Prognostic role of oestrogen and progesterone receptors in patients with breast cancer: relation to

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1 922 lin Pathol 1996;49: The Gade Institute, Departmnent of Pathology, University of Bergen, Haukeland Hospital, Bergen, Norway K ollett F Hartveit B Mahle Setion for Medial Informatis and Statistis, The Gade Institute R Skjxrven orrespondene to: Dr Karin ollett, Department of Pathology, Haukeland Hospital, N-521 Haukeland, Norway. Aepted for publiation 4June 1996 Prognosti role of oestrogen and progesterone reeptors in patients with breast aner: relation to age and lymph node status K ollett, F Hartveit, R Skjaerven, B Mtehle Abstrat Aims-To onsider the prognosti role of oestrogen reeptor and progesterone reeptor status in relation to the age at surgery, length of follow up and lymph node status. Methods-The study population omprised 977 patients with histologially onfirmed breast arinoma, with a median follow up of nine years. The atuarial life table method was used to test for survival differenes. The ox proportional hazard model was used to test for interation effets between eah hormone reeptor and age, lymph node status and length of follow up. As the analysis involved multiple subgroups, signifiane was set at the 1% level (p <.1). Results-When the patients were subdivided into groups aording to lymph node status and age, progesterone and oestrogen reeptor status predited prognosis in middle aged (46-6 years) patients with lymph node positive breast aner. Their prognosti effet in this subgroup, however, was restrited to the first five years after surgery. Progesterone reeptor status was the strongest preditor of outome. onlusion-the prognosti power of oestrogen and progesterone reeptor status varies depending on age, lymph node status and length of follow up after surgery. (7 lin Pathol 1996;49:92-925) Keywords: oestrogen reeptor, progesterone reeptor, breast aner, prognosis. Despite the trend towards the use of adjuvant therapy in most patients with breast aner,' prognosti fators are still needed to identify patients at high, and low, risk of reurrene and, perhaps most importantly, patients who are unlikely to benefit from a partiular treatment.2 Several new markers have been introdued to identify these patients, but none has yet improved our ability to determine survival.3 The searh for better markers has, to some extent, led to less interest in traditional histopathology.4 Intrinsi fators suh as -erbb-2, -my, DNA index, and S-phase fration have, however, been shown to lose prognosti power after inlusion of histologial grade in multivariate analysis for survival.5 In ontrast to the more reent prognosti indiators, oestrogen and progesterone reeptor status are well established markers,3 and they were inluded in the 1992 St Gallen reommendations for the adjuvant treatment of breast aner.' Interations with other fators have been shown to have an impat on the prognosti role of oestrogen and progesterone reeptor status. Previous reports have shown that the hormone reeptors are stronger fators in lymph node positive than negative patients" and are more important in prediting short rather than long term prognosis.9"' Their effets in relation to menopausal status have also been studied, but no onsensus has been reahed as to whether their effet is stronger in pre-' 12 or postmenopausal women."'3-' This ould result from different definitions of menopausal status and suggests that oestrogen and progesterone reeptor status should be examined in middle aged patients separately. Few reports have foused on the effet of oestrogen and progesterone reeptor status in relation to age. Shek et al'6 showed a weak effet for oestrogen reeptor status in patients aged 45 years or less, whereas the strongest effet was found in those between 45 and 54 years of age. We have shown that oestrogen, progesterone and androgen reeptor status are more important in prediting five year survival in patients aged 6 years or less than in those over 6.'7 The assoiation with age beame even stronger after onsideration of lymph node status and tumour diameter. As this study inluded 269 patients only, it did not permit further subdivision aording to age. By exluding the need for androgen reeptor status in the present study we ould inrease the study population to 977 and follow up to about nine years. Based on these onsiderations we hypothesise that the prognosti importane of oestrogen and progesterone reeptor status should be examined in middle aged patients separately, taking lymph node status and length of follow up into onsideration. Identifiation of interations between these variables would allow these well established prognosti markers to be used more preisely in patients with breast aner. Methods The study population omprised 977 patients with unilateral breast aner treated by modified radial mastetomy with axillary dissetion. All types of histologially onfirmed infil- J lin Pathol: first published as /jp on 1 November Downloaded from on 11 January 219 by guest. Proteted by opyright.

2 Prognosti role of oestrogen and progesterone reeptors in breast aner trating arinoma were inluded. The speimens were reeived at this Institute between January 1974 and January 1989 and patients were followed up via data from the Norwegian Statistial entral Bureau until death or to January All patients under 7 years of age reeived perioperative hemotherapy. Between 1976 and 1981, 33 patients under 75 years of age were randomised in a trial to reeive different ourses of MF/MFP (ylophosphamide, methotrexate, 5-fluorourail/prednisolone). Before 1983, patients did not reeive tamoxifen postoperatively. Thereafter, as a general rule, tamoxifen was given daily postoperatively for two years in lymph node positive patients with oestrogen reeptor >1 fmol/mg. As we do not have detailed information on tamoxifen treatment, we have re-analysed our findings in lymph node positive patients who underwent surgery before and after In both periods oestrogen and progesterone reeptor status exerted the strongest effet in middle aged patients (data not shown). Thus, this observation indiates that any age dependent effet of oestrogen and progesterone reeptor status is not a result of tamoxifen treatment. As part of the primary treatinent an unknown proportion of patients reeived postoperative radiotherapy. Information on oestrogen and progesterone reeptor status and age at surgery was available for all patients. As information on progesterone reeptor onentration was not available before January 1976, only 852 patients were inluded in this arm of the study. As information on lymph node status was missing in some ases, the analyses were based on 965 and 843patients for oestrogen reeptor and progesterone reeptor, respetively, when lymph node status was inluded. When adjusting for tumour diameter only patients with known tumour diameter were inluded in the analyses: 853 and 741 ases for oestrogen reeptor and progesterone reeptor, respetively. Median follow up was 18 (61-238) and 14 (61-27) months for oestrogen reeptor and progesterone reeptor, respetively. Oestrogen reeptor and progesterone reeptor ontent was measured by the dextran oated haroal tehnique as desribed by Thorsen.'8 All analyses were done in a single laboratory using the same method, eliminating the problem of interlaboratory differenes; 15 fmol/mg protein was hosen as the ut-off point for oestrogen reeptor and progesterone reeptor, and 6 years was hosen as the upper ut-off point for age, as used in our previous study."7 Pilot studies showed that the effet of oestrogen and progesterone reeptor status differed in patients aged 45 years or less ompared with those between 45 and 6 years of age; therefore, 45 years was hosen as the lower ut-off point for middle aged patients. hanging this ut-off point for age from 45 to 5 years gave a similar pattern for oestrogen reeptor and progesterone reeptor as prognosti variables. All statistial analyses were used as suggested by Dixon.'9 Patients dying of auses other than breast aner were ensured-that is, treated as living until death and then exluded. As the 921 analysis involves multiple subgroups, signifiane was set at the 1% level (p <.1). The atuarial life table method was hosen, using the log rank test (Mantel-ox), to test for differenes in survival. The ox proportional hazard model was used to estimate the relative risk of dying and interations between eah hormone reeptor and age, lymph node status and length of follow up. This model relies on the assumption that the ratio of death rates in groups of patients does not hange with time. To assess whether the effet of oestrogen reeptor and progesterone reeptor differed during the first (first five years) ompared with the last (next five years) period, a time dependent variable was designed for eah hormone reeptor and tested for signifiane. The proportionality assumption was heked in eah five year period using plots of the log minus log survival funtion.'9 No serious deviations from the proportionality assumptions were found (data not shown). Results Overall, a weak survival advantage was seen for oestrogen reeptor positive patients (table 1). When stratified aording to lymph node status, oestrogen reeptor status was signifiant in lymph node positive patients only. A weak effet was seen for oestrogen reeptor status in young and old patients, while no survival differene was found between oestrogen reeptor positive and oestrogen reeptor negative middle aged women. On stratifying aording to lymph node status and age simultaneously (fig 1), oestrogen reeptor status tended to give survival information in middle aged and in young lymph node positive patients, oestrogen reeptor negative patients being at higher risk than oestrogen reeptor positive ones. The differene between the groups delined after five years. In the middle aged lymph node negative group, however, more deaths were seen in patients with oestrogen reeptor positive tumours than in those with oestrogen reeptor negative ones after five years of follow up. Using the ox proportional hazard model in eah five year period (table 2), oestrogen reeptor status was signifiant in lymph node positive patients in the first five years after surgery. It showed a signifiant reverse of effet in the seond period in middle aged patients, those with oestrogen reeptor positive tumours having a 3.3-fold higher risk of dying than oestrogen reeptor negative patients. When testing for interations a weak differene in effet was seen between the periods overall (p =.7). A signifiant differene was not seen in effet between the nodal strata in the first or last period (p >.25) or between the age groups in the first period (p >.33). In the last period a signifiantly different effet was found between middle aged and elderly patients (p =.8), while that between young and middle aged patients was weaker (p =.9). When patients were grouped aording to both age and lymph node status (table 2) oestrogen reeptor status was signifiant in middle aged lymph node positive patients during the J lin Pathol: first published as /jp on 1 November Downloaded from on 11 January 219 by guest. Proteted by opyright.

3 922 ollett, Hartveit, Skjerven, Maehle Table 1 Number (%) ofpatients dying of oestrogen reeptor positive or negative breast aner, stratified aording to lymph node status and age at operation (years), by means of atuarial survival analyses estimating 1 year survival. The p values were derived using the log rank test Subgroup Oestrogen reeptor status Deathsltotal (%) p value Total Positive 156/579 (26.9).19 Negative 12/398 (3.2) Lymph node negative Positive 53/312 (17.).73 Negative 43/239 (18.) Lymph node positive Positive 99/262 (37.8).3 Negative 76/152 (5.) Age (years) <45 Positive 15/73 (2.5).13 Negative 25/8 (31.3) 46-6 Positive 5/165 (3.3).98 Negative 42/149 (28.2) >6 Positive 91/341 (26.7).19 Negative 53/169 (31.4) Table 2 Relative risk (RR) of dying and 99% onfidene interval (I) in patients with oestrogen reeptor negative versus oestrogen reeptor positive tumours overall and in subgroups ofpatients stratified aording to lymph node status and age at operation (years) in the first and seondfive years offollow up using the ox proportional hazard regression model. The p values were derived using the Wald test Firstfive years RR I p value Seond five years RR I pvalue Total Nodal status Negative Positive Age < * > Nodal status/age Negative/ Negative/ Negative/> Positive/< Positive/ Positive/> *The differene in effet between the first five years ompared with the seond five years of follow up is signifiant (p <.1). 3).5 o X.5 first five years of follow up only. Oestrogen reeptor status also tended to have an effet in young, lymph node positive patients. After five years, middle aged, lymph node negative patients with oestrogen reeptor positive tumours had a fivefold higher risk of dying than those with oestrogen reeptor negative ones. This effet, however, was not signifiant. Adjusting for tumour diameter gave similar results (data not shown). Although more progesterone reeptor positive patients survived for 1 years than progesterone reeptor negative ones, the unertainty was great (table 3). However, this differene was signifiant in lymph node positive patients and in middle aged patients. No effet was found in node negative nor in young and old patients. A signifiant survival differene was found for progesterone reeptor status in middle aged, lymph node positive patients, but this differene delined after five years (fig 2). A weaker effet of borderline signifiane was also found in elderly, lymph node positive patients. No effet was found in any other subgroup. Using ox proportional hazard regression analysis (table 4), progesterone reeptor status was signifiant in the first five years of follow up overall. A reversed effet of borderline signifiane was found in the seond five year,orla.25 A :- -- L---, P=-.17 I-- N+ I-- p =.7 3. L 5 1.) U).. 4- a a1) ) L.. :.75 o..5 a) X.25 --_ N ---- R- 9/46 N R- 15/31 R+ 3/35 R+ 11/37 N- ~~~~R- 9/82 N R- 33/66 R+ 19/8 N_ R+ 3/84 N- 5 R- 25/111 N ----R- 28/55 R+31/197 R+58/141 Figure 1 stimated umulative proportion ofpatients surviving, after stratifiation aording to age [(A) <45 years; (B) 46-6 years; () > 6years] and lymph node status, as predited by oestrogen reeptor (R) status. period. In the first five year period progesterone reeptor status was signifiant in lymph node positive and in middle aged patients. This was not the ase for the seond five year period. J lin Pathol: first published as /jp on 1 November Downloaded from on 11 January 219 by guest. Proteted by opyright.

4 Prognosti role of oestrogen and progesterone reeptors in breast aner Table 3 Number (%) ofpatients dying ofprogesterone reeptor positive or negative breast aner, stratified aording to lymph node status and age at operation (years), by means of atuarial survival analyses estimating 1 year survival. The p values were derived using the log rank test Subgroup Progesterone reeptor status (%/) p value Total Positive 15/419 (25.1).6 Negative 129/433 (29.8) Lymph node negative Positive 36/224 (16.1).99 Negative 41/256 (16.) Lymph node positive Positive 67/19 (35.3).6 Negative 85/173 (49.1) Age (years) <45 Positive 2/8 (25.).98 Negative 13/54 (24.1) 46-6 Positive 25/122 (2.5).9 Negative 52/154 (33.8) >6 Positive 64/225 (28.4).66 Negative 6/217 (27.6) When testing for interations a signifiant differene in effet was seen between the periods overall (p =.1). In the first five year period the prognosti importane of progesterone reeptor status differed in lymph node positive and negative patients but the differene did not reah signifiane (p =.4). A signifiantly different effet was found between middle aged and elderly patients (p =.8), whereas that between young amd middle aged patients was weaker (p =.8). Thus, with regard to length of follow up, lymph node status and age the effet of progesterone reeptor status differs more than that of oestrogen reeptor status. As for oestrogen reeptor, progesterone reeptor status was signifiant in middle aged, lymph node positive patients during the first five years of follow up only (table 4). A weaker effet of borderline signifiane was found in elderly, lymph node positive patients. Progesterone reeptor status was of no importane after five years of follow up, irrespetive of age and lymph node status. Adjusting for tumour diameter gave a similar result in middle aged and elderly patients in both nodal groups (data not shown). Beause of small numbers it was not possible to adjust further for tumour diameter in the youngest age groups. onsidering middle aged, lymph node positive patients only (fig 3), the ombined effet of Table 4 Relative risk (RR) of dying and 99% onfidene interval (I) in patients with progesterone reeptor negative versus progesterone reeptor positive tumours overall and in subgroups ofpatients stratified aording to lymph node status and age at operation (years) in the first and seond five years offollow up using the ox proportional hazard regression model. The p values were derived using the Wald test First five years RR I p value Seond five years RR I p value Total* Nodal status Negative Positive* < Age < * > Nodal status/age Negative/< Negative/ Negative/> Positive/< Positive/46-6* Positive/> *The differene in effet between the first five years ompared with the seond five years of follow up is signifiant (p <.1).. a A 1. :.75 I D.5 a.5.,o i.25 Y).5 U,.-., _- _I=. 5 p =.68 N------PgR- 5/3 N PgR- 7/22 PgR+ 4/41 PgR+ 15/ I i,- B 1. IN p= N ) m en t a., s, p = p N- PgR- 12/8 N+ PgR- 391/3 PgR+ 9/64 PgR+ 16/ N ---- PgR- 24/146 N PgR- 39/78 PgR+ 23/119 PgR+ 36/95 Figure 2 The estimated umulative proportion ofpatients surviving, after stratfiation aording to age [(A) <45 years; (B) 46-6 years; () >6 years] and lymph node status, as predited by progesterone reeptor (PgR) status. oestrogen and progesterone reeptor status was a good preditor of prognosis in the first five years of follow up. Patients with progesterone reeptor negative/oestrogen reeptor negative 1 J lin Pathol: first published as /jp on 1 November Downloaded from on 11 January 219 by guest. Proteted by opyright.

5 924 ollett, Hartveit, Skj*rven, Mehle ). a) Figiure 3 The estimated umulative proportion of middle differene was of borderline signifiane only. aged, lymph node positive patients surviving as predited by The loss of effet of oestrogen reeptor in the the ombined effet ofprogesterone (PgR) and oestrogen seond five year period in middle aged, lymph (lr) reeptor status in the first five years offollow up. node negative patients ontributed to the overle 5 Regression oeffiients for oestrogen and all loss of effet in this period and also to the Tab prodgesterone reeptor, relative risk (RR) of dying, 99% loss of effet in lymph node negative rot patients on, fidene interval (I), andp values, derivedfrom the overall. Other authors have also reported a lak WaM Reteptor Regression oeffiient p value women five years after surgery These data Oes Prol turnours faired poorly, while the best prognosis In a series inluding 269 patients we found wa is found in progesterone reeptor positive/ that progesterone reeptor, oestrogen reeptor oer strogen reeptor positive and in progesterand androgen reeptor status were all stronger on tiv e patients. No deaths were reorded for the <6 years than in those over 6.'7 The present laty ter patients. study onfirms these findings for progesterone then analysing both reeptors simultane- reeptor and oestrogen reeptor, but showed onlsly in middle aged, lymph node positive that progesterone reeptor status is an imporlients p inthefirstfive ion ahazrstfivarsdof yearsoffollow re sow upsi tant pai tients a sing preditor of patients prognosis in middle aged only. The effet of oestrogen reeptor )x proportional hazard regression analysis sau a togri on n ideae (ta str hoi but beause of the relatively small number of of progesterone reeptor varies with age. pal tients, the unertainty of the estimate was Although many reports have shown that the gre ~at. Middle aged, lymph node positive preditive effet of progesterone and oestrogen pal tients with oestrogen reeptor negative/ reeptor varies with menopausal state, the patprdgesterone reeptor negative tumours had a tern of divergene is unlear. This may be dighnotge 1 )gesteronhihereeptor beause the behaviour of aner is different in re short term prognosis in both lymph node positive and negative patients. A stratified analysis,.75 _ however, was not done.22 Although the present study also supports previous findings showing that oestrogen reeptor status is more important in lymph node positive than in lymph node ~l negative patients,6714we agree with Winstanley.5 - p <.1 et a12' that the interation between oestrogen reeptor and lymph node status does not reah signifiane Spyratos et allo found that progesterone reeptor status was an independent prognosti marker of metastasis free survival at two and. 3 five years, but lost its signifiane at 1 years We found that oestrogen reeptor status affets prognosis in the short term, whih is in agree- ment with other reports.69"5 23 In the present -- - PgR+R- / PgR-R+ 9/3 series the differene between the effets in the PgR+R+ 5/46 PgR-R- 24/43 two periods was signifiant for progesterone reeptor, while for oestrogen reeptor this test, in middle aged, lymph node positive patients of benefit for oestrogen reeptor positive RR I suggest that regression analysis should be limited to relatively short periods. Indeed, even in trogen (.84.5).8 the short periods used in our study the relative gesterone (1.6-2.).5 risk of progesterone reeptor negative and positive patients may hange.22 e reeptor positive/oestrogen reeptor nega- preditors of five year survival in patients aged ible 5), progesterone reeptor status was the status was stronger in young and middle aged ongest fator. Additional information was, patients than in elderly ones, but the differene wever, given by oestrogen reeptor status, was not signifiant (p =.22). Thus, the effet.3-fold higher risk of dying than oestrogen young, middle aged and elderly patients, mak- tiv( e ones. ing the hoie of a ut-off age ritial in pre- eptor positive/progesterone reeptor posi- ingt ie of a- ageritialsi preand postmenopausal women. The present study also shows that when lymph node status and length of follow up are Di isussion onsidered, oestrogen reeptor and progesterie prognosti effet of progesterone reeptor one reeptor status have a signifiant effet on Th stattus was signifiant in lymph node positive survival in middle aged, lymph node positive pal tients only, whih is in agreement with patients only during the first five years of follow re ent findings,782 but itis in ontrast to those up. Most of these middle aged patients may of: Pihon et al.2' The interation between pro- harateristially be in a state of hormonal flux ges sterone reeptor and lymph node status was as a result of a derease in irulating oestrogen Signifiant in this study, indiating that patients onentrations. The results reported here lend she )uld be stratified by lymph node status when support to the hypothesis that hormones influ- the effet of progesterone reeptor. ene the biologial behaviour of breast an- evailuating We have reported previously that progesterone er.2627 This influene seems to stronger in re:eptor status is an important preditor of lymph node positive than lymph node negative J lin Pathol: first published as /jp on 1 November Downloaded from on 11 January 219 by guest. Proteted by opyright.

6 Prognosti role of oestrogen and progesterone reeptors in breast aner patients. The loss of effet of oestrogen reeptor status seen in lymph node negative patients lends further support to the hypothesis that breast aner behaves differently depending on lymph node status. We therefore disagree with a Norden et al,'5 who reported that it is unneessary to stratify patients aording to lymph node status. Although it is well known that established biologial prognosti fators suh as steroid hormone reeptors show patterns of assoiations that vary with age,29 the prognosti value of oestrogen reeptor and progesterone reeptor in different age groups, when stratified by nodal status, does not seem to have been reported previously. These results require onfirmation in a larger series. However, it is important to stress that in lymph node positive patients who underwent surgery before and after 1983, oestrogen reeptor and progesterone reeptor were the strongest preditors of prognosis in middle aged patients during the first five years in both periods. In onlusion, this report shows that age, lymph node status and length of follow up are important for the evaluation of oestrogen reeptor and progesterone reeptor as prognosti variables. It has been stressed that new fators should be ombined with traditional ones in multivariate analyses and inluded in indexes used to evaluate prognosis in patients with breast aner.' If oestrogen and progesterone reeptor status are to be used to predit survival of patients with breast aner, then different riteria (indexes) should be used in different age and lymph node groups. The authors are indebted to T Thorsen for measuring the oestrogen and progesterone reeptor ontent. 1 Glik JH, Gelber RD, Goldhirsh A, Senn H-J. 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