Treatment of Advanced Male Breast Cancer

WILLIAM G. KRAYBILL, MD,' RICHARD KAUFMAN, MD,t AND DAVID KINNE. MD,$

The modalities used to treat 27 male patients with metastatic breast cancer at Memorial Hospital f rom 1957-1979 are reviewed. The overall objective orchiectomy response rate was 48% (11123). The median response was 11 months (6-96 months). The median survival in responders was 58 months, whereas the median survival in orchiectomy failures was 24 months. Four patients had estrogen receptor protein determinations (EKP). Two positive ERP patients and one borderline ERP patient responded (18-34 months). One ERP-negative patient failed orchiectomy. The number o f major ablations in this series (two responsedtwo adrenalectomies, two failuredtwo hypophysectomies) does not permit conclusions. although revicw of the literature suggests that major ahlation may he valuable in patients responding to orchiectomy. Two o f three patients who refused ablative therapy responded (three months, ten months) to single agent provera. Administering stilhesterol to the ten-month responder and to the patient who failed provera resulted in two additional responses (four months, continuing, and 22 months). Of six patients who failed orchiectomy and subsequently received chemotherapy, four patients responded (7-40 months). The median survival in these patients was 40 months (33-44 months). This review supports the importance o f orchiectomy in the treatment o f nietastatic niale breast cancer. Although the numbers are small. these data suggest that estrogen receptor determinations may he useful in selecting patients for orchiectomy. Selective additive hormone therapy may he useful in patients who refuse orchiectomy. Chemotherapy may provide worthwhile palliation in patients who fail orchiectomy.

Cancer 47:2 185 - 2 189, 198 1.

t i t s P A P E R will review the various therapies carried T out in patients with metastatic male breast cancer at Memorial Sloan-Kettering Cancer Center from 1958-1979. Male breast cancer is a rare tumor ac- counting Tor about 1c/r of all breast cancer in most countries.'.' Moreover, male breast cancer is unique because of the frequency with which i t responds to endocrine manipulation and ablation.'." Twenty-seven patients with adequate follow-up are described herein.

Cl in i ca l M a t e r i a l

Only those male patients with advanced breast cancer who had all or part of their therapy at Memorial Hospital between 1958 and 1970 are included. Proof of active disease was obtained in all patients who were

From Memorial Sloan-Kettering Cancer Center, Kew York. New York. ' Departmcnt of Surgery. Ellis Fischel State Cancer Hospital;

A\wciale Scientist. Cancer Research Center: and Assistant Pro- fe\sor. Department of Surgery. University of Missouri Medical Center. Columbia. Missouri.

+ Department of Medical Oncology, Memorial Sloan-Kelrering. :: Department of Surgery. Breast Service. Memorial Sloan-

Address for reprints: William G . Kraybill. MD, Ellis Fischel State

Accepted for publication Octoher 28, 1980.

Kcllering.

Cancer Hospj~al. I t 5 Busines 70 West. Columbia. MO hSZOI.

offered therapy. Twenty-seven patients were evaluable for review. Twenty-five of those patients had meta- static disease. Two of those patients had advanced local disease. A further breakdown of the distribution of the metastatic disease and local disease is noted in Table I . A complete response was defined as disappearance of all lesions for at least four weeks. In the case of lytic osseous metastasis, there had to be roentgenographic evidence of complete recalcification. Partial response was defined at 50% or more decrease of the size of measurable tumor lesions without the appearance of new lesions. Stable disease was defined as improve- ment with less than a partial response or less than 25% increase in the size of measurable lesions. Progressive disease was defined as a 25% or more increase in the size of measurable lesions or the appearance of the new lesions. These criteria were used as an indication for hormonal and other additive therapies. For ablative therapies, a duration of improvement of at least six months was required. In the text of this report. survival is defined as the time from recurrence to death. I n Table 2 , survival is defined as the time from the institution of the therapy being evaluated to death. The ages of these patients range from 28-78 years. Four- teen of the orchiectomy patients have been reviewed previously by Holleb in 1968.l.' When hormone re-

OOOX-543X/Xt/OSO1/2 1x5 S0.75 (' American Cancer Society

2185

2186 CANCER Mrry I 1981 Vol. 41

TABLE 1. Metastatic Sites in Advanced Male Breast Cancer

Soft Lymphatic Brain tissue Liver Bone Lung local

1 2 3 4 5 6

7 8 9

10 x 11 12 13 x 14 15 16 17 18 19 2 20 21 2 2 23 24 25 26 27

X

X

x X

X

Y

X

X

X X

X X

x K

., x

X

X

X

X

X

x X

X

X

X

X

X

X

*:

Y

x

\

X

X

x x (supra-

clavicular)

X

X

n

X

X

ceptor proteins were done, the dextran-coated charcoal method of analysis was used."

Orchiectomy was the most commonly used modality in this series. Forty-three percent (10/23) of the patients having orchiectomy for advanced male breast cancer had either a partial or complete response. When the overall response rate of patients in this series was compared with the response rates for those patients whose ages were above or below the mean age in the series, the difference was not statistically significant. The mean and median responses of those patients with partial and complete responses were 27 months and 17 months, respectively. The mean and median survivals from time of recurrence in patients with partial and complete responses to orchiectomy were 58.4 months and 57 months, respectively, whereas the mean and median survivals in patients with progression or stabilization were 26.4 and 24 months from the time of recurrence.

In 91%, (21123) of these patients, orchiectomy was the first systemic chemotherapy provided. Neither of the two patients who underwent orchiectomy following previous systemic therapy responded. Response rates varied between 36 and 57% in patients with male breast cancer that had metastasized to bone, soft tissue, and lung (Table 3). The one patient whose major meta- static involvement was in the liver did not respond to

orchiectomy. The response rate to orchiectomy cor- related well with the disease-free interval (DFI). Sixty- one percent of the patients with a disease-free interval greater than 12 months had either partial or complete response to orchiectomy, whereas only 20% of patients with the disease-free interval less than or equal to 12 months had partial or complete response to or- chiectomy.

Orchiectomy was done in four patients in whom hor- mone-receptor protein determinations were done (Table 4). Two of these patients were estrogen receptor protein (ERPI-positive. One was ERP-borderline and one was ERP-negative. The two positive patients and one borderline patient had partial responses lasting 24 months, 34 months, and 18 months, respectively. The patients with responses of 34 and 18 months had progesterone receptor studies. The former was strongly positive and the latter was negative. The ERP-negative patient did not respond to orchiectomy, although he later had a partial response to 5-FU, Cytoxan, and prednisone for 12 months.

Four major ablations were done in this series. One patient had undergone orchiectomy elsewhere. That procedure was not considered evaluable for this series. He subsequently underwent adrenalectomy. This re- sulted in stabilization of his osteoblastic metastasis and 100% resolution of his symptoms for 13 months. Another patient who had responded to orchiectomy had a 24-month complete response to adrenalectomy. There were two hypophysectomies. One patient had a six-month partial response to orchiectomy and sub- sequently failed to respond to hypophysectomy. An- other patient had a six-month stabilization of his disease followed by progression of disease. He under- went hypophysectomy but died in the immediate post- operative period. All of the major ablations are from Holleb's series except for the first hypophysectomy discussed.'.' The small number of ablations does not permit any conclusions to be drawn concerning their effectiveness in male breast cancer.

Hormonal and chemotherapeutic drugs were used effectively in selected patients. A partial response for ten months and a stabilization for three months re- sulted from the treatment of two noncastrated patients with Provera in doses of 4-80 mg per day. Three patients did not respond to a single-agent Provera. Only one of the three Provera failures previously had under- gone orchiectomy. That patient had had a complete response for ten months of orchiectomy. Upon relapse following a ten-month partial response to Provera, the addition of stilbesterol resulted in a three-month partial response in one patient. Thus, two of five patients treated with a single agent Provera responded. One pa- tient who failed Provera and refused orchiectomy had a

No. 9 MALE BREAST CANCER TREATMENT ’ Krciybill et al. 2187

TABLE 2 . Therapeutic Modalities and Responses in Advanced Male Breast Cancer

Response Mean survival response* Treatment

Therapeutic modality Patients CR PR Stabilized Failure (mo) (mo)

Orchiectomy

Provera

Adrenalectoniy

Hypophysectomy

Stilbesterol

Provera t Stilbesterol

C y to xi i n

Cytoxan + Pn-ednisone

Cytoxan. 5-FU, Prednisone

5-FU. Cytoxan. Methotrexate. Testosterone, Decadron

Prednisone

5-FLI t Provera

Provera t Prenisolone

Nitrogen Mu5t;ird (chest)

Provera t Leukeran

Le ukeran

Velhan

Leuheran + Act. D

5-FU

23

5

2

2

5

7 -

1

7 - I

1

5

I

I

2

I

7 - I

1

I

12.6

2.6

13.5

0

2.0 response

12.5

0

32.0

12.0

0

2.4

4.0

9.0

6.5

7.0

7.0

0

0

0

33.x

23.0

69.0

15.0

19.5

29.0

23.0

35.0

33.0

6.0

17.4

6.0

36.0

14.5

’8.0

36.0

8.0

5.0

2.0

Survival i s calculated from time of institution of therapy

22-month complete response with the addition of di- ethylstilbesterol, 10 mg daily, to his Provera. One pa- tient had a partial response to Provera, 15 mg daily, and Prednisolone 20 mg daily for nine months. This patient had had a partial response to orchiectomy. Five patients received stilbesterol as a single agent at doses between 3-15 mg daily. There were four nonre- sponders and one possible stabilization. None of the patients in this series was treated with Tamoxifen or antiestrogenic spbstances.

Ten of the 27 patients evaluated in this study re- ceived chemotherapy in various combinations (Tables 2 and 5). Six of those ten patients had failed orchiec-

TABU 3 . Partial and Complete Response Rate to Orchiectomy a s Related to Major Site of Metastatic Involvement

Soft tissue Bone Liver Lung (%) (% 1 (%) (7r)

Response rates 57 (417) 36 (4111) 0 (011) 50 (214)

2188 CANCER May I 1981 Vol. 47

TABLE 4. Hormone Receptor Status vs. Response to Orchiectomy

Value Value (fmoYmg PRO ( f m o h g

ERP protein) status protein) Response

42 mo. PR (+) 61.1 ND -

(+) 206 + 193 34 mo. PR

(*)* 8.2 (-) 9.6 18 mo. PR 68% 5% inhibition

( - ) 3.7 ND - 0 progression

97% inhibition

29% inhibition

ND = Not done. * Value became negative on repeat biopsy.

tomy. There were three partial responses and one com- plete response lasting between seven and 40 months. Of interest, three of the responding patients had failed orchiectomy and one had a six-month stabilization fol- lowing orchiectomy. The mean and median survivals from the time of recurrence in these patients were 43 months and 40 months, respectively. The mean sur- vival from the time of institution of therapy is noted in Table 2. This compares favorably with the mean and median survivals in other orchiectomy failures of this series. Daily Cytoxan and prednisone were com- ponents in the regimens of three of these four patients. 5-FU, 500 mg every two weeks also was given to one of these three patients. The remaining patient had a seven- month response to Leukeran.

Discussion

A comparison of the response rate to orchiectomy in this series with previous series reveal it to be less than that reported from other There was no correlation between age and response rate as demonstrated by some very elderly patients who re- sponded nicely to orchiectomy. Our median response length in patients with partial and complete response was 17 months. The median survival of 58.4 months in patients with partial and complete responses compares

TABLE 5 . Response and Survival Following Failure of Orchiectomy in Patient Responding to Chemotherapy

Re- Sur- Patient sponse vival

no. Drug (mo) (mo)

I Leukeran PR 7 45 2 Cytoxan, prednisone PR 17 36 3 Cytoxan, S F U , prednisone PR 23 33 4 Cytoxan. prednisone CR 40* 47

* Ongoing.

favorably with that in Meysken's review, which re- ported a survival in responders of 56 months and in nonresponders of 38 months. As has been noted in female breast cancer by Fracchia et al . , there was a strong correlation between DFI and the response rate to castration in this series. *'I Good responses in patients who were ERP-positive and borderline and in the one patient who was also PRP-positive occurred in this series. The one patient who was ERP-negative did not respond to orchiectomy.

In a combined study of several institutions, Everson et a/ . reported 34 male breast cancer patients who had estrogen receptor assays done." Of 29 patients who were ERP-positive, 13 underwent orchiectomy. The overall response rate was 31%. The incidence of ERP- positive tumors is comparable to other reported series." However, the overall clinical response rate to orchiectomy of 31% is less than that reported in this series and half that reported in some other series.':' Perhaps because the overall response rate was so low, there was no significant relationship between estrogen receptor values and response rate. The authors could not explain their low response rate as compared with other investigators. They did underline the importance of comparing the responses in patients with actual values of estrogen receptors in femtomoles rather than positive vs. negative. Their review and our series sup- port further evaluation of the usefulness of estrogen receptor proteins and other hormone receptor proteins in patients with male breast cancer. And, on the basis of these data, it would be inappropriate to withhold orchiectomy from patients who are ERP-negative.

The number of major ablations in this series does not permit conclusions to be drawn concerning their ef- ficacy in advanced male breast cancer. The use of major ablation in this disease has been reviewed extensively by others and found to be useful in providing palliation in selected patients.Ig-l6

In this series, progestational hormones were useful as single agents and in combination with other hor- mones. In women who had breast cancer, response rates of 25% (6/24) have been reported after treatment with proge~terone. '~ Pannuti reported response rates of 43% in women with breast cancer who were treated with massive doses of medroxyprogesterone acetate.'" Geller obtained an excellent response to 17-A hydroxy- progesterone in a man with breast cancer.l9 Kennedy noted a male patient who responded for ten months to a combination of progesterone and estrogen.'' The use- fulness of progesterone and a combination of progester- one and estrogen in this series is consistent with these cases reported previously. Single agent estrogen therapy in this small number of patients was not use-

No. 9 MALE BREAST CANCER TREATMENT . Krayhill et nl. 2189

ful. Others have reported response rates as high as 38% using diethylstilbesterol."' Exacerbation of male breast cancer with this drug has been reported by Kennedy.'' The place of single agent estrogen therapy in the treatment of this disease is unclear. None of the patients rn this review was treated with antiestrogen compounds. Responses to Tamoxifen have been re- ported i n patients with male breast cancer (6/9).21 Estrogen receptor data were not available for these patients.

Noteworthy in this series, combination chemother- apy was a valuable therapeutic measure in four of six patients who previously had failed orchiectomy. The mean survival of 43 months in these patients compares favorably with the survival of other patients failing orchiectomy. Cytoxan and prednisone appeared to be the most active agents. Male breast cancer has been reported to respond to Adriamycin, Cytoxan, 5-FU, methotresate, and thiotepa.r".'J However, these re- ports have been infrequent. Most probably this is be- cause of the infrequent occurrence of this tumor. The present series suggests that in selected patients this modality may be valuable in providing palliation. And, as noted in another recent review, male breast cancer is probably as responsive to chemotherapy as is female breast cancer.22

Summary

The treatment of metastatic carcinoma of the male breast at Memorial Hospital for the past 20 years has been reviewed. This series supports the importance of orchiectomy in the treatment of metastatic male breast cancer. A review of the literature demonstrates that major endocrine ablation is useful in these patients. Although the place of hormonal receptor studies needs to be more carefully worked out in this disease, they certainly will be of importance in a tumor so sensitive to hormonal manipulation. The use of additive pro- gesterone and of a combination of progesterone and estrogen should be considered in the treatment of patients who are not candidates for other endocrine manipulations. Although they were not used in this series. the fact that antiestrogenic compounds may be useful in this disease are reported elsewhere." Chemotherapy may provide palliation for selected pa- tients whose cancers have failed to respond to other therapies.

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