It has been demonstrated that progesteronereceptors (PRs) are at least as valuable asestrogen receptors (ERs) for predictingoutcome in breast cancer patients. Retrospective analysis indicates that the presence of PRs may be the second most criticalfactor, after the number of positive nodes,in predicting disease-free survival, with acorrelation between length of survival andnumber of tumor PRs. The presence of PRshas been shown to be of value for predicting response in both early and advancedbreast cancer patients. In studies of assayconsistency, major discordance rates wereminimal in simultaneous assays, but extremely high in sequential assays of tumorsthat were PR-positive in initial assay. Theresponsible factor was interim endocrinetherapy, and it was subsequently determined that the prognosis was worse forthose patients whose tumors lost PR between assays.

The possible significance of progesterone receptors (PRs) in human breastcancer has evoked a great deal of interest

Dr. McGuire is Professor of Medicine and Chiefof Oncology at the University of Texas HealthScienceCenter in San Antonio,Texas.Dr. Clark is Professor of Medicine in the Departmentof Medicine/Oncologyof the University of Texas Health ScienceCenter in San Antonio, Texas.Supportedby the NationalCancerInstitutegrantCA3O195.Reprintedby permissionfrom Semin Oncol 12(suppl):12—l6,1985.

in the medical community. What, for example, is their significance in comparison with that of estrogen receptors. (ERs)'!What roledo theyplayinthetreatmentof early or advanced breast cancer? Andfinally, how does a change in PR levelover the course of the disease affectprognosis and survival?

Progesterone Receptors versusEstrogen Receptors

Hubay and colleagues conducted a randomized study in which stage II breast cancer patients underwent radical mastectomyfollowed by chemotherapy with cyclophosphamide, methotrexate, and 5-fluorouracilalone, or in combination with tamoxifen ortamoxifen plus bacillus Calmette-Guérin(BCG) (a nonspecificimmunostimulant).A total of 318 patients made up the studypopulation, of which 311 patients wereevaluable. Of those, 189 patients were assayed for both ER and PR.'

As has long been recognized, diseasefreesurvivalwas relatedtoER status—thatis, ER-positive patients had significantlylonger survival at study points up to 60months (Fig. 1). ER-negative patients havea higher risk of early recurrence than dopatients whose tumors are ER-positive according to the disease-free survival curvesand the significant difference between thetwo curves. Similarly, the difference between the two curves in PR-positive andPR-negative patients (Fig. 2) is also highly

302 CA-A CANCERJOURNALFORCL!NICIANS

Roleof ProgesteroneReceptorsIn Breast Cancer

William L. MCGuire,M.D.Gary M. Clark, Ph.D.

significant and again suggests the probability of earlier recurrence of disease for thosepatients with PR-negative tumors.

The impactof PRs on breastcancerpatients was then examined in relation toother known prognostic factors, such as thenumber of positive nodes. size of the primary tumor, type of treatment, and menopausal status. It was determined using univariant analysis that positive nodes (p<.0001), size of primary tumor (p = .0008).ER (p= .0008), and PR (p<.0001) are allvaluable for predicting disease-free survival.2 Furthermore, it was possible. usingmultivariant analysis techniques. to assignan order of importance to the factors andthus to determine the impact of each inpredicting recurrence in this patient population.

As anticipated, the number of positivenodes (p<.000l) was the most importantfactor for predicting early recurrence. Unexpectedly, however, the second most critical factor was PR (p= .004). The thirdfactor, of borderline statistical significance, was the size of the primary tumor(p= .07). ER was not found to be significant at all. Thus, if the PR value is known,ER status offers no additional prognosticinformation. The converse, however, is nottrue; if the ER status is known, useful information is still provided by assessing thePR status. In this particular subset of patients, treatment and menopausal status didnotplayaroleinidentifyingwhichpatienthadrecurrences.

If it is accepted that PR is an importantbiologic variable, it might be anticipatedthatthenumberofPRsinthetumorswouldhave some impact as well. Disease-freesurvival was therefore studied with respectto quantitative PR levels. Patients wereseparated into three groups: those whosetumors contained greater than 50 fmol ofPR, those with between five and 49 fmol.and those with less than five fmol. Comparison revealed that disease-free survival increased with increased level of tumor PRs.

In summary, the presence of PRs wasdetermined to be a more significant prognostic factor for disease-free survival thanwas the presence of ER. Thus, PR levelsshould be routinely measured and incorpo

rated into adjuvant therapy trials.

The Value of PR Analysis In BreastCancer Therapy

EarlyCancer

The mostclear-cutdataregardingtheroleof PR analysis in planning treatment forearly breast cancer tome from a NationalSurgical Adjuvant Breast Project study inwhich patients with stage II breast cancerwere randomized to chemotherapy with Lphenylalanine mustard plus 5-fluorouracilor chemotherapy plus tamoxifen.3 Table 1compares the receptor status. disease-freesurvival rate, and absolute survival rate of

The survival ofpatients whose tumors

lose progesteronereceptors is significantly

shorter than that of thoseretaining progesterone

receptors.

patients under 50 years of age who receivedchemotherapy alone and those who received chemotherapy plus tamox ifen.

Results indicate that there were onlythree categories in which significant differences were evident in patients under 50years of age. First, in the group of patientslacking both receptors, addition of tamoxifen to the chemotherapy regimen yielded ashorter total survival. Second, in those patients who were ER-positive but PR-negative. the addition of tamoxifen decreasedboth disease-free and overall survival. Itwas concluded that the absence of PR in atumor is predictive of a shorter disease-freeand overall survival with this combinationof therapy.

In the group of patients older than 50years, the only significant difference betweenthosetreatedwithchemotherapyaloneand those treated with chemotherapy plustamoxifen occurred in the PR-positive tumor patients. Here the disease-free survivalrate was improved in those patients who

VOL 36, NO 5 SEPTEMBER/OCTOBER1986 303

100

@, 80

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0

ER+ (N = 143)

12 24 36 48 60

Disease-freeInterval(months)

Fig 1 Estrogen receptor (ER)status has long been accepted as a predictive factor in diseasefree survivalof breast cancer patients (adapted from Clark et al2)

Fig. 2 Progesterone receptor (PR)status appears to be at least as predictive of disease-freesurvival in breast cancer patients as ERstatus (adapted from Clark et aI2)

304 CA-ACANCERJOURNALFORCLINICIANS

100

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00 12 24 36

Disease-freeInterval(months)

PR+(N = 110)

p < .0001

48 60

ER PR Tr*tment DF$Prcsnt SPircint

Age < 50 Years

—¿�—PF

PFT50 478662(.003)+—PF

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+ —¿� PF 6584++PFT

PF

PFT74

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8081

90

94

Key: ER = Estrogen receptor; PR = Progesterone receptor; DFS =Disease-freesurvival;S = Absolute survival; PF = L-Phenylalanine mustard and 5-fluoroura

cii; PFT = Chemotherapy + tamoxifen.

Objective Response

ER PR11%ER+PR

27%ER+PR+77%

Key: ER = Estrogen receptor; PR = Progesterone receptor.

VOL 36, NO 5 SEPTEMBER/OCTOBER 1986 305

10

20

Ca,C.,

a 30a,uC

‘¿�::60 -

First Secondassay assay

Chemotherapy(17)

No chemotherapy(29)

Fig. 3. Treatment with chemotherapy had no effect on the major discordance rate (positive tonegative) between sequential PR assays (adapted from Gross et aI6).

Fig. 4. A striking association was found between major discordance (positive to negative) andendocrine therapy in sequential PR-assayedpatients (adapted from Gross et a16).

306 CA-A CANCERJOURNAL FORCLINICIANS

10

20

Ca

3@

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0U

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60 . LFirst Secondassay assay

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@ .80>

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00 12 24 36 48 60 72 84 96 108

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Fig. 5. Change in PR status was found to play an important role in the prognosis for survival ofbreast cancer patients (adapted from Gross et at6).

received tamoxifen. Preliminary interpretations of this study indicate that PR is anextremely important factor in identifyingwhich subsets of patients could be expectedto improve and which to worsen with thecombination of this particular chemotherapy and antiestrogen.

Advanced Cancer

In a retrospective analysis of 345 patientsworldwide,4 the overall results showed thatthe absence of both ER and PR in patientswith advanced disease was associated withthe lowest rate of response, whereas thosewhose tumors were positive for both ERand PR had the best prognosis (Table 2). Aprospective randomized trial of the role ofPR in predicting response to endocrinetherapy was reported by Cavalli et al.5 Patients were randomized to receive highdose or low-dose medroxyprogesteroneacetate (MPA). In 91 patients receivinghigh-dose MPA. the response rate was 70percent if PR was present and only 10 per

cent if PR was absent. For those patientswith unknown PR values, the response ratewas 30 percent, consistent with numerousearlierreports.The studyrepresentsanexcellent example of the importance of PR inpredicting response in advanced breastcancer.

Repeated PR Assays

Consistency

The next step was to study the consistencyof repeated receptor assays in the samepatient. In San Antonio, 283 patients whowere biopsied more than once for PR wereidentified. Of those, 109 patients had simultaneous assays (within the same week)and 174 patients had sequential assays. Apositive PR assay was defined as greaterthan 10 fmol/mg protein in the 8S fractionof sucrose gradient; negative PR values asless than five fmob/mg protein; and ±values as between five and 10 fmol/mg protein. Patients whose initial biopsies were

VOL. 36. NO 5 SEPTEMBER/OCTOBER 1986 307

either positive or negative and remainedpositive or negative were described as concordant. Discordance was defined in twoways. Major discordance referred to thosepatients whose biopsy changed from an initial positive or negative to the alternate onlaterbiopsy.Minordiscordancedescribedboth those patients whose initial assay waseither positive or negative but later biopsywas equivocal, and those who began asequivocal and changed to positive or negative.

In the group receiving simultaneous assays, the major discordance rate was approximately 14 percent. The minor discordance rate for the same group was 18percent. This result indicates that simultaneous assays for PR are reliable on thesame order as assays for ER.

In contrast, results of the sequential assays were inconsistent. Although the discordance rates for PR-negative tumors (threepercent and eight percent for minor andmajor discordance, respectively) and theminor discordance rate for PR-positive tumors (seven percent) were low, the majordiscordance rate for PR-positive tumors washigh(44percent).

In an attempt to explain this high discordance rate, many factors were considered. Tumor size, axillary lymph node status, menopausal status, and the intervalbetweenbiopsieswerenotfoundtobeimportant. Similarly, the discordance rate between the first and second assays was notfound to be affected by chemotherapy administered during the interim period (Fig.3). Endocrine therapy, however, appearedto be a likely explanation for the majordiscordance rate in PR-positive tumor as

References

says. Those patients who did not receiveendocrine therapy had a minimal change intheir receptor status, whereas a strikingchange was noted in those who did receiveendocrine therapy (Fig. 4).

Significance of Changes in PR Status

It was subsequently questioned whetherthere is any biologic or prognostic significance of a change in PR status. To answerthis question, survival rates among patientsreceiving sequential assays were analyzed(Fig. 5). Those patients whose tumors wereinitially PR positive and remained PR positive were clearly shown to have the bestprognosis. The worst prognosis was associated with those patients whose tumorswere initially PR negative and remained PRnegative.The mostclinicallyinterestingsubset of patients is represented by the middle curve of Figure 5. Their initial biopsywas PR positive, but their second biopsywas PR negative. It is clear that these patients, although initially PR positive, havea worse prognosis than those whose tumorsremained PR positive. Thus, the loss ofPRs is an ominous sign.6

Conclusions

PRs appear to be an important factor in theprognosis and management of breast cancer. The survival of patients whose tumorslose PRs is significantly shorter than that ofthoseretainingPRs.Frequentreassessmentof PRs is therefore recommended to ensureoptimal treatment planning for patients whoare initially PR positive.

1. HubayCA, PearsonOH, MarshallJS, et al:Adjuvanttrialof stageII breastcancer:48 monthfollow-upofaprospectiverandomizedclinicaltrial. BreastCancerResTreat 1:77—82,1981.2. Clark GM, McGuire WL, Hubay CA, et al:Progesteronereceptor as a prognostic factor instage II breast cancer. N Engi J Med 309:1343—1347,1983.3. FisherB, RedmondC, BrownA, et al: Influ

ence of tumor estrogen and progesterone receptor levels on the response to tamoxifen andchemotherapyin primary breast cancer. J ClinOncol 1:227—241,1983.4. McGuire WL: Hormone receptors: Their rolein predicting prognosis and response to endocrine therapy. SeminOncol5:428—433,1978.5. CavalliF, GoldhirschA, Jungi F, et al: Randomized trial of low- versus high-dose me

308 CA-A CANCERJOURNALFORCLINICIANS

droxyprogesterone acetate in the induction treat- 6. Gross GE, Clark GM, Chamness GC, et ab:ment of postmenopausab patients with advanced Multiple progesterone receptor assays in humanbreast cancer. J Clin Oncob2:414—419,1984. breast cancer. Cancer Res 44:836—840,1984.

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