
`tients with primary resistance to initial treatment
`with tamoxifen had objective responses (1 CR
`and 1 PR) on the high-dose treatment. These
`
`Table 2. Overall Response to Megestrol Acetate
`by Dose Level
`
`Dose
`(mg/d)
`480
`800
`1.280
`1,600
`
`No. Patients
`3
`3
`3
`48
`
`CR
`1
`2
`1
`2
`
`PR
`1
`0
`O
`5
`
`SD
`1
`1
`1
`20
`
`PD
`0
`O
`1
`21
`
`Abbreviations: SD, stable disease: PD, progressive disease.
`
`women all may play a role in the mechanism of
`action of these compounds.
`Recent evidence has shown that progestins also
`down regulate their own receptors and stimulate
`production of autocrine growth factors and their
`receptors." These growth factors are proteins
`produced by normal and malignant breast cancer
`cells. In vitro experiments have demonstrated
`that
`transforming growth factor-a, epidermal
`growth factor, and epidermal growth factor re-
`ceptors tend to increase with progestin stimula-
`tion, while transforming growth factor-6 and in-
`sulin growth factor-I are decreased by progestin
`treatment. No consensus has been reached yet as
`to the precise role these factors play in the reg-
`ulation of breast cancer growth. It is likely, how-
`ever, that progestins have direct effects on the
`genome and corresponding gene products.
`
`Recent and Ongoing Trials
`
`postmenopausal
`(56
`patients
`Fifty-seven
`women and 1 man) with biopsy-proven meta-
`static breast cancer, positive or unknown estrogen
`or progesterone receptors, and measurable or
`evaluable disease, were treated in a phase I-Il trial
`at the University of Maryland Cancer Center.
`Megestrol acetate, in escalating dosages ranging
`from 480 to 1,600 mg/d. was given as specially
`formulated l60-mg tablets (Bristol Myers On-
`cology Division, Evansville, IN). All patients had
`chemotherapy or hormonal therapy before en-
`tering the trial; 37 had measurable disease. and
`20 had evaluable but nonmeasurable disease.
`
`Toxicity in this trial was notable for increased
`appetite and weight gain. especially at the highest
`dose (1,600 mg/d). For those treated longer than
`6 weeks, weight gain occurred at all dose levels
`and ranged from 1 to 20 lb (median, 2.5). Phar-
`macokinetic modeling of this drug effect dem-
`onstrated that the weight gain was best described
`by a function in which there was an initial lag
`
`Table 3. Results With High-Dose Megestrol Acetate
`by Dominant Lesion
` No Patients CR PR SD PD
`
`Soft tissue
`9
`3
`O
`3
`3
`Bone
`24
`O
`4
`1 5
`5
`Viscera
`Liver
`Other
`
`
`
`0
`2
`
`5
`1 9
`
`0
`3
`
`
`
`
`
`0
`5
`
`5
`9
`
`Total
`
`57
`
`6
`
`6
`
`23
`
`22
`
`AstraZeneca Exhibit 2149 p. 3
`
`

`

`HIGH-DOSE PROGESTINS IN BREAST CANCER
`
`Table 4. CALGB Megestrol Acetate Trial
`Megestrol
`Acetate
`Stratification
`Dose (mg/d)
`
`
`160
`ER and PgR status
`800
`Randomize
`Prior adjuvant chemotherapy
`
`Prior hormonal therapy 1,600
`Abbreviations: ER, estrogen receptor; PgR, progesterone re-
`ceptor.
`
`provocative initial findings indicate that a dose-
`response effect might exist for megestrol acetate.
`The Piedmont Oncology Association recently
`reported preliminary results of their randomized
`phase 111 trial comparing high—dose (800 mg/d)
`with conventional-dose (160 mg/d) megestrol
`acetate in patients with metastatic breast cancer.‘9
`All patients in this trial had undergone at least
`one prior course of treatment with a nonprogestin
`hormone; tamoxifen accounted for the vast ma—
`jority. Positive or unknown estrogen or proges-
`terone receptor status was required for study en-
`try. Toxicity in the trial was minimal, with weight
`gain (mean, 17 lb) reported as the major side ef-
`fect. The results demonstrate an impressive ben-
`efit for the high-dose arm, with a 26% overall
`response rate compared with 1 1% in the standard-
`dose arm. The significant differences in progres-
`sion-free interval (7.8 v 3.2 months) and median
`survival (18 v 1
`1 months) for the high- and stan-
`dard-dose arms, respectively, also reflect the dose-
`response effect.
`Since June 1987. Cancer and Leukemia Group
`B has been conducting the largest trial to date
`testing the dose-response concept with megestrol
`acetate. This three-arm trial
`for patients with
`metastatic breast cancer is comparing standard-
`dose (160 mg) megestrol acetate with both five
`(800 mg) and ten times (1.600 mg) the standard
`dose. The study is projected to accrue 315 patients
`and should meet this goal by the fall of 1990.
`Patients are randomized for
`treatment after
`
`stratification according to estrogen or progester-
`one receptor status, prior hormonal therapy, and
`prior adjuvant chemotherapy (Table 4). Patients
`in this trial may have had only one prior hor-
`monal maneuver (including both adjuvant and
`metastatic treatment) and cannot have received
`chemotherapy except for adjuvant treatment, in
`which case they must be disease-free for at least
`1 year from the end oftherapy. Interim analysis
`
`71
`
`of 163 patients with the blind still in effect reveals
`an overall response rate (CR and PR) of 29%,
`although 49% of the patients have stable disease
`and could yet respond. With 100 patients per
`arm. when completed. this trial will have suffi-
`cient power to correlate response with estrogen
`and progesterone receptor levels and disease
`sites. It should also provide an answer to the
`dose-effect question for megestrol acetate in this
`population of patients with advanced breast
`cancer.
`
`CONCLUSIONS
`
`In an era in which new biologic features (such
`as cell-proliferative indices, DNA ploidy, and ca-
`thepsin D levels) of primary breast tumors are
`increasingly influencing therapeutic decisions in
`the adjuvant setting, it is noteworthy that less
`attention has been paid to these factors in met-
`astatic disease. Studies with conventional meges-
`trol acetate doses have indicated some pretreat-
`ment characteristics that influence treatment with
`
`progestins (Table 5)."‘7'l0‘n‘27‘28 However. as with
`most hormonal treatments, multivariate analysis
`shows that estrogen and progesterone receptor
`levels have correlated most closely with response.
`and in several studies, progesterone receptor lev-
`els have proven to be the most important prog-
`nostic indicator for successful progestin treat-
`ment.2"‘2°'3' Yet, as the described trials indicate,
`patients with hormone-resistant disease as well
`as those who progress on standard progestin doses
`may respond to high-dose megestrol acetate.
`These initial findings obligate (1) clinical inves-
`tigators to elucidate other features of these tumors
`that might predict response and (2) laboratory
`researchers to pursue the mechanism of action
`of high-dose progestins.
`Trials comparing high-dose megestrol acetate
`with tamoxifen are already under way. Better
`understanding of how progestins work in breast
`cancer could lead to more innovative trials. It is
`
`possible that high-dose progestin therapy could
`be combined or alternated with antiestrogens or
`
`Table 5. Clinical Prognostic Factors for Response
`to Progestins
`
`Prewous response to hormone therapy
`Disease-free interval
`Menopausal status (and time from menopause)
`Metastatic site (nonvisceral v visceral)
`
`AstraZeneca Exhibit 2149 p. 4
`
`

`

`72
`
`ABRAMS, PARNES, AND AISNER
`
`aromatase inhibitors to allow more complete
`blockade of the sex hormones and increase in-
`
`terference with their receptors. Another avenue
`ofbenefit might result from combining progestin
`
`therapy with chemotherapy, since breast tumors
`are heterogeneous and possess cells with different
`growth kinetics that might be preferentially sen-
`sitive to one or the other modality.
`
`REFERENCES
`
`I. Schacter L, Rozencweig M, Canetta R, et al: Megestrol
`acetate: Clinical experience. Cancer Treat Rev 16:49-63, 1989
`2. Sedlacek SM: An overview of megestrol acetate for the
`treatment of advanced breast cancer. Semin Oncol 15:3-13,
`1988
`3. Henderson 1C: Endocrine therapy in metastic breast
`cancer, in Harris JR. Hellman S, Henderson 1C, et al (eds):
`Breast Diseases. Philadelphia, PA, Lippincott, 1987, pp 398-
`428
`4. Ettinger DS, Allegra J, Bertino J R, et al: Megestrol acetate
`v tamoxifen in advanced breast cancer: Correlation of hor-
`mone receptors and response. Semin Oncol 13:9-14. 1986
`5. Muss HB, Paschold EH, Black WR, et al: Megestrol
`acetate v tamoxifen in advanced breast cancer: A phase III
`trial of the Piedmont Oncology Association (POA). Semin
`Oncol 12:55-61. 1985 (suppl 1)
`6.
`lngle JN, Ahmann DL. Green SJ, et al: Randomized
`clinical trial of megestrol acetate v tamoxifen in paramenr»
`pausal or castrated women with advanced breast cancer. Am
`J Clin Onc015:155-160. 1989
`7. Morgan LR: Megestrol acetate v tamoxifen in advanced
`breast cancer in postmenopausal patients. Semin Oncol 12:
`43-47, 1985(suppl I)
`8. Stoll BA: Progestin therapy of breast cancer: Comparison
`of agents. Br MedJ 3:338-341, 1967
`9. Tchekmedyian NS, Tait N, Aisner J: High-dose meges~
`trol acetate in the treatment of postmenopausal women with
`advanced breast cancer. Semin Oncol 13:20-25, 1986
`10. Cavalli F, Goldhirsch A, Jungi F. et al: Randomized
`trial of low- versus high—dose medroxyprogesterone acetate in
`the induction treatment of postmenopausal patients with ad
`vanced breast cancer. J Clin Oncol 2:414-419, 1984
`I l. Della Cuna GR, Calciati A, Strada M, et al: High dose
`medroxyprogesterone acetate treatment in metastatic carci—
`noma of the breast: A dose-response CValuation. Tumori 64:
`143-149. 1978
`12. DeLena M, Brambilla C, Valagussa P, et al: High-dose
`medroxyprogesterone acetate in breast cancer resistant to en-
`docrine and cytotoxic therapy. Cancer Chemother Pharmacol
`2:175-180, 1979
`I3. Pannuti F. Martoni A, DiMarco AR. et al: Prospective,
`randomized clinical trial oftwo different high dosages of me-
`droxyprogesterone acetate in the treatment of metastatic breast
`cancer. EurJ Cancer 15:593-599, 1979
`14. Martin F, Adlercreutz H: Aspects of megestrol acetate
`and medroxyprogesterone acetate metabolism, in Garattini
`S. Brendes HW (eds): Pharmacology of Steroid Contraceptive
`Drugs. New York, NY. Raven. 1977. pp 99-1 15
`IS. Canetta R, Florentine S. Hunter 11, et al: Megestrol
`acetate. Cancer Treat Rev 10:141-157. 1983
`
`16. Morgan LR, Donley PJ, Savage J: High dose megestrol
`acetate in advanced breast cancer: Bioavailability, toxicity and
`response. Proc Am Assoc Cancer Res 28:19. 1983(abstr)
`l7. Alexicva-Figusch J, Blankenstein MA, Hop WCJ. et
`al: Treatment of metastatic breast cancer patients with different
`dosages of megestrol acetate; dose relations. metabolic and
`endocrine effects. Eur J Cancer Clin Oncol 20:33-40. 1984
`18. Blossey HC, Wander HE, Kocbberling J. et al: Phar-
`macokinetic and pharmacodynamie basis for the treatment
`of metastatic breast cancer with high-dose medroxyproges-
`terone acetate. Cancer 54:1208-1215, 1984
`I9. Muss H, Case D, Cates-Wilkie S, et al: High vs standard
`dose oral progestin therapy (megestrol acetate) for metastatic
`breast cancer: A phase III trial of the Piedmont Oncology
`Association. Proc Am Soc Clin Oncol 8:22, 1989 (abstr)
`20. Tseng L. Gurpide E: Effects of progestins on estradiol
`receptor levels in human endometrium. J Clin Endocrinol
`Metab 41:402-404. 1975
`21. Allegra JC. Kiefer SM: Mechanisms of action of pro-
`gestational agents. Semin Oncol 1223-5. 1985
`22. Nagel GA, Wander HE. Blossey HC: Phase 11 study of
`aminoglutethimide and medroxyprogesterone acetate in the
`treatment of patients with advanced breast cancer. Cancer
`Res 42:3338-3444, 1982 (suppl)
`23. Lippman M, Bolan G, Huff K: The effects of glucr»
`corticoid and progesterone in hormone-responsive human
`breast cancer in long term tissue culture. Cancer Res 36:4602-
`4609. 1976
`24. Meeting report: Progestin action and progesterone re-
`ceptors in breast cancer. Cancer Res 49:7176-7179. 1989
`25. Parnes H, Tait N. Aisner J: The potential of megestrol
`acetate in the treatment of cancer cachexia. Nutrition 5:206-
`209. 1989
`26. Haller 00. Click J H: Progestational agents in advanced
`breast cancer: An overview. Semin Oncol 13:2-8. I986
`27. Alexieva-Figusch J, Van Glise HA, Hop WCJ: Progestin
`therapy in advanced breast cancer. Cancer 46:2369-2372. 1980
`28. Ansficld FJ, Kallas GH. Sinson JP: Clinical results with
`megestrol acetate in patients with advanced carcinoma of the
`breast. Surg Gynecol Obstet 1552888-890, I982
`29. Bonomi P, Johnson P, Anderson K, et al: Primary hor-
`monal therapy of advanced breast cancer with megestrol ac-
`etate: Predictive value of estrogen and progesterone receptor
`levels. Semin Oncol I2:48~54. I985
`30. Gregory EJ. Cohen SC. Oines DW. et al: Megestrol
`acetate therapy for advanced breast cancer. J CIin Oncol 3:
`155-160, I985
`31. Johnson PA, Bonomi PD, Anderson KM. et al: Me-
`gestrol acetate: First-line therapy for advanced breast cancer.
`Semin Oncol 13:15-19. 1986
`
`AstraZeneca Exhibit 2149 p. 5
`
`