More than 80% of all mammary gland masses in cats are malignant, and the behavior of these tumors is characterized by local invasion into the vasculature and surrounding tissues and metastasis to draining lymph nodes and distant locations, including the lungs, pleura, and liver.1–10 Because of this aggressive biological behavior, mammary adenocarcinoma requires aggressive treatment in cats. Treatment options that have been reported include surgical excision, chemotherapy, immunotherapy, radiation therapy, and various combinations of these treatments.1–10 Numerous studies have evaluated prognostic factors for mammary adenocarcinoma in cats, and factors found to be significant in individual studies include tumor size,11,12 TNM stage,8 histologic subtype,10,13 histologic grade,8,14 and lymphatic invasion3,8 as well as a variety of proliferative markers including mitotic index,8,15 Ki67 positivity,8 and mean AgNOR count per neoplastic cell.16 Administration of adjuvant chemotherapy has been suggested to have a beneficial prognostic effect in some studies4; however, in 1 study6 that included a control population that did not receive adjuvant chemotherapy, no obvious beneficial effect of chemotherapy was seen.
Surgical approach has been reported to affect disease-free interval in cats when the outcome of full-chain (sometimes referred to as radical) mastectomy is compared with the outcome of regional mastectomy.1 On the basis of this finding, a recommendation to perform full-chain mastectomy of the affected mammary chain has become well accepted, regardless of tumor size. A more challenging question for clinicians is whether to perform unilateral mastectomy or bilateral mastectomy because of possible contact between individual glands, connections between the left and right mammary chains, or de novo development of mammary adenocarcinoma in the contralateral chain that remains present. The lymphatic anatomy has been well studied in healthy cats. The drainage patterns of the various glands to their respective ipsilateral nodes has been established, and there are studies17–19 that broadly agree on this variability. However, evidence for lymphatic cross-connections from ipsilateral to contralateral glands appears to be absent in all current published studies17–19 regardless of assessment technique.
Bilateral mastectomy can be performed as a single-session procedure or in a staged fashion; for the latter, the 2 procedures are typically performed several weeks apart. In 1 study,4 37 cats undergoing staged bilateral mastectomy had a longer disease-free interval than those undergoing unilateral mastectomy (917 days vs 348 days); however, this result was only statistically significant in the univariable model. Limited information exists in the published literature on cats treated with bilateral mastectomy for management of mammary adenocarcinoma, and the complication rate associated with this procedure is largely unknown.
As such, the objectives of the study reported here were to compare outcome among cats with mammary adenocarcinoma following excision with or without various systemic adjuvant treatments, and to evaluate potential associations of surgical approach with progression-free and disease-specific survival times. Our primary null hypothesis was that progression-free and disease-specific survival times would be superior for cats with mammary adenocarcinoma undergoing bilateral mastectomy compared with unilateral mastectomy. Secondary hypotheses were that no differences would exist in the surgical complication rate for unilateral mastectomy versus bilateral mastectomy whether performed in a single-session or staged approach, and that adjuvant chemotherapy would prolong the disease-specific survival time in affected cats.
Materials and Methods
Animals
Cats in which mammary adenocarcinoma was diagnosed at 9 veterinary institutions in North America and Europe between September 16, 1991, and September 1, 2014, were included in the study. Medical records from the participating institutions were reviewed, and telephone interviews were conducted with owners or referring veterinarians to assess long-term outcome.
Criteria for selection of cases
Only cats that had a complete medical record and underwent surgical excision of histopathologically confirmed mammary adenocarcinoma by means of unilateral mastectomy or bilateral (single-session or staged) mastectomy were eligible for study inclusion. Cats were excluded if they underwent local or regional mastectomy, if they underwent unilateral mastectomy but had bilateral disease, or if they had distant metastasis at the time of surgery.
Medical records review
Information collected from the medical records of cats included in the study consisted of age and weight at the time of surgery, sex, breed, use of progestins, previous pregnancy, whether an ovariectomy or ovariohysterectomy had been performed, and time from onset of clinical signs to examination by a veterinarian. Information recorded from diagnostic imaging studies included abnormalities identified by means of thoracic radiography and abdominal ultrasonography prior to the first surgery. The number of mammary masses, location of mammary masses (right, left, or bilateral), and which specific glands were affected (1 through 4) were recorded, along with the diameter of the largest mammary mass and presence or absence of ulceration. From these results a TNM stage was designated for each cat on the basis of clinical and diagnostic imaging findings and the modified World Health Organization staging system.1
Surgical variables recorded included the surgical procedure performed (ie, unilateral mastectomy, single-session bilateral mastectomy, or staged bilateral mastectomy). Surgery time was recorded and, in the case of staged bilateral mastectomy, the surgery time for each of the 2 procedures was recorded as a separate event. If lymphadenectomy was performed, the lymph nodes removed were noted. Intra- and postoperative complications (if applicable) were recorded and compared between procedures.
Results of histologic evaluation of all resected mammary gland tissue and lymph nodes were recorded. Results of margin evaluation and histologic grade (determined on the basis of degree of differentiation and evidence of lymphatic and vascular invasion) were also recorded when available.
For cats in which adjuvant chemotherapy was administered, the number of doses, dose range, and type of chemotherapy drugs administered were recorded, along with whether the cat completed the prescribed course of chemotherapy.
Outcome measures
Progression-free survival time and the nature of disease progression (ie, local vs distant) were recorded. Progression-free survival time was defined as the time from mastectomy until documentation of local tumor progression, regional or distant metastasis, or tumor-related death. When possible, local progression was categorized as recurrence at or close to the previous resection site (surgical scar) or at a location distant from the previous resection site. However, because of the challenges inherent in retrospectively classifying location of recurrence, these categories were combined for statistical purposes as local progression.
Disease-specific survival time was also recorded. Disease-specific survival time was defined as the time from mastectomy to tumor-related death. Tumor-related death was defined as death or euthanasia as a result of local tumor recurrence, de novo tumor development, regional metastasis, or distant metastasis. For both progression-free survival time and disease-specific survival time, deaths associated with treatment or because of unknown causes were considered tumor-related.
Statistical analysis
Baseline characteristics were examined, and summary statistics were calculated for all measured variables. Categorical variables were reported as numbers and percentages. Distribution of continuous variables was evaluated with histograms and the Shapiro-Wilk test, and results were reported as mean (SD) if data were normally distributed and as median (range) if data were not normally distributed. Baseline characteristics were compared among mastectomy type groups with χ2 or Fisher exact tests for categorical variables and independent t tests or Mann-Whitney U tests for continuous variables. For cats undergoing staged bilateral mastectomy, surgery times for the first and second procedures were compared with the signed rank test for pairwise comparisons. A nonparametric test for trends was used to compare local recurrence rates across ordered histopathology margin groups (clean, narrow, and incomplete). All tests were two-sided, and results were considered significant for values of P ≤ 0.05.
Cats lost to follow-up or alive at the time of data collection were censored on the date they were last recorded alive. Cats that died of documented causes unrelated to their mammary carcinoma were censored to minimize the influence of competing risks. The Kaplan-Meier product limit method was used to describe unadjusted progression-free survival and disease-specific survival times for all cats. Log-rank tests were used to compare progression and survival time distributions according to mastectomy type. The Cox proportional hazards regression method was used to model variables associated with progression-free survival and disease-specific survival times. Univariable analyses were performed, and covariates were retained if their likelihood ratio test or Wald test P values were ≤ 0.05 or if covariates were confounding the association of interest (defined as a > 15% change in the HR). No covariates were forced into the model on an a priori basis. Two-way interactions between the main effects were investigated. In instances when the likelihood ratio test could not be used because of missing covariate data, the Akaike information criterion was used for model comparisons. Proportional hazards assumptions were evaluated with Shoenfeld residuals and the score test, with values of P > 0.05 considered acceptable. Overall model fit was assessed with deviance and Cox-Snell residuals. All statistical analyses were performed with statistical software.a
Results
Patient characteristics
Records of 116 cats treated with mastectomy were reviewed. Three cats were excluded because of the presence of distant metastasis prior to surgery, and 5 cats were excluded because a unilateral mastectomy was performed without subsequent contralateral mastectomy despite the presence of bilateral mammary adenocarcinoma. One cat was excluded because it developed respiratory distress and died following single-session bilateral mastectomy, and tissue samples for histopathologic examination were not submitted. Thus, 107 cats from 9 veterinary hospitals were included (Table 1). Sixty-one (57%) cats were treated with unilateral mastectomy, 32 (30%) cats with single-session bilateral mastectomy, and 14 (13%) cats with staged bilateral mastectomy.
Characteristics of 107 cats that underwent unilateral (n = 61) or bilateral (46) mastectomy for treatment of mammary adenocarcinoma.
Variable | Unilateral mastectomy | Bilateral mastectomy | P value |
---|---|---|---|
Institution | 0.001 | ||
University of Pennsylvania | 17 (27.9) | 11 (23.9) | |
University of California-Davis | 16 (26.2) | 4 (8.7) | |
Colorado State University | 11 (18.0) | 7 (15.2) | |
Ontario Veterinary College | 3 (4.9) | 5 (10.9) | |
Alta Vista Animal Hospital | 0 (0.0) | 9 (19.6) | |
Clinica Veterinaria Nerviano | 7 (11.5) | 1 (2.2) | |
University of Turin | 3 (4.9) | 3 (6.5) | |
University of Florida | 3 (4.9) | 3 (6.5) | |
University of Tennessee | 1 (1.6) | 3 (6.5) | |
Year treated | 0.003 | ||
1991–2006 | 26 (42.6) | 7 (15.2) | |
2007–2014 | 35 (57.4) | 39 (84.8) | |
Age (y) | 10.7 (2.8) | 10.3 (3.5) | 0.543 |
Weight (kg) | 4.3 (2.3–7.0) | 4.0 (2.7–7.8) | 0.150 |
Sex | 0.851 | ||
Castrated male | 1 (1.6) | 1 (2.2) | |
Sexually intact female | 4 (6.6) | 2 (4.3) | |
Spayed female | 56 (91.8) | 43 (93.5) | |
Breed | 0.176 | ||
Domestic shorthair | 33 (54.1) | 25 (54.3) | |
Domestic longhair | 17 (27.9) | 8 (17.4) | |
Siamese | 5 (8.2) | 2 (6.4) | |
Other pure breed | 6 (9.8) | 11 (23.9) | |
Duration of clinical signs (d)* | 30 (0–700) | 21 (0–730) | 0.750 |
Number of tumors | 0.016 | ||
1 | 40 (65.6) | 19 (41.3) | |
2–5 | 18 (38.3) | 18 (39.1) | |
> 5 | 3 (4.9) | 9 (19.6) | |
Location of tumors† | 1.000 | ||
Right chain | 34 (55.7) | 17 (54.8) | |
Left chain | 27 (44.3) | 14 (45.2) | |
Largest tumor diameter (cm)‡ | 2 (0.2–10.0) | 2 (0.3–10.0) | 0.365 |
Ulcerated tumor | 6 (9.8) | 6 (13) | 0.759 |
TNM stage§ | 0.384 | ||
Stage 1 (T1, N0, M0) | 19 (31.7) | 14 (31.8) | |
Stage 2 (T2, N0, M0) | 16 (26.7) | 7 (15.9) | |
Stage 3 (T1–2, NI, M0 or T3, any N, M0) | 25 (41.7) | 23 (52.3) | |
Lymph node metastasis‖ | 20 (33.3) | 21 (44.7) | 0.401 |
Lymphatic or vascular invasion¶ | 26 (42.6) | 20 (42.6) | 1.000 |
Surgical margins# | 0.226 | ||
Clean (> 2 mm) | 41 (75.9) | 37 (90.2) | |
Narrow (0–2 mm) | 8 (14.8) | 3 (7.3) | |
Incomplete | 5 (9.3) | 1 (2.4) |
Categorical data are given as number (%); continuous data are given as mean (SD) or as median (range).
Data were missing for 19 cats.
Fifteen cats treated with bilateral mastectomy had masses located in both the right and left chains.
Data were missing for 8 cats.
Data were missing for 3 cats.
Data were missing for 1 cat.
Data were missing for 15 cats.
Data were missing for 12 cats.
Ninety-nine of the 107 (93%) cats were spayed females, 6 (5%) were sexually intact females, and 2 (2%) were castrated males. The type of sterilization procedure was known for 44 of the neutered female cats; 28 (64%) cats had undergone ovariectomy and 16 (36%) had undergone ovariohysterectomy. Parturition status was known for 44 cats; 11 (25%) cats had at least 1 pregnancy and 33 (75%) were nulliparous. No cats had previously been treated with progestins PO. Tumor location was reported for 103 cats. The first (axillary) glands were involved in 33 (32%) cats, the second (thoracic) glands were involved in 29 (28.2%), the third (abdominal) glands were involved in 40 (38.8%), and the fourth (inguinal) glands were involved in 58 (56.3%). Tumors were located in more than 1 mammary gland in 34 (33%) cats.
Three-view thoracic radiography was performed in 93 (86.9%) cats, and abdominal ultrasonography was performed in 45 (42.1%). No cats had evidence of distant metastasis on radiography or ultrasonography, although inguinal or iliac lymphadenopathy was noted in 9 of 45 cats. Fine-needle aspiration of regional lymph nodes was reportedly performed in 18 (16.8%) cats, but results were available for only 15. Results of cytologic examination indicated metastasis to the axillary nodes in 1 of 6 cats, to the inguinal nodes in 7 of 7 cats, and to the iliac lymph nodes in 1 of 2 cats. Information about why certain staging tests were or were not performed in individual cats was not available.
Surgery and histopathologic findings
Surgical time was reported for 88 of 107 (82%) cats. Median procedure time was 70 minutes (range, 40 to 160 minutes) for 58 cats that underwent unilateral mastectomy (including the first stage for cats treated with staged bilateral mastectomy) and 72.5 minutes (range, 35 to 165 minutes) for 31 cats that underwent single-session bilateral mastectomy; these times were not significantly (P = 0.798) different. For cats that underwent staged bilateral mastectomy, the median time between surgeries was 4 weeks (range, 2.5 to 7.0 weeks). Median second surgery time was 70 minutes (range, 41 to 115 minutes) in the 9 cats for which surgery time was recorded and was not significantly (P = 0.671) different from that reported for the first surgery. Regional lymph nodes were not removed in 14 cats. Superficial inguinal lymph nodes were removed in 64 cats, and both inguinal and axillary lymph nodes were removed in 29 cats. Patterns of lymph node removal were not significantly (P = 0.946) different among mastectomy types.
Postoperative complications occurred in 31 of 107 (29%) cats (Table 2). One cat that underwent unilateral mastectomy experienced > 1 complication (incisional infection and pleural effusion). Complications occurred in 13 of 61 (21.3%) cats that underwent unilateral mastectomy, 5 of 14 (35.7%) cats that underwent staged bilateral mastectomy, and 13 of 32 (40.6%) cats that underwent single-session bilateral mastectomy. Complications were significantly (P = 0.027) more likely in cats that underwent bilateral mastectomy than in cats that underwent unilateral mastectomy. For the 14 cats that underwent staged bilateral mastectomy, complications were associated with the first surgery in 2, the second surgery in 2, and both surgeries in 1. More complications occurred in cats undergoing single-session bilateral mastectomy (13/32 [40.6%]), compared with unilateral mastectomy or staged bilateral mastectomy (18/75 [24%]); but the difference was not significant (P = 0.058). Two cats died in the immediate postoperative period; 1 cat experienced cardiac arrest after unilateral mastectomy, and 1 cat experienced respiratory failure attributed to excessive wound closure tension after single-session bilateral mastectomy.
Postoperative complications in 107 cats that underwent unilateral mastectomy (n = 61), staged bilateral mastectomy (14), or single-session bilateral mastectomy (32) for treatment of mammary adenocarcinoma.
Complication | Unilateral mastectomy | Staged bilateral mastectomy | Single-session bilateral mastectomy | All cats |
---|---|---|---|---|
Infection or dehiscence | 9 (14.8) | 2 (14.3) | 8 (25) | 19 (17.6) |
Seroma | 1 (1.6) | 1 (7.1) | 3 (9.4) | 5 (4.6) |
Abdominal hernia | 1 (1.6) | 0 (0.0) | 1 (3.1) | 2 (1.9) |
Respiratory distress | 1 (1.6) | 0 (0.0) | 1 (3.1) | 2 (1.9) |
Other | 1 (1.6)* | 2 (14.3)† | 0 (0.0) | 3 (2.8) |
Data are given as number (%).
One cat experienced multiple complications, and 3 cats died of causes related to complications.
Cardiac arrest.
Seizures (n = 1) and esophageal stricture (1).
Results of histopathologic examination of tumor tissue samples were available for all 107 cats. However, type of histopathologic evaluation and terminology used to describe tumors was not uniform for all samples. Most tumors were described simply as adenocarcinoma, but other mammary carcinoma diagnoses were also reported, including simple, cystic, tubular, tubulopapillary, tubuloacinar, papillary, ductal, intraductal, infiltrative, secretory, complex, lobular, basaloid, scirrhous, and comedo carcinomas. Heterogeneity of descriptions precluded further classification and analysis on the basis of histopathologic subtype. Extent of differentiation was reported in 57 of 107 (53.3%) cats; 12 (21.1%) tumors were well differentiated, 21 (36.8%) were moderately differentiated, and 24 (42.1%) were poorly differentiated. Lymphatic invasion was reported in 43 of 107 (40.2%) cats, and vascular invasion was reported in 16 (15.0%). Tissue margins were evaluated in 95 cats and were clean (> 2 mm) in 78 (82.1%) cats, narrow (0 to 2 mm) in 11 (11.6%) cats, and incomplete in 6 (6.3%) cats. Of the 93 cats for which regional lymph nodes were evaluated histologically, 41 (44.1%) had evidence of lymph node metastasis.
Adjuvant chemotherapy
Follow-up information was analyzed for 105 cats that survived the postoperative period, including 60 cats treated with unilateral mastectomy and 45 cats treated with bilateral mastectomy. Adjuvant chemotherapy was administered to 53 of these 105 (50.5%) cats, including 28 (46.7%) cats treated with unilateral mastectomy and 25 (55.6%) cats treated with bilateral mastectomy. There was no significant (P = 0.432) difference in the proportion of cats receiving chemotherapy between the mastectomy groups. Doxorubicin was administered to 44 cats at recommended dosages for a median of 4 doses (range, 1 to 6 doses); 8 of these cats were also treated concurrently with recommended dosages of cyclophosphamide for a median of 4 doses (range, 1 to 4 doses). Carboplatin was administered to 15 cats, including 12 that also received doxorubicin. The remaining 6 cats received other chemotherapy drugs, including experimental liposomes (n = 2), epirubicin (2), mitoxantrone (1), and toceranib and chlorambucil (1). Following doxorubicin, carboplatin, or both, 6 cats were treated with additional chemotherapy, including toceranib (n = 2), vincristine (1), vinorelbine (1), dacarbazine (1), and vincristine, toceranib, and chlorambucil (1). Among chemotherapy-treated cats, 40 of 53 (75.5%) completed their planned treatment protocol; treatment was stopped early in 13 cats because of progressive disease (n = 6), non-tumor-related death (3), delayed postoperative complications (1), kidney disease (1), persistent neutropenia (1), and owner relocation (1). Additionally, NSAIDs (meloxicam or ketoprofen) were administered to 17 of 105 (16.2%) cats, including 9 cats that were also treated with chemotherapy.
Progression-free survival time
Progressive disease was reported for 64 of 105 (61.0%) cats. Local recurrence and regional or distant metastasis occurred in 28 of 60 and 33 of 60 cats that underwent unilateral mastectomy, respectively, and in 9 of 45 and 16 of 45 of cats that underwent bilateral mastectomy, respectively. Local progression and regional or distant metastasis were more frequently reported following unilateral mastectomy than bilateral mastectomy (Table 3). Both local progression and metastasis occurred in 17 cats treated with unilateral mastectomy and 5 cats treated with bilateral mastectomy. For these 22 cats, the first reported event was local progression in 12 cats and metastasis in 6 cats; in the remaining 4 cats, both local progression and metastasis were identified concurrently. Location of local progression was not reported in 5 cats. Among the remaining 32 cats, local recurrence developed close to the surgical site in 10 cats treated with unilateral mastectomy and in 5 cats treated with bilateral mastectomy, and was at a different site within the mammary tissue in the remaining 17 cats. The incidence of local recurrence did not differ significantly (P = 0.209) between cats undergoing unilateral versus bilateral mastectomy. For the 94 cats that survived the postoperative period and had surgical margins reported, the prevalence of local progression increased significantly (P = 0.035) from the clean to narrow to incomplete margin groups. Site of metastasis was not reported in 2 cats. Metastatic disease was identified in the lungs (33/47 cats), regional lymph nodes (17/47), and other distant sites (5/47) including the spleen, brain, peritoneal space, muscle, and sciatic nerve.
Reported disease progression in 107 cats that underwent unilateral (n = 61) or bilateral (46) mastectomy for treatment of mammary adenocarcinoma.
Variable | Unilateral mastectomy | Bilateral mastectomy | P value |
---|---|---|---|
No progression | 17 (27.9) | 26 (56.5) | 0.003 |
Local recurrence* | 28 (46.7) | 9 (20.0) | 0.005 |
Near surgical site | 10 (16.7) | 5 (11.1) | |
Distant from surgical site | 15 (25.0) | 2 (4.4) | |
Regional or distant metastasis† | 33 (55.0) | 16 (35.6) | 0.048 |
Lymph node | 15 (25.0) | 2 (4.4) | |
Lungs | 20 (33.3) | 13 (28.9) | |
Other distant site | 3 (5.0) | 2 (4.4) |
Data are given as number (%). Twenty-two cats developed both local recurrence and metastatic disease.
Site of recurrence was not reported for 3 cats that underwent unilateral mastectomy and 2 cats that underwent bilateral mastectomy.
Site of metastasis was not reported for 1 cat that underwent unilateral mastectomy and 1 cat that underwent bilateral mastectomy; multiple sites of metastasis were reported for 4 cats that underwent unilateral mastectomy and 2 cats that underwent bilateral mastectomy.
Median progression-free survival time was 375 days (95% CI, 289 to 513 days) for all cats, 542 days (lower 95% confidence limit, 346 days; upper limit not reached) for cats treated with bilateral mastectomy, and 289 days (95% CI, 153 to 386 days) for cats treated with unilateral mastectomy. Unadjusted progression-free survival time was significantly (P = 0.004) longer among cats undergoing bilateral versus unilateral mastectomy (Figure 1). In univariable Cox regression analyses, institution, year, age, body weight, duration of clinical signs prior to mastectomy, postoperative incisional infection, and treatment with chemotherapy were not significantly associated with progression-free survival time. Tumor location, tumor ulceration, number of tumors, type of mastectomy, incomplete surgical margins, TMN stage, lymph node metastasis at the time of surgery, and lymphatic or vascular invasion were significantly (P < 0.25) associated with progression-free survival time in univariable analyses and were tested in the multivariable model. The final multivariable model included type of mastectomy, tumor ulceration, lymph node metastasis at the time of surgery, and tumor location, all of which had significant associations with progression-free survival time; no additional variables were retained as confounders. Interactions between the 4 retained variables were tested and none were significant. Risk factors for disease progression included unilateral mastectomy (HR, 3.09; 95% CI, 1.67 to 5.77), tumor ulceration (HR, 4.35; 95% CI, 1.81 to 10.42), lymph node metastasis at the time of surgery (HR, 2.49; 95% CI, 1.35 to 4.60), and tumors arising in a fourth (inguinal) gland (HR, 2.25; 95% CI, 1.23 to 4.12). Although lymph node status was associated with progressive disease, 13 of 41 (31.7%) cats with histologic evidence of lymph node metastasis at the time of surgery did not progress to further metastasis. The multivariable model indicated that bilateral mastectomy was protective against disease progression even when lymph node metastasis was identified.
Disease-specific survival time
At the time of follow-up, 54 of 107 cats had died of mammary adenocarcinoma (including 2 cats that died in the perioperative period and 2 that died of unknown causes). Of the 107 cats, 25 were lost to follow-up at a median 298 days (range, 17 to 3,278 days) after surgery, 16 were alive, and 12 had died of causes unrelated to feline mammary adenocarcinoma, including other neoplasia (n = 4), cardiac disease (2), kidney disease (1), esophageal stricture (1), bacterial cholangitis (1), endocrine disease (1), iatrogenic injury (1), and old age (1). The median disease-specific survival time was 375 days (95% CI, 289 to 513 days) for all cats, 1,140 days (lower 95% confidence limit, 513 days; upper limit not reached) for cats treated with bilateral mastectomy, and 473 days (95% CI, 296 to 1,134 days) for cats treated with unilateral mastectomy. Unadjusted disease-specific survival time was significantly (P = 0.027) longer among cats undergoing bilateral versus unilateral mastectomy (Figure 2). In univariable Cox regression analyses, institution, year, body weight, duration of clinical signs, number of tumors, tumor location, surgical margins, and development of local recurrence were not associated with survival time. Age, type of mastectomy, tumor ulceration, TNM stage, lymphatic or vascular invasion, lymph node metastasis at the time of surgery, treatment with chemotherapy, and development of regional or distant metastasis were associated (P < 0.25) with disease-specific survival time in univariable analyses and were tested in the multivariable model. Age, tumor ulceration, lymphatic or vascular invasion, and TNM stage were excluded from the model, and interactions between the remaining 4 variables (type of mastectomy, lymph node metastasis at time of surgery, treatment with chemotherapy, and development of regional or distant metastasis) were examined. A significant interaction between type of mastectomy and development of metastasis was identified. The final multivariable model included the 4 retained variables and the interaction term. Development of regional or distant metastasis after surgery was strongly associated with death (HR, 10.52; 95% CI, 2.79 to 39.68) in all cats. Among cats that did not develop metastasis, treatment with unilateral mastectomy rather than bilateral mastectomy increased the risk of death (HR, 4.56; 95% CI, 1.27 to 16.4). For cats that developed postoperative metastasis, the type of mastectomy was not significantly associated with disease-specific survival time (HR, 0.73; 95% CI, 0.33 to 1.60). Lymph node metastasis at the time of surgery was also associated with increased risk of death (HR, 2.14; 95% CI, 1.11 to 4.14), whereas treatment with chemotherapy was protective (HR, 0.36; 95% CI, 0.19 to 0.70).
Discussion
Results of the present multi-institutional retrospective study evaluating a large cohort of cats treated surgically for mammary adenocarcinoma supported the use of bilateral mastectomy for the treatment of mammary adenocarcinoma in cats to improve progression-free and disease-specific survival time. It is generally agreed that surgery plays a pivotal role in the management of cats with mammary adenocarcinoma as it does in people with breast cancer. Many previous studies have attempted to elucidate the effects of various surgical approaches on outcome, and some helpful data exist suggesting that local or regional mastectomy is associated with a significantly shorter disease-free interval than unilateral mastectomy.1 Despite full-chain mastectomy having become the standard of care, the question of whether a unilateral or bilateral approach should be used even in the event of unilateral disease has been more controversial. Several studies have attempted to answer this question, although none have concluded that unilateral mastectomy is a risk factor for shorter progression-free survival, disease-specific survival, or overall survival time when considered in a multivariable statistical model that incorporates other known risk factors. One study6 documented a progression-free survival time of 793 days versus 115 days for bilateral mastectomy versus unilateral mastectomy; however, only 3 cats underwent bilateral mastectomy and no significant differences were found. A second study4 compared bilateral mastectomy, unilateral mastectomy, and regional mastectomy and reported disease-free intervals of 917 days, 348 days, and 428 days, respectively. Despite there being a significant difference on univariable analysis between bilateral mastectomy and unilateral mastectomy, this difference was insignificant on multivariable analysis. In the present study, median progression-free survival times for bilateral and unilateral mastectomy were 542 and 289 days, respectively, and unilateral mastectomy was found to be an independent risk factor for local recurrence or metastasis.
The relatively higher incidence of local recurrence in the cats with mammary adenocarcinoma undergoing unilateral versus bilateral mastectomy in the present study could have had a number of explanations. In human patients with breast cancer, for which mammary adenocarcinoma in cats has previously been considered a good experimental model,20,21 much debate has surrounded the indications for contralateral prophylactic mastectomy, the human corollary to bilateral mastectomy in cats. The use of contralateral prophylactic mastectomy has been increasing in large part because of fear of recurrence in the contralateral breast in women with invasive ductal carcinoma and the increasing use of MRI of the contralateral breast that can detect occult lesions that may not be clinically important causes of longer term morbidity.22,23 The therapeutic benefit of contralateral prophylactic mastectomy in most women with early-stage breast cancer is likely to be small, as the incidence of contralateral breast cancer has been reported24,25 to be approximately 3% to 10% and has been declining in recent years. There are, however, certain subgroups of women who have a much higher risk of contralateral breast cancer who may benefit from contralateral prophylactic mastectomy, such as women with the
BRCA1 or BRCA2 genetic mutations and women who have a family history of at least 2 first-degree relatives with breast or ovarian cancer.23 In women with the BRCA1 and BRCA2 mutations that undergo contralateral prophylactic mastectomy, a 91% reduction in the risk for development of contralateral breast cancer was documented in 1 study,26 although no improvement in overall survival time was reported. The role of genetic mutations in cats with mammary adenocarcinoma has not been studied as extensively as it has been in women, and BRCA1 and BRCA2 mutations were not detected in a study21 evaluating 5 cats. Women with so-called triple-negative breast cancer are also at higher risk of recurrence and distant metastasis and have been reported27 to have a poorer outcome than women with other forms of breast cancer. Tumor cells in triple-negative breast cancer lack estrogen and progesterone receptors and overexpress Her-2/neu, a transmembrane receptor that is encoded by the Her-2/neu protooncogene. In 1 study,28 14 of 24 tumor samples from cats with mammary adenocarcinomas were classified as triple negative on the basis of results of immunohistochemical staining, suggesting that certain mammary adenocarcinomas in cats might behave in a manner biologically similar to triple-negative breast cancers in women. Expression of Her-2/neu has also been associated with breast cancers demonstrating more aggressive biological behavior in women29; however, data on Her-2/neu overexpression in cats are limited and conflicting. Nonetheless, at least 1 study28 has documented overexpression of Her-2/neu in cats with mammary adenocarcinoma and reported reduced overall survival time, compared with that for cats with Her-2/neu-negative mammary adenocarcinoma.
Why cats in the present study that were treated with bilateral mastectomy versus unilateral mastectomy developed fewer local recurrences, regional metastases, or distant metastases was difficult to explain, but there may be a disease-modifying effect of contralateral mastectomy. Similar findings30 have emerged from a meta-analysis of women with the most aggressive forms of breast cancer. Prolongation of progression-free survival time has been demonstrated in women who undergo contralateral prophylactic mastectomy, although no effect on overall survival time was documented.30 Further investigation of the molecular genetics of mammary adenocarcinoma in cats is indicated; nonetheless, we suggest that the high incidence of local recurrence for cats of the present study mirrored the outcomes reported for the most aggressive forms of human breast cancers.
The lymphatic drainage system of the feline mammary glands comprises one of the primary routes for locoregional metastasis in cats with mammary adenocarcinoma. Lymphatic invasion and lymph node metastasis have been reported10 to be independent risk factors for decreased survival time in cats. Several studies17–19 have evaluated lymphatic anatomy and found somewhat consistent patterns of lymphatic drainage from the mammary glands of healthy cats with in vivo CT lymphography performed with contrast medium or indirect injection of India ink. Generally, the first 2 mammary glands drain to the accessory axillary lymph node, the third mammary gland can drain to either the axillary or superficial inguinal lymph node, and the fourth mammary gland drains to the superficial inguinal lymph node. Less commonly, the third and fourth glands can drain to the medial iliac lymph nodes.18 Quite commonly, the first 3 mammary glands also drain to the cranial sternal lymph nodes.17 Interestingly, none of these studies were able to demonstrate any connections between the left and right mammary chains. Therefore, lymphatic metastasis to the contralateral mammary chain would seem unlikely. However, all these studies were performed in healthy cats and it may be possible that lymphangiogenesis in cats with mammary adenocarcinomas enhances the possibility of contralateral mammary recurrence. Nonetheless, 1 study31 that evaluated VEGFR-3 concentrations in the intratumoral and extratumoral stroma of benign and malignant mammary adenocarcinoma samples from cats found no evidence for enhanced lymphangiogenesis. The authors suggested that lymphatic metastasis occurs via preexisting lymphatic channels.31
Outcomes associated with the various surgical approaches for cats undergoing treatment of mammary adenocarcinoma may also be in part a function of the adequacy of local resection. In the present study, incomplete or narrow (< 2 mm) surgical margins were reported in 13 of 54 (24.1%) and 4 of 41 (9.8%) of cats that underwent unilateral mastectomy and bilateral mastectomy, respectively, although these percentages were not significantly different. Whether part of the difference in progression-free survival time for patients of the present study was related to the adequacy of local resection was difficult to determine; however, we suggest that improvement in the ability to achieve adequate local resection may be another reason to consider bilateral mastectomy for the management of mammary adenocarcinoma in cats.
Little attention has been paid to complications associated with the various surgical approaches for treatment of mammary adenocarcinoma in cats. Single-session bilateral mastectomy has rarely been reported in the literature, with most studies1,4,6 involving bilateral mastectomy reporting results of the staged procedure. In the present study, cats undergoing unilateral mastectomy had overall significantly (P = 0.027) fewer complications, compared with those undergoing bilateral mastectomy. Although we noted more complications in cats undergoing single-session bilateral mastectomy (13/32 [40.6%]), compared with unilateral mastectomy or staged bilateral mastectomy (18/75 [24%]), the difference was not significant (P = 0.058). Whereas the factors involved in wound healing for a patient undergoing a staged bilateral mastectomy cannot be considered equivalent to those for 2 separate unilateral mastectomies, we suggest that they are probably more similar than for when a single-session bilateral procedure is performed. Single-session bilateral mastectomy is generally a much more invasive surgical procedure and it is our clinical opinion, supported by anecdotal discussion with surgical colleagues, that there is subjectively greater wound tension following primary closure. Incisional complications affected a higher proportion of cats treated with bilateral mastectomy, compared with unilateral mastectomy or staged bilateral mastectomy in the present study. Furthermore, 1 cat died in the immediate postoperative period because of respiratory failure, and excessive closure tension was thought to play a role.
Results of the present study indicated a beneficial effect of adjuvant chemotherapy on disease-specific survival time in cats with mammary adenocarcinoma when all drugs were combined. Most cats (46/55) for which data were available received doxorubicin-based protocols. Analysis of the data by type of chemotherapy drug administered was not possible because of the small numbers of cats that received drugs other than doxorubicin. The only other published study6 comparing cats with mammary adenocarcinoma treated with surgery alone versus surgery and chemotherapy did not find a significant effect of the administration of adjuvant chemotherapy on overall survival times; however, cats treated with unilateral mastectomy and chemotherapy had significantly longer survival times than cats treated with unilateral mastectomy alone.6 In women with aggressive forms of breast cancer, it is generally accepted that chemotherapy has a beneficial effect, and because there are similarities between aggressive breast cancer in women and mammary adenocarcinoma in cats, results of the present study supported the use of adjuvant chemotherapy in cats with mammary adenocarcinoma. Further prospective studies are needed to evaluate the effects of surgical approach, chemotherapy protocols, and other forms of adjuvant therapy in cats with mammary adenocarcinoma. It is plausible that certain subpopulations of cats with different types of mammary adenocarcinoma would benefit from individually tailored treatments. Larger studies as well as studies of molecular profiling and genomics will be necessary to identify these subpopulations and their potential therapeutic targets, a process which is already well under way in human breast cancer research.
There were a number of limitations to the present study. Tissue samples were reviewed by multiple pathologists most likely using multiple tissue-processing techniques. The histopathologic evaluation was not uniform, precluding further classification in terms of grade or histopathologic subtype. Cats were treated at multiple referral hospitals with different monitoring and follow-up protocols. Additionally, allocation to treatment was not random. Necropsy data were generally not available, necessitating interpretation of medical records to determine cause of death or euthanasia. As such, it is possible that some deaths were incorrectly categorized, although we were careful to consider all deaths mammary adenocarcinoma-related unless medical records strongly supported an alternative cause. We did not attempt to investigate the effects of treatment in mammary adenocarcinoma subgroups because of small group sizes and the potential for systematic biases inherent in the retrospective study design; however, it is possible that the optimal treatment approach could differ among cats with different disease features. Because of the heterogeneity of adjuvant chemotherapy protocols administered, we avoided investigating variable effects of single agents and instead grouped all chemotherapy agents for the analyses. This approach provided limited information on the efficacy of specific chemotherapy protocols for the adjuvant treatment of mammary adenocarcinoma.
Findings of the present study supported the use of bilateral mastectomy for treatment of mammary adenocarcinoma in cats to improve progression-free survival and disease-specific survival times. Performing bilateral mastectomy in a staged fashion may help to reduce complications.
ABBREVIATIONS
CI | Confidence interval |
HR | Hazard ratio |
Footnotes
Stata statistical software, release 14, StataCorp LP, College Station, Tex.
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