兽研1. 引言
猫乳腺肿瘤是家猫最重要的肿瘤性疾病之一，其发病率在造血系统肿瘤和皮肤肿瘤之后位居第三[1,2,3]。其患病率因地区而异，主要归因于绝育实践的差异，但因其侵袭性生物学行为、高转移潜能以及恶性病例比例极高（估计为85–95%）而在全球范围内被公认[4,5]。
猫乳腺癌（FMC）是猫最常见的恶性乳腺肿瘤，因其在组织学、分子和临床上的相似性，已被作为人类乳腺癌的自发性比较模型进行研究[1,2,3]。FMC占猫乳腺肿瘤的80%以上，表现出浸润性生长模式、早期淋巴扩散和不良临床结局[4,5,6]。
在组织学上，FMC呈现多种亚型，包括管状乳头状、实性、筛状和微乳头状模式。这些亚型通常以明显的核多形性、淋巴血管侵犯和高核分裂指数为特征[7,8,9,10]。值得注意的是，人类乳腺癌中发现的若干亚型，如导管原位癌，以及管状、乳头状、筛状、浸润性微乳头状和分泌性癌，在猫中也有记载[5,7,11]。其中，筛状和浸润性微乳头状变异型尤其具有侵袭性，与人类对应病变具有相同的独特临床病理特征[5,12]。
FMC的恶性率约为85%，与犬的数据相当，但显著超过女性中报告的15%，因此FMC可能提供有用的比较肿瘤学模型[5,11,13]。其比较价值得到与人类乳腺癌在流行病学、生物学和分子方面某些相似性的支持[5,10,12]。这些相似性尤其在激素受体阴性/三阴性和HER2相关表型中得到了研究[10,14,15]。尽管手术和化疗方案取得了进展，预后仍然谨慎；乳房切除术后中位生存时间很少超过一年[5,7]。因此，全身治疗证据有限且异质性大，促使了对靶向和免疫相关通路的探索[16,17,18,19,20,21]。
本整合性综述的目的不是将猫乳腺癌确立为人类乳腺癌的直接替代模型，而是批判性地评估两种疾病在临床病理学、分子、免疫学和治疗方面的趋同程度，并确定猫肿瘤可能提供比较价值的具体领域。
1.1. 综述设计与文献检索
本研究设计为关于猫乳腺癌（FMC）的整合性文献综述，重点关注流行病学、临床病理特征、预后和预测生物标志物、分子和多组学特征、肿瘤微环境、治疗方法以及比较肿瘤学。检索在PubMed/MEDLINE、Scopus和Web of Science核心合集进行，时间从数据库建库至2026年3月30日。鉴于本综述的整合性，检索过程采用结构化和迭代方式，将猫乳腺癌相关核心术语与代表综述主要领域的主题特异性术语相结合，包括比较肿瘤学、人类乳腺癌、分子表型、生物标志物、肿瘤微环境、免疫治疗方法、蛋白质组学、磷酸蛋白质组学、肽组学和酪氨酸激酶抑制剂。数据库特定的电子检索策略，包括检索字段、布尔运算符和应用的限制条件，见补充表S1。优先考虑近期文献以提供最新概述，同时保留提供基础流行病学、病理学、分子或临床证据的较早出版物。手动筛选相关出版物和综述的参考文献列表以识别其他相关研究。由于本综述设计为整合性而非系统性综述，检索和选择过程为迭代式，未维护逐条记录的定量筛选日志；因此，未生成对已识别或排除记录的回顾性估计。
1.2. 纳入标准
当研究涉及猫乳腺肿瘤（FMC）或猫乳腺肿瘤形成与流行病学、生殖风险因素、组织病理学分类或分级、临床分期、预后或预测因素、免疫组织化学特征、分子分型、上皮-间质转化、肿瘤微环境、免疫调节、基于组学的方法、新兴生物标志物、手术、全身治疗、靶向治疗、免疫治疗或比较肿瘤学的关系时，研究被认为符合纳入标准。纳入同行评审的原创研究、临床研究、病理学和免疫组织化学研究、分子和多组学研究以及相关比较研究。综述文章用于提供历史或概念背景并识别原始研究，在可获得的情况下优先采用猫科原始证据。人类乳腺癌文献被选择性纳入以界定相应的人类框架，但不作为猫科疾病的直接证据。会议摘要、社论、评论、聚焦于无关肿瘤且无相关比较成分的研究以及信息不足的文献被排除。孤立的病例报告通常被排除，除非它们提供了关于罕见实体、生物标志物或治疗观察的特别相关证据。
1.3. 研究选择与证据综合
研究选择以综述的目标和主题范围为指南。评估标题和摘要的相关性，随后在适当情况下进行全文评估。通过参考文献列表筛选发现的额外研究，在其提供了数据库检索中未充分体现的相关证据时予以考虑。选择基于科学相关性、对预定主题领域的贡献以及可用证据的充分性，而非预定的发表配额。提取的数据包括研究特征、猫群体或生物材料、肿瘤分类、组织病理学特征、临床分期、预后变量、免疫组织化学标志物、分子改变、免疫和肿瘤微环境特征、组学发现、候选生物标志物、治疗干预、临床结局以及与人类乳腺癌相关的比较观察。由于研究设计、样本量、病理分类、免疫组织化学方法、分子技术、治疗方案和临床终点存在显著异质性，证据以定性方式综合。猫科来源的发现与源自人类肿瘤学的观察被明确区分，表型或通路层面的相似性被解释为比较性或产生假设的证据，而非生物学等效性的证据。未进行定量荟萃分析。
2. 流行病学与风险因素
猫乳腺肿瘤是猫群体中最常见且生物学上最具侵袭性的恶性肿瘤之一，占所有诊断肿瘤的12–17%[1,2,3]。全球流行病学调查一致将FMC列为该物种三种最常见肿瘤之一[1,2]。其临床特征为侵袭性生长、频繁的淋巴和远处播散以及不良结局[5,11,12]。
Souza等人（2024）的一项涉及418只猫和858个病变的综合回顾性分析强调了该疾病的严重性；研究发现88.8%的乳腺病变为恶性，其中近半数病例在诊断时显示淋巴结转移[11]。此外，该研究通过记录罕见或此前未报道的实体（如乳腺孢子丝菌病、良性叶状肿瘤和基底样癌），扩展了该疾病的已知病理谱[11]。
2.1. 激素与生殖风险因素
FMC发生的主要流行病学驱动因素是长期暴露于卵巢激素。未绝育雌性发生乳腺肿瘤的风险是绝育个体的七倍[2,4,22]。虽然早期卵巢子宫切除术提供显著保护作用，但延迟绝育或给予外源性孕激素会大幅提高易感性[2,4,5]。然而，卵巢切除猫中FMC的发生表明非激素致癌途径和遗传易感性在肿瘤发生中也起关键作用[4]。
在两个物种中，该疾病与内分泌紊乱有关，如性腺功能障碍或暴露于外源性激素。例如，雄性中给予醋酸环丙孕酮与乳腺肿瘤的发生直接相关[13]。
关于雄性猫的临床数据表明疾病进程高度侵袭性。尽管中位生存期约为344天，许多病例呈现晚期预后标志物，包括肿瘤超过3 cm和淋巴管侵犯证据[23]。终末期常涉及肺转移，表现为呼吸窘迫和恶病质。这些发现强调在使用基于孕激素的治疗（如醋酸甲羟孕酮）时需仔细进行风险-获益评估，并强调对两性进行长期临床监测以促进早期发现的必要性[24]。
2.2. 年龄、性别和品种分布
FMC主要影响中年至老年猫，发病高峰在10至12岁之间。这一时间分布反映了激素暴露的累积影响以及基因改变的逐渐积累[1,5]。尽管该病在混合品种猫群体中最为常见（该群体占全球家养猫的大多数），但已有研究提示暹罗猫的风险较高[2,5]。然而，这一潜在的品种易感性仍存在争议，因其可能受区域群体结构而非潜在遗传易感性的影响。
与之形成鲜明对比的是，公猫乳腺肿瘤极为罕见，仅占所有病例的1%[23]。公猫FMC诊断时的平均年龄略大，为12.8岁，与人类男性乳腺癌形成了引人注目的平行对照[23,24]。
3. 组织病理学与分期
3.1. 概述及更新分期方法的依据
在猫肿瘤学中，预后评估在很大程度上依赖临床分期来指导治疗策略和预测生存期。尽管传统的世界卫生组织（WHO）肿瘤-淋巴结-转移（TNM）分类被广泛使用，但应用于猫乳腺肿瘤（FMTs）时存在显著局限性[25,26,27]。其主要缺陷在于该系统未能区分大型原发肿瘤与伴有区域转移的肿瘤；两者均可能归入III期，尽管其预后意义截然不同[25,28]。此外，该系统缺乏T4类别（人类医学中用于分类侵犯胸壁或皮肤的肿瘤），限制了其描述能力[25]。
为弥补这些不足，研究人员提出将T4类别纳入以涵盖溃疡性病变[25]。在此基础上，一项改编自AJCC癌症分期手册第7版的分期系统在75只猫中进行了评估[28]。该改良框架将III期细分为IIIA（T3N0M0）、IIIB（T4N0M0）和IIIC（AnyTN1M0），旨在细化风险分层并使兽医实践更贴近人类肿瘤学标准。
3.2. 组织病理学多样性
猫乳腺肿瘤表现出与人类乳腺癌谱系相似的显著形态学多样性（图1）。已记录的亚型包括导管原位癌，以及管状癌、乳头状癌、筛状癌、微乳头状癌、小叶样癌和分泌性癌[10,11,29]。
其中，筛状癌和浸润性微乳头状癌变体因其侵袭性生物学行为和不良预后而尤为重要[9,11]。
一项纳入418只猫的大型临床病理系列研究确定，管状乳头状癌（17.1%）、筛状癌（16.8%）和恶性腺肌上皮瘤（12.1%）是最常见的恶性组织学类别[11]。管状乳头状癌和筛状癌通常表现为明显的细胞大小不均/核大小不均、高核分裂计数和坏死，而p63免疫组化在2024年大型系列研究中有助于识别恶性腺肌上皮瘤[11]。
3.3. 分级系统与临床分期的整合
为确保诊断一致性，多种改编自人类医学的组织学分级系统被应用于FMTs。Elston和Ellis（EE）或Nottingham系统通过评估管状结构形成、核多形性和核分裂计数将肿瘤分为I、II或III级（表1）。鉴于猫的高核分裂率，核分裂改良Elston和Ellis（MMEE）系统及修订版Elston和Ellis（REE）系统提供了猫特异性改良方案，其中REE系统还纳入了核形态和淋巴血管侵犯[7,8,30]。组织学分级仍是强有力的预后指标；例如，III级癌的死亡风险较I级增加近十倍[7]。
这些分级方案辅以形态学分类（表2）和临床分期（表3），后者整合了肿瘤大小、淋巴结状态和远处转移[25,26,27,29]。所提出的修订分期系统旨在通过区分III期内的亚组来细化预后分层。具体而言，IIIC期病例（淋巴结转移）预后最差，中位总生存期仅为288天[28]。此外，皮肤溃疡（存在于18.7%的病例中）是独立的负面预后因素，使中位生存期缩短至约九个月[25]。这与人类肿瘤学一致，在人类分期框架中溃疡是正式组成部分。
胸部影像学在检测猫乳腺癌远处转移性疾病中发挥核心作用，尤其是肺部受累（图2），因此是临床分期的重要组成部分。
4. 比较临床病理学见解
近期研究通过聚焦肿瘤性与非肿瘤性病变之间的关键鉴别，深化了对猫乳腺病变临床行为和病理谱系的认识。
4.1. 年龄相关与人口学相关性
年龄与乳腺病变的生物学性质之间存在明确相关性，因为被诊断为恶性肿瘤的猫显著比表现为良性肿瘤或非肿瘤性病变的猫年龄更大[2,5,11]。虽然这些队列中杂交猫占多数并反映了全球种群人口统计学特征，但年龄较大和未绝育雌性的持续过度代表强化了累积激素暴露与恶性肿瘤之间的既定联系[1,4,11]。
4.2. 非肿瘤性和良性病变谱
识别非肿瘤性病变对于准确的鉴别诊断至关重要，因为这些过程常常模仿恶性肿瘤的临床表现。乳腺炎、普通型导管增生和纤维腺瘤样增生是最常见的非肿瘤性发现，而腺瘤和导管乳头状瘤仍然是最常见的良性肿瘤[11]。值得注意的是，在超过一半的报道病例中观察到的普通型导管增生与并发恶性肿瘤之间的强关联提示其潜在的癌前作用，这与人类乳腺病理学中的观察结果相呼应。
4.3. 新兴病理实体和罕见变异型
近期的诊断工作通过记录以前主要在人类或犬肿瘤学中认识的罕见实体，扩展了猫乳腺病变的谱系。这些包括基底样癌和良性叶状肿瘤以及乳腺孢子丝菌病，后者是在年轻猫中的一个重要发现，突显了感染性肉芽肿性过程如何在临床上表现为淋巴结受累并导致转移性肿瘤的误诊[11]。
此外，详细的显微镜比较揭示，虽然高级别癌如管状乳头状和筛状变异型一致表现出高核分裂指数和坏死灶，但恶性腺肌上皮瘤通常表现为较低的细胞学异型性和更惰性的行为[7,11]。尽管这些发现提示腺肌上皮瘤可能比其他猫乳腺 carcinoma 具有更有利的预后，但仍需要进一步的前瞻性研究来确认其具体的临床轨迹。
猫乳腺 carcinoma 表现出显著的分子、组织病理学和免疫学异质性，这显著影响预后和治疗选择。
4.4. 分子亚型和免疫组化分析
免疫组化分析揭示，猫肿瘤经常显示雌激素（ER）和孕激素（PR）类固醇受体的可变蛋白表达，通常低于人类 luminal 乳腺癌中观察到的水平。促进细胞生长的 HER2（ERBB2）受体酪氨酸激酶在约10-20%的病例中过表达，通常与高组织学分级和升高的增殖活性相关[14,15,16]。值得注意的是，相当比例的 FMC 缺乏 ER、PR 和 HER2 表达。这些三阴性亚型表现出最具侵袭性的生物学行为，与人类患者中三阴性乳腺癌的临床轨迹相似[14,16]。
除了受体状态之外，几种标志物可作为重要的预后指标。通过 Ki-67 评估的高增殖指数与侵袭性临床病理特征和较短生存期相关，一项主要研究提出了14%的截断值[31]。E-钙黏蛋白表达降低也与恶性肿瘤和转移相关，支持其作为侵袭行为标志物的研究[32]。
5. 免疫组化发现和细胞动力学
免疫组化分析为猫乳腺肿瘤的细胞起源和表型可塑性提供了关键见解。细胞角蛋白在肿瘤性上皮细胞中强烈标记，而基质成纤维细胞显示波形蛋白免疫反应性，分别反映其上皮和间充质表型。
5.1. 上皮-间充质转化（EMT）的证据
细胞角蛋白和波形蛋白的共表达已在猫乳腺 carcinoma 中描述，特别是在具有基底样特征的激素受体阴性肿瘤中[10]。在人类肿瘤学中，EMT 是一个公认的与肿瘤细胞可塑性、侵袭和播散相关的生物学过程[33,34]。然而，在 FMC 中，标志物共表达应被解释为表型可塑性的证据，而非跨物种完全保守的 EMT 程序的证明。
5.2. 增殖活性的比较
通过 Ki-67（一种与细胞周期活跃期严格相关的蛋白质）评估细胞增殖，揭示了原发部位和继发部位之间的重要差异。与相应的原发肿瘤相比，淋巴结和远处转移中报道了更高的 Ki-67 指数，支持增殖活性增加与转移进展之间的关联[31]。
虽然这些发现与恶性疾病的预期进展一致，但猫乳腺 carcinoma 中 Ki-67 的标准化预后截断值仍是持续争论的主题[7,31,35]。有趣的是，近期特定病例中报道的指数偶尔低于先前提出的阈值，提示即使增殖计数相对较低的肿瘤也可以表现出显著的转移潜能[31]。
肿瘤微环境（TME）是一个复杂的生态系统，对疾病进展和治疗反应具有关键性的塑造作用[17]。猫乳腺癌利用“免疫检查点”——即正常情况下防止自身免疫的调节分子——来逃避免疫系统[16,18,33,34,36,37]。
PD-1（程序性细胞死亡蛋白1，一种免疫细胞上的受体）及其配体PD-L1（存在于肿瘤细胞上）的表达与更高的组织学分级和淋巴管侵犯相关[16]。其他已鉴定的检查点包括CTLA-4（参与免疫耐受）[38]；TIM-3（其表达与临床结局相关的蛋白）[37]；以及VISTA（一种新近鉴定的T细胞反应调节因子）[18]。此外，瘦素及其受体ObR等代谢介质将营养状态与肿瘤侵袭性联系起来，而失调的炎性细胞因子如IL-6和TNF-α进一步促进免疫逃逸[36]。
功能性肿瘤浸润淋巴细胞（TILs）和活跃的检查点轴的存在支持免疫靶向策略的整合。例如，靶向HER2的单克隆抗体疗法已显示出临床前潜力。HER2靶向方法在猫细胞模型中已显示出抗增殖效应[39]，而PD-1/PD-L1、CTLA-4、VISTA和TIM-3等检查点通路已在FMC中被表征[16,17,18,37,38]。这些发现为进一步的临床前研究提供了依据，但尚未确立临床疗效或跨物种治疗等效性。
近期大规模蛋白质组学研究已在FMC中鉴定出超过16,000种蛋白质。转移性肿瘤显示出独特的蛋白质特征，包括IL18R1和DIMT1升高以及GSDMC等蛋白质的改变，而NOP14和SCN8A则属于在转移/高级别组中表达降低的蛋白质[40]。
ACTN4（一种细胞骨架重塑蛋白）和GSDMC（一种参与炎性细胞死亡或焦亡的蛋白）的富集进一步支持了转移性进展，而NOP14和SCN8A钠通道等肿瘤抑制蛋白则显著下调[40]。这些改变与先前关于磷酸化蛋白质组学的发现相吻合，其中PPP1CA等信号酶和PRKAG3等代谢调节因子的失调进一步巩固了FMC作为比较研究的稳健模型[41]。
对微创诊断的需求促使人们探索通过血清肽组学进行液体活检。与蛋白质组学（表征生物样本的完整蛋白质库）不同，肽组学侧重于生物体液中天然存在的内源性肽的鉴定和定量，可能提供疾病进展和转移行为的高灵敏度生物标志物。Paphussaro等人（2024）使用非胰蛋白酶消化的LC-MS/MS，鉴定出与转移性（mFMC）和非转移性猫乳腺癌（NmFMC）相关的独特血清肽组学特征[42]。
该血清肽组学研究鉴定出转移性与非转移性FMC之间存在差异性的肽/蛋白质相关特征，包括来源于参与增殖、代谢、凋亡抵抗和肿瘤进展的蛋白质的肽[42]。
转移组显示出独特的血清肽组学谱，其中包括与肿瘤进展和转移相关通路有关的肽[42]。这些发现支持血清肽组学作为一种有前景的生物标志物发现方法，但尚未确立其在临床风险分层或治疗反应预测中的价值；需要更大规模的队列和独立验证[42]。
6. 猫乳腺癌的治疗策略
手术切除仍然是猫乳腺肿瘤治疗的主要基石，因为通常需要积极干预以应对高恶性率。一般建议行双侧乳腺切除术，因为猫乳腺肿瘤常为多灶性和侵袭性[6,11]（图3）。尽管如此，实现完整的手术切缘仍然是一个持续存在的挑战，特别是在溃疡性或浸润性肿瘤病例中，局部复发频繁[8,19]。
鉴于这些手术局限性以及与犬乳腺肿瘤学相比综合临床病理数据的相对匮乏，精确的组织病理学分类和分期对于有效的术后管理至关重要[3,25,28]。标准化猫的分期可能改善预后评估并促进更具可重复性的比较研究[25,28]。最终，统一的诊断方法对于克服当前细胞毒性治疗的局限性和改善猫患者的长期结局至关重要。
6.1. 靶向与比较治疗策略
传统化疗在FMC中的证据仍然有限且异质性较大[19,43]，这促使人们研究靶向方法。这些策略聚焦于塑造肿瘤微环境的生长因子受体和免疫调节通路。
6.1.1. 酪氨酸激酶抑制剂（TKIs）与临床反应
对TKIs的关注源于猫乳腺癌中VEGFR（血管内皮生长因子受体）、PDGFR（血小板衍生生长因子受体）和KIT等受体的已记录表达[20,21]。
磷酸托西尼布是一种多靶点酪氨酸激酶抑制剂（TKI），在患有宏观乳腺腺癌的猫中已显示出64.7%的临床获益率[21]。在前瞻性托西尼布研究中，一部分猫报告了客观缓解，中位总生存期为145天[21]。这些试验中一个值得注意的观察是“生物学不一致性”，即原发肿瘤对治疗有反应而远处转移灶却在进展。原发肿瘤与转移灶之间观察到的反应不一致，突显了病灶间生物学异质性的潜在重要性，尽管该研究并未确定其机制。
除托西尼布外，拉帕替尼作为EGFR（表皮生长因子受体）和HER2的双重抑制剂，在猫细胞系中已显示出强效的抗增殖作用[20]。然而，药代动力学研究表明，由于猫的全身暴露量低于犬或人类，需要优化给药方案。
6.1.2. 免疫治疗比较研究进展
现代肿瘤学将肿瘤按免疫学特征分为“热”（炎症型）、“排斥型”或“冷”（免疫荒漠型），这一区分决定了对免疫治疗的应答性[44,45,46]。由于部分猫乳腺 carcinoma（FMC）显示激素受体阴性/三阴性表型及免疫检查点改变，FMC可能为研究与侵袭性乳腺癌相关的肿瘤-免疫相互作用提供互补系统[10,16,17,18]。
当前治疗格局以免疫检查点抑制剂（ICI）为中心。除PD-1/PD-L1轴外，在两种物种中均已鉴定出若干新兴靶点：LAG-3：一种在耗竭T细胞上共表达的抑制性受体。其阻断通常与PD-1抑制剂联合，在逆转T细胞耗竭方面显示出协同潜力[45,46]。
VISTA：一种免疫调节检查点，已在侵袭性猫乳腺 carcinoma 亚型中进行研究，并被提出作为潜在治疗靶点[18]。
TIM-3：一种固有免疫调节因子，其在FMC中的表达 paradoxically 与临床结局相关，与人类TNBC数据相呼应[37]。
CTLA-4：T细胞活化的基本调节因子。其可溶性异构体已在人和猫血清中检测到，可作为潜在的非侵入性生物标志物[38]。
6.2. 未来方向：多模式整合
TKIs与免疫调节策略的潜在整合代表了未来FMC研究的假设。虽然当前研究常受限于小样本量和方案不一，但观察到的这些药物活性支持进一步研究，但并未确立比较疗效[16,18,20,21,37,38]。
展望未来，更大规模的随机试验对于确定这些疗法的最佳作用至关重要，尤其是在微观疾病的辅助治疗环境中。统一的诊断框架可促进更严格的比较研究和个体化方法的评估，而两种物种的临床获益仍有待确立[6,7]。
7. 猫乳腺 carcinoma 与人类乳腺癌：比较肿瘤学视角
对FMC的比较研究兴趣基于其与人类乳腺癌中描述的若干临床病理和分子特征的重叠。这些包括侵袭性侵袭行为、淋巴和远处播散、激素受体表达改变、HER2相关信号、增殖活性、肿瘤-免疫相互作用以及肿瘤进展相关通路的失调[5,12,14,15,16,17,18]。然而，这些相似性应在特定生物学过程层面解读，而非作为完全生物学或分子等效性的证据。特别是，FMC中描述的免疫组化表型不应被视为人类乳腺癌分子定义亚型的直接替代。
7.1. 临床病理学趋同
FMC的特征是恶性肿瘤比例高和频繁的侵袭性生长，而肿瘤大小、组织学分级、淋巴血管侵犯和淋巴结受累已被研究作为预后因素[5,7,8,25,30]。猫乳腺 carcinoma 中已描述了多种组织学模式，包括管状乳头状、实性、筛状和侵袭性微乳头状模式[5,9]。侵袭性微乳头状 carcinoma 具有特别的比较研究意义，因为其组织学结构和淋巴播散倾向与人类乳腺 carcinoma 有相似之处[9]。然而，仅形态学相似并不能确立猫组织学实体与人类乳腺病理学中更为广泛的分类之间的等效性。
组织学分级已作为FMC的预后工具进行研究，多项研究报告了较高级别、增殖活性增加与较差结局之间的关联[7,8,30]。然而，各研究中单个分级系统的预后性能存在差异，方法学差异使已发表队列的直接比较复杂化[5,7,26]。当从比较肿瘤学角度考虑FMC时，这些局限性具有重要意义，因为可重复的病理分类是有意义跨物种比较的前提。
肿瘤负荷和区域淋巴结受累同样代表了临床病理学的交汇领域。较大的原发肿瘤和淋巴结转移通常与猫的更晚期疾病和更差预后相关[5,7,8,25,30]。类似变量构成了人类乳腺癌分期的既定组成部分。因此，这些参数可能为比较研究提供有用的共同临床终点，尽管分期系统和治疗意义仍具有物种特异性。
FMC在免疫功能正常的动物中自发发生是一个潜在的比较优势。与实验诱导的肿瘤或常规细胞系异种移植不同，自然发生的FMC在完整宿主体内发展，并受肿瘤微环境、免疫系统、基质相互作用和自然发生的转移过程影响[12,17]。这一特征对于研究肿瘤进展和宿主-肿瘤相互作用可能特别具有信息价值。然而，自发发生不应被解释为FMC再现人类乳腺癌完整生物学谱系的证据。
7.2. 激素受体、HER2和基于表型的分子分类
雌激素受体（ER）、孕激素受体（PR）、HER2、细胞角蛋白和Ki-67的免疫组化评估已被广泛用于表征FMC[14,15,16,17,18,31,35]。与人类乳腺癌相比，猫乳腺 carcinoma 显示激素受体阴性肿瘤的频率相对较高，尤其是在侵袭性 carcinoma 中[5,12,14,15]。这一特征促使研究者将FMC作为选定激素受体阴性和基底样人类乳腺癌的潜在比较系统进行研究[12]。
猫乳腺 carcinoma 可使用基于IHC的替代表型进行分组，类似于人类乳腺癌临床应用中使用的表型。Soares等人鉴定了猫乳腺 carcinoma 中的luminal A、luminal B、HER2阳性和三阴性/基底样表型，并报告了这些组之间生存率的差异[14,15]。特别是，三阴性/基底样肿瘤在研究队列中与较短生存期和无病间隔相关[15]。这些发现支持FMC的生物学异质性，并为侵袭性乳腺肿瘤表型的比较研究提供了依据。
然而，"三阴性"一词在比较背景下需要特别谨慎。在人类乳腺癌中，TNBC在临床上定义为ER、PR和HER2表达缺失，但代表一组具有独特转录、基因组和生物学特征的异质性肿瘤[47]。因此，ER−/PR−/HER2−猫肿瘤可被视为人类TNBC的表型类似物，但仅受体阴性并不能证明与任何特定人类TNBC亚型的分子等效性。比较基因表达分析已鉴定出猫乳腺 carcinoma 与人类TNBC之间的相似性[48]，支持进一步研究，但这些观察仍不足以确立FMC再现人类TNBC完整分子异质性的结论。
HER2提供了生物学趋同和方法学局限性的另一个重要例子。已在猫乳腺 carcinoma 中检测到HER2表达，并且猫HER2已在蛋白质和基因水平上进行了研究[18,20,39]。然而，研究报告的HER2阳性频率在各研究之间差异相当大。Soares等人证明FMC中HER2评估需要优化的IHC和原位杂交方法，并强调了先前可用数据的不一致性[49]。同样，Rasotto等人使用优化的IHC方案仅在5.5%的猫乳腺 carcinoma 中检测到HER2过表达[49]。这些发现表明，抗体、染色方案、评分标准和分析阈值的差异可能显著影响所报告的HER2阳性FMC患病率。
这一方法学问题尤为重要，因为HER2检测在人类乳腺癌中高度标准化，使用经过验证的IHC和原位杂交标准来确定HER2靶向治疗的资格[50]。因此，猫肿瘤中HER2表达的检测应被解释为潜在保守生物学通路的证据，而非猫HER2阳性肿瘤等同于人类HER2阳性乳腺癌的直接证据。
7.3. 增殖、侵袭和转移进展
增殖活性是FMC与人类乳腺癌之间趋同的另一个领域。Ki-67表达已在猫乳腺肿瘤中广泛研究，并在多项研究中与组织学分级和临床结局相关[31,35]。然而，各研究报告的临界值和预后关联强度存在差异，缺乏标准化方法仍是重要局限性[5,26,31,35]。因此，Ki-67可被视为FMC中有前景的预后标志物，但猫特异性阈值不应直接从人类乳腺癌外推。
FMC的侵袭和转移行为为比较研究提供了进一步的机会。猫乳腺 carcinoma 可能表现为淋巴血管侵犯、区域淋巴结转移和远处播散，尤其是向肺部转移[5,8,15,25]。侵袭性微乳头状形态的存在也与淋巴管受累相关[9]。这些特征使得自然发生的FMC可能为研究肿瘤播散机制提供信息。
在分子水平上，已在猫乳腺 carcinoma 中研究了上皮-间质转化（EMT）相关过程[33,34,41]。在猫肿瘤中已描述了上皮和间质标志物的共表达，这与侵袭和转移相关的表型可塑性一致。EMT在人类乳腺癌中也作为促进肿瘤细胞可塑性、侵袭和耐药的生物学过程被广泛研究[33,34]。然而，FMC中EMT相关标志物的存在不应被解释为相同EMT程序在不同物种中以相同方式运作的证据。
7.4. 肿瘤微环境与免疫调节
肿瘤微环境（TME）是比较研究的另一个领域。FMC研究已鉴定出肿瘤浸润淋巴细胞和其他免疫细胞群体，以及免疫检查点通路的改变[16,17,18]。Nascimento等人表征了FMC中肿瘤浸润免疫细胞的全景，并证明了免疫细胞组成、病理特征和临床行为之间的关联[17]。同样，PD-1/PD-L1表达已在猫乳腺 carcinoma 中进行了研究，包括在HER2阳性和三阴性/正常样表型中[17]。VISTA和TIM-3也被提出作为猫乳腺 carcinoma 的潜在免疫调节靶点[18,37]。
这些观察为肿瘤-免疫相互作用的比较研究提供了生物学依据。然而，同源免疫检查点通路的存在并不能确定免疫检查点抑制剂在猫和人类中具有等效活性。配体表达、受体生物学、免疫细胞组成、抗体交叉反应性、药代动力学和治疗暴露的差异可能影响治疗反应。因此，目前猫免疫检查点研究应被视为产生假设性的，并作为人类实验和临床研究的补充。
然而，FMC在免疫健全宿主中的自发发展可能为研究自然发生疾病条件下的肿瘤-免疫相互作用提供机会[17]。这可能与理解肿瘤表型、免疫细胞浸润、转移进展和治疗反应之间的关系特别相关。需要纳入标准化病理、免疫学和临床终点的前瞻性研究，以确定这些发现可在多大程度上跨物种转化。
7.5. 分子和基于组学的趋同
最近的转录组学、蛋白质组学、磷酸化蛋白质组学和肽组学研究扩展了FMC的分子表征[14,40,41,42]。转录组分析已鉴定出与代谢和细胞周期调控相关的候选生物标志物和可成药通路[12]，而磷酸化蛋白质组分析已鉴定出参与细胞周期控制、信号传导、代谢和其他与肿瘤进展相关过程的蛋白质改变[41]。组织蛋白质组研究进一步鉴定出与转移状态和组织病理学特征相关的蛋白质特征[40]，血清肽组分析已鉴定出区分转移性和非转移性FMC的候选特征[42]。
这些方法可能为比较假设的产生提供有用基础。例如，在猫肿瘤中鉴定出的几种蛋白质和信号通路在人类乳腺癌中已被认识到具有作用。然而，通路重叠应谨慎解释。保守蛋白质或信号通路的鉴定并不能确定其调控、生物学重要性或治疗反应在两个物种中相同。
因此，组学方法的比较价值将取决于跨物种验证，而不是孤立分子相似性的鉴定。未来的研究理想情况下应使用统一的分析流程、预定义的生物学问题、足够效能的队列和临床相关终点来比较猫和人类肿瘤。
7.6. 治疗和转化相关性
治疗格局是比较肿瘤学的重要组成部分。手术仍然是FMC的主要治疗方法，而人类乳腺癌管理根据肿瘤亚型和分期包括手术、放疗、化疗、内分泌治疗、HER2靶向治疗、免疫治疗和其他靶向方法[5,19]。猫的全身治疗研究通常涉及比人类肿瘤学可用的更小的队列，辅助全身治疗的证据仍然相对有限[19,21,43]。
尽管如此，靶向治疗已受到越来越多的关注。针对涉及HER2、EGFR、VEGFR、PDGFR及相关受体通路的酪氨酸激酶抑制剂在猫乳腺癌模型中已显示出抗增殖活性[20]。Toceranib也已在患有宏观乳腺腺癌的猫中进行了临床研究，提供了生物学和临床活性的初步证据[21]。这些研究说明自发发生的猫肿瘤如何有助于比较治疗研究。
然而，靶向药物在猫细胞系或临床患者中的活性不应被解释为在人乳腺癌中具有同等疗效的证据。药物药代动力学、靶点表达、受体结构、组织穿透、毒性及耐药机制在物种间可能存在显著差异。同样，曲妥珠单抗或其他HER2靶向方法在实验系统中与猫HER2相互作用的证据支持生物学研究，但并不能确立临床等效性[39]。
因此，最合适的转化框架是双向且假设驱动的。FMC可能有助于研究自发发生的肿瘤进展、治疗反应、耐药性及肿瘤-宿主相互作用，而人类肿瘤学的发现可为猫疾病的候选生物标志物和治疗策略提供信息。这种互补方法避免将FMC视为人乳腺癌的替代品，同时认识到其在选定比较问题中的潜在价值。
7.7. FMC作为比较模型的局限性
在将FMC解释为人乳腺癌的比较模型时，应考虑若干局限性。首先，猫的分子分类仍不如人乳腺癌分类标准化。基于IHC的替代表型有助于描述生物学异质性，但不能捕捉人乳腺癌完整的基因组和转录组多样性[14,15,47]。
其次，方法学异质性仍是猫文献的主要局限性。组织处理、抗体、IHC方案、评分标准、分子检测、分期系统和临床终点的差异使研究间的比较复杂化[5,26]。这一问题在HER2和Ki-67中尤为明显，不同的分析方法可能产生显著不同的结果[31,35,49]。
第三，许多FMC研究为回顾性研究，纳入的队列相对较小。正如Zappulli等人所强调的，现有证据大多具有回顾性性质且缺乏方法学标准化，降低了预后结论的强度并限制了研究间的可比性[5]。类似的局限性也适用于探索性组学研究，这些研究需要在独立队列中验证后，候选生物标志物才能被认为具有临床实用性。
第四，猫和人类乳腺癌的临床管理存在显著差异。人乳腺癌受益于标准化筛查、多学科分期、前瞻性临床试验和经过验证的全身治疗。在猫中，手术仍是主要的治疗干预手段，支持全身和靶向治疗的证据较为有限[19,21,43]。因此，在不考虑这些差异的情况下，无法直接比较治疗反应和生存结局。
最后，FMC的比较相关性在所有人类乳腺癌亚型中不太可能是一致的。现有证据表明，对侵袭性、激素受体阴性、基底样及选定的HER2相关表型尤其值得关注[12,14,15,16,17,18]。这并不意味着FMC再现了人乳腺癌的全部生物学谱系。相反，其价值可能在对侵袭性肿瘤生物学、转移进展、肿瘤-免疫相互作用、生物标志物开发及治疗反应等特定问题上最为突出。
综上所述，现有证据支持将FMC用作补充性比较肿瘤学系统，而非人乳腺癌的直接替代品。自发发生的猫肿瘤可能提供难以在传统实验系统中重现的信息，特别是关于免疫健全宿主中的肿瘤发展、自发转移进展及自发发生的肿瘤-宿主相互作用。然而，转化结论应基于经过验证的分子和临床终点，而非仅基于表型相似性。需要标准化的病理学和分子定义、统一的方法学、足够效力的多中心队列、前瞻性临床研究及独立的跨物种验证，才能确定FMC对乳腺癌研究的精确转化贡献。
猫乳腺癌与人乳腺癌在临床病理学、分子、免疫及生物标志物方面的主要汇聚领域及其主要转化局限性总结于图4和表4。
8. 结论
猫乳腺 carcinoma 是一种侵袭性肿瘤，常见局部浸润、淋巴结受累和远处转移进展。手术仍是主要治疗手段，而组织病理学分级、临床分期和免疫组织化学评估可提供重要的预后信息。近期的转录组学、蛋白质组学、磷酸化蛋白质组学和血清肽组学研究拓展了对 FMC 的表征，并识别出候选生物标志物和信号通路。部分临床病理学、分子和免疫特征与人类乳腺癌中描述的特征重叠，尤其是在侵袭性激素受体阴性和部分 HER2 相关表型中。然而，这些相似性并不能确立生物学等效性。分子分类、分析方法、治疗标准、队列规模和临床验证方面的差异目前限制了直接的转化推断。因此，FMC 最好被视为一个互补的、针对特定问题的比较肿瘤学系统，可能有助于侵袭性肿瘤生物学、转移、肿瘤-宿主相互作用、生物标志物发现和治疗反应的研究。靶向和免疫调节方法仍是研究领域，但大多数猫科证据尚属初步。未来研究应优先考虑标准化的病理学和分子定义、统一的方法学、具有足够把握度的前瞻性队列以及独立的跨物种验证，以阐明 FMC 对人类乳腺癌研究的具体转化贡献。
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1. Introduction
Feline mammary neoplasms represent one of the most significant oncological conditions in domestic cats, ranking as the third most common tumor type after hematopoietic and cutaneous neoplasms [1,2,3]. Their prevalence varies geographically, primarily due to differences in spaying practices, but they are universally recognized for their aggressive biological behavior, high metastatic potential, and the remarkably high proportion of malignant cases, estimated at 85–95% [4,5].
Feline mammary carcinoma (FMC) is the most common malignant mammary tumor in cats and has been investigated as a spontaneous comparative model of human breast cancer because of its histological, molecular, and clinical similarities [1,2,3]. Accounting for over 80% of feline mammary neoplasms, FMCs demonstrate an infiltrative growth pattern, early lymphatic spread, and poor clinical outcomes [4,5,6].
Histologically, FMC presents a diverse spectrum of subtypes, including tubulopapillary, solid, cribriform, and micropapillary patterns. These are typically defined by pronounced nuclear pleomorphism, lymphovascular invasion, and high mitotic indices [7,8,9,10]. Notably, several subtypes identified in human breast cancer, such as ductal carcinoma in situ, as well as tubular, papillary, cribriform, invasive micropapillary, and secretory carcinomas, are also documented in cats [5,7,11]. Among these, the cribriform and invasive micropapillary variants are particularly aggressive, sharing distinct clinicopathological features with their human counterparts [5,12].
With a malignancy rate of approximately 85%, comparable to canine figures but significantly exceeding the 15% reported in women, FMC may provide a useful comparative oncology model [5,11,13]. Its comparative interest is supported by selected epidemiological, biological, and molecular similarities to human breast cancer [5,10,12]. These similarities have been investigated particularly in hormone receptor-negative/triple-negative and HER2-associated phenotypes [10,14,15]. Despite advancements in surgical and chemotherapeutic protocols, the prognosis remains guarded; median survival times rarely surpass one-year post-mastectomy [5,7]. Consequently, the limited and heterogeneous evidence for systemic therapies has encouraged investigation of targeted and immune-related pathways [16,17,18,19,20,21].
The aim of this integrative review is not to establish feline mammary carcinoma as a direct surrogate of human breast cancer, but to critically evaluate the extent of clinicopathological, molecular, immunological, and therapeutic convergence between the two diseases and to identify the specific areas in which feline tumors may provide comparative value.
1.1. Review Design and Literature Search
This study was designed as an integrative review of the literature on feline mammary carcinoma (FMC), with emphasis on epidemiology, clinicopathological characteristics, prognostic and predictive biomarkers, molecular and multi-omic features, tumor microenvironment, therapeutic approaches, and comparative oncology. Search was conducted in PubMed/MEDLINE, Scopus, and Web of Science Core Collection from database inception to 30 March 2026. Given the integrative nature of this review, the search process was structured and iterative, combining core terms related to feline mammary carcinoma with topic-specific terms representing the main domains addressed in the review, including comparative oncology, human breast cancer, molecular phenotypes, biomarkers, tumor microenvironment, immunotherapeutic approaches, proteomics, phosphoproteomics, peptidomics, and tyrosine kinase inhibitors. Database-specific electronic search strategies, including search fields, Boolean operators, and applied limits, are reported in Supplementary Table S1. The recent literature was prioritized to provide an updated overview, while older publications were retained when they provided foundational epidemiological, pathological, molecular, or clinical evidence. Reference lists of relevant publications and reviews were manually screened to identify additional pertinent studies. Because the review was designed as an integrative rather than a systematic review, the search and selection process was iterative and no quantitative record-by-record screening log was maintained; therefore, retrospective estimates of records identified or excluded were not generated.
1.2. Eligibility Criteria
Studies were considered eligible when they addressed FMC or feline mammary neoplasia in relation to epidemiology, reproductive risk factors, histopathological classification or grading, clinical staging, prognostic or predictive factors, immunohistochemical characterization, molecular subtyping, epithelial–mesenchymal transition, tumor microenvironment, immune regulation, omics-based approaches, emerging biomarkers, surgery, systemic treatment, targeted therapy, immunotherapy, or comparative oncology. Peer-reviewed original studies, clinical studies, pathological and immunohistochemical investigations, molecular and multi-omic studies, and relevant comparative studies were included. Review articles were used for historical or conceptual context and to identify primary studies, with preference given to primary feline evidence when available. Human breast cancer publications were included selectively to define the corresponding human framework and were not treated as direct evidence of feline disease. Conference abstracts, editorials, commentaries, studies focused on unrelated neoplasms without a relevant comparative component, and publications with insufficient information were excluded. Isolated case reports were generally excluded unless they provided particularly relevant evidence on rare entities, biomarkers, or therapeutic observations.
1.3. Study Selection and Evidence Synthesis
Study selection was guided by the objectives and thematic scope of the review. Titles and abstracts were assessed for relevance, followed, when appropriate, by full-text evaluation. Additional studies identified through reference-list screening were considered when they provided relevant evidence not adequately represented in the database searches. Selection was based on scientific relevance, contribution to the predefined thematic domains, and adequacy of the available evidence rather than on a predefined publication quota. Data extracted included study characteristics, feline population or biological material, tumor classification, histopathological features, clinical stage, prognostic variables, immunohistochemical markers, molecular alterations, immune and tumor-microenvironment characteristics, omics findings, candidate biomarkers, therapeutic interventions, clinical outcomes, and comparative observations relevant to human breast cancer. Evidence was synthesized qualitatively because of substantial heterogeneity in study design, sample size, pathological classification, immunohistochemical methodology, molecular techniques, treatment protocols, and clinical endpoints. Feline-derived findings were explicitly distinguished from observations derived from human oncology, and phenotypic or pathway-level similarities were interpreted as comparative or hypothesis-generating evidence rather than as evidence of biological equivalence. No quantitative meta-analysis was performed.
2. Epidemiology and Risk Factors
Feline mammary carcinoma stands as one of the most prevalent and biologically aggressive malignancies in the feline population, representing 12–17% of all diagnosed tumors [1,2,3]. Global epidemiological surveys consistently place FMC among the three most common neoplasms in this species [1,2]. Its clinical profile is characterized by invasive growth, frequent lymphatic and distant dissemination, and poor outcome [5,11,12].
A comprehensive retrospective analysis by Souza et al. (2024), involving 418 cats and 858 lesions, underscores the severity of this condition; the study found that 88.8% of mammary lesions were malignant, with nearly half of these cases demonstrating lymph node metastasis at the time of diagnosis [11]. Furthermore, this research expanded the known pathological spectrum of the disease by documenting rare or previously unreported entities, such as mammary sporotrichosis, benign phyllodes tumors, and basaloid carcinoma [11].
2.1. Hormonal and Reproductive Risk Factors
The primary epidemiological driver for FMC development is prolonged exposure to ovarian hormones. Intact females face a seven-fold higher risk of developing mammary neoplasia compared to spayed individuals [2,4,22]. While early ovariohysterectomy provides a significant protective effect, delayed sterilization or the administration of exogenous progestins substantially elevates susceptibility [2,4,5]. Nevertheless, the occurrence of FMC in ovariectomized cats suggests that non-hormonal oncogenic pathways and genetic predispositions also play a critical role in tumorigenesis [4].
In both species, the disease is linked to endocrine disturbances, such as gonadal dysfunction or exposure to exogenous hormones. For instance, the administration of cyproterone acetate in males has been directly associated with the onset of mammary carcinoma [13].
Clinical data regarding male cats indicate a highly aggressive disease course. Despite a median survival of approximately 344 days, many cases present with advanced prognostic markers, including tumors exceeding 3 cm and evidence of lymphatic invasion [23]. The terminal stages often involve pulmonary metastasis, manifesting as respiratory distress and cachexia. These findings highlight the need for careful risk-benefit assessments when using progestin-based therapies, such as medroxyprogesterone acetate, and emphasize the necessity of long-term clinical surveillance for both sexes to facilitate early detection [24].
2.2. Age, Sex, and Breed Distribution
FMC predominantly affects middle-aged to geriatric cats, with a peak incidence between 10 and 12 years of age. This timing reflects the cumulative impact of hormonal exposure and the gradual accrual of genetic alterations [1,5]. Although the disease is most common in mixed-breed feline populations, which constitute the majority of the global domestic population, a higher risk has been suggested in Siamese cats [2,5]. However, this potential breed predisposition remains a subject of debate, as it may be influenced by regional population structures rather than underlying genetic susceptibility.
In stark contrast, mammary neoplasms in male cats are exceptionally rare, accounting for only 1% of all cases [23]. Diagnosed at a slightly older mean age of 12.8 years, male FMC offers a compelling parallel to male breast cancer in humans [23,24].
3. Histopathology and Staging
3.1. Overview and Rationale for Updated Staging Approaches
In feline oncology, prognostic evaluation relies heavily on clinical staging to dictate therapeutic strategies and predict survival. While the traditional World Health Organization (WHO) tumor–node–metastasis (TNM) classification is widely utilized, it presents significant limitations when applied to feline mammary tumors (FMTs) [25,26,27]. A primary deficiency is the system’s failure to differentiate between large primary tumors and those with regional metastasis; both may fall within Stage III despite distinct prognostic implications [25,28]. Furthermore, the absence of a T4 category; used in human medicine to classify tumors invading the thoracic wall or skin, limits the system’s descriptive power [25].
To address these gaps, researchers proposed integrating a T4 category for ulcerated lesions [25]. Building upon this, a staging system adapted from the 7th edition of the AJCC Cancer Staging Manual was evaluated in 75 cats [28]. This modified framework subdivides Stage III into IIIA (T3N0M0), IIIB (T4N0M0), and IIIC (AnyTN1M0), aiming to refine risk stratification and align veterinary practices more closely with human oncological standards.
3.2. Histopathological Diversity
Feline mammary tumors exhibit substantial morphological diversity that parallels the spectrum of human breast cancers (Figure 1). Documented subtypes include ductal carcinoma in situ, as well as tubular, papillary, cribriform, micropapillary, lobular-like, and secretory carcinomas [10,11,29].
Among these, cribriform and invasive micropapillary variants are especially significant due to their aggressive biological behavior and poor prognosis [9,11].
A large clinicopathological series of 418 cats identified tubulopapillary carcinoma (17.1%), cribriform carcinoma (16.8%), and malignant adenomyoepithelioma (12.1%) as the most frequent malignant histological categories [11]. Tubulopapillary and cribriform carcinomas commonly show marked anisocytosis/anisokaryosis, high mitotic counts, and necrosis, whereas p63 immunohistochemistry was useful in identifying malignant adenomyoepithelioma in the large 2024 series [11].
3.3. Grading Systems and Clinical Staging Integration
To ensure diagnostic consistency, several histological grading systems adapted from human medicine are applied to FMTs. The Elston and Ellis (EE) or Nottingham system evaluates tubular formation, nuclear pleomorphism, and mitotic count to categorize tumors into Grades I, II, or III (Table 1). Given the high mitotic rates in cats, the Mitotic-Modified Elston and Ellis (MMEE) and Revised Elston and Ellis (REE) systems provide feline-specific adaptations, with the REE system additionally incorporating nuclear form and lymphovascular invasion [7,8,30]. Histological grade remains a powerful prognosticator; for instance, Grade III carcinomas are associated with a nearly tenfold increase in mortality risk compared to Grade I [7].
These grading schemes are complemented by morphological classifications (Table 2) and clinical staging (Table 3), which integrates tumor size, nodal status, and distant metastasis [25,26,27,29]. The proposed revised staging system was designed to refine prognostic stratification by distinguishing subgroups within Stage III. Specifically, Stage IIIC cases (nodal metastasis) carry the worst prognosis, with a median overall survival of only 288 days [28]. Additionally, skin ulceration (present in 18.7% of cases) is an independent negative prognostic factor, reducing median survival to approximately nine months [25]. This mirrors human oncology, where ulceration is a formal component of staging frameworks.
Thoracic imaging plays a central role in the detection of distant metastatic disease in cats with mammary carcinoma, particularly pulmonary involvement (Figure 2), and therefore represents an essential component of clinical staging.
4. Comparative Clinicopathological Insights
Recent investigations have refined the understanding of the clinical behavior and pathological spectrum of feline mammary lesions by focusing on the critical differentiation between neoplastic and non-neoplastic conditions.
4.1. Age-Related and Demographic Correlations
A clear correlation exists between age and the biological nature of mammary lesions because cats diagnosed with malignant tumors are significantly older than those presenting with benign tumors or non-neoplastic conditions [2,5,11]. While crossbred cats predominate in these cohorts and reflect global population demographics, the persistent overrepresentation of older and intact females reinforces the established link between cumulative hormonal exposure and malignancy [1,4,11].
4.2. The Non-Neoplastic and Benign Spectrum
Recognizing non-neoplastic conditions is essential for accurate differential diagnosis as these processes often mimic the clinical appearance of malignancy. Mastitis, usual ductal hyperplasia, and fibroadenomatous hyperplasia represent the most frequent non-neoplastic findings, while adenomas and ductal papillomas remain the most prevalent benign neoplasms [11]. Notably, the strong association observed between usual ductal hyperplasia and concurrent malignancy in more than half of reported cases suggests a potential preneoplastic role that mirrors observations in human breast pathology.
4.3. Emerging Pathological Entities and Rare Variants
Recent diagnostic efforts have expanded the feline mammary landscape by documenting rare entities previously recognized primarily in human or canine oncology. These include basaloid carcinoma and benign phyllodes tumors along with mammary sporotrichosis, which is a significant finding in younger cats that highlights how infectious granulomatous processes can clinically present with nodal involvement and lead to a misdiagnosis of metastatic neoplasia [11].
Furthermore, detailed microscopic comparisons reveal that while high-grade carcinomas such as tubulopapillary and cribriform variants consistently exhibit high mitotic indices and necrotic foci, malignant adenomyoepitheliomas often present with lower cytological atypia and more indolent behavior [7,11]. Although these findings suggest that adenomyoepitheliomas may carry a more favorable prognosis than other feline mammary carcinomas, further prospective research is required to confirm their specific clinical trajectory.
Feline mammary carcinoma exhibits marked molecular, histopathological, and immunological heterogeneity, which significantly influences both prognosis and therapeutic selection.
4.4. Molecular Subtypes and Immunohistochemical Profiling
Immunohistochemical profiling reveals that feline tumors frequently display variable protein expression of the estrogen (ER) and progesterone (PR) steroid receptors, generally at lower levels than those observed in human luminal breast cancers. The HER2 (ERBB2) receptor tyrosine kinase, which promotes cell growth, is overexpressed in approximately 10–20% of cases and is typically associated with high histological grade and elevated proliferative activity [14,15,16]. Notably, a substantial proportion of FMCs lack ER, PR, and HER2 expression. These triple-negative subtypes exhibit the most aggressive biological behavior, paralleling the clinical trajectory of triple-negative breast cancer in human patients [14,16].
Beyond receptor status, several markers serve as vital prognostic indicators. High proliferation indices assessed via Ki-67 correlate with aggressive clinicopathological features and shorter survival, with a 14% cutoff proposed in one major study [31]. Reduced E-cadherin expression has also been associated with malignant tumors and metastases, supporting its investigation as a marker of invasive behavior [32].
5. Immunohistochemical Findings and Cellular Dynamics
Immunohistochemical analysis provides critical insights into the cellular origin and phenotypic plasticity of feline mammary tumors. Cytokeratin expression is strongly marked in neoplastic epithelial cells, whereas stromal fibroblasts exhibit vimentin immunoreactivity, reflecting their epithelial and mesenchymal phenotypes, respectively.
5.1. Evidence of Epithelial-to-Mesenchymal Transition (EMT)
Co-expression of cytokeratin and vimentin has been described in feline mammary carcinomas, particularly in hormone receptor-negative tumors with basal-like characteristics [10]. In human oncology, EMT is a recognized biological process associated with tumor-cell plasticity, invasion, and dissemination [33,34]. In FMC, however, marker co-expression should be interpreted as evidence of phenotypic plasticity rather than as proof of a fully conserved EMT program across species.
5.2. Comparative Proliferative Activity
The assessment of cellular proliferation via Ki-67, a protein strictly associated with active phases of the cell cycle, reveals important differences between primary and secondary sites. Higher Ki-67 indices have been reported in nodal and distant metastases compared with corresponding primary tumors, supporting an association between increased proliferative activity and metastatic progression [31].
While these findings align with the expected progression of malignant disease, standardized prognostic cut-off values for Ki-67 in feline mammary carcinoma remain a subject of ongoing debate [7,31,35]. Interestingly, the indices reported in recent specific cases have occasionally fallen below previously proposed thresholds, suggesting that even tumors with relatively low proliferative counts can demonstrate significant metastatic potential [31].
The tumor microenvironment (TME) is a complex ecosystem that critically shapes disease progression and therapeutic responsiveness [17]. Feline mammary carcinoma utilizes “immune checkpoints”; regulatory molecules that normally prevent autoimmunity, to evade the immune system [16,18,33,34,36,37].
Expression of PD-1 (Programmed Cell Death 1), a receptor on immune cells, and its ligand PD-L1, found on tumor cells, correlates with higher histological grades and lymphatic invasion [16]. Other identified checkpoints include CTLA-4, which contributes to immune tolerance [38]; TIM-3, a protein whose expression correlates with clinical outcomes [37]; and VISTA, a recently identified regulator of T-cell responses [18]. Furthermore, metabolic mediators like leptin and its receptor ObR connect nutritional status with tumor aggressiveness, while dysregulated inflammatory cytokines such as IL-6 and TNF-alpha further facilitate immune escape [36].
The presence of functional tumor-infiltrating lymphocytes (TILs) and active checkpoint axes supports the integration of immune-targeted strategies. For example, monoclonal antibody-based therapies targeting HER2 have shown preclinical potential. HER2-targeted approaches have shown antiproliferative effects in feline cell-based models [39], while checkpoint pathways such as PD-1/PD-L1, CTLA-4, VISTA, and TIM-3 have been characterized in FMC [16,17,18,37,38]. These findings provide a rationale for further preclinical investigation, but do not establish clinical efficacy or cross-species therapeutic equivalence.
Recent large-scale proteomic studies have identified over 16,000 proteins in FMC. Metastatic tumors showed distinct protein signatures, including increased IL18R1 and DIMT1 and alterations in proteins such as GSDMC, while NOP14 and SCN8A were among proteins showing decreased expression in metastatic/high-grade groups [40].
Metastatic progression is further supported by the enrichment of ACTN4 (a cytoskeletal remodeling protein) and GSDMC (a protein involved in inflammatory cell death or pyroptosis), while tumor-suppressive proteins like NOP14 and the SCN8A sodium channel are significantly downregulated [40]. These alterations converge with earlier findings regarding phosphoproteomics, where the dysregulation of signaling enzymes like PPP1CA and metabolic regulators like PRKAG3 reinforces FMC as a robust model for comparative research [41].
The need for minimally invasive diagnostics has prompted the exploration of liquid biopsy through serum peptidomics. Unlike proteomics, which characterizes the complete protein repertoire of a biological sample, peptidomics focuses on the identification and quantification of endogenous peptides naturally present in biological fluids and may provide highly sensitive biomarkers of disease progression and metastatic behavior. Using non-trypsinized LC-MS/MS, Paphussaro et al. (2024) identified distinct serum peptidomic signatures associated with metastatic (mFMC) and non-metastatic feline mammary carcinoma (NmFMC) [42].
The serum peptidomic study identified differential peptide/protein-associated signatures between metastatic and non-metastatic FMC, including peptides derived from proteins involved in proliferation, metabolism, apoptosis resistance, and tumor progression [42].
The metastatic group showed a distinct serum peptidomic profile that included peptides associated with pathways implicated in tumor progression and metastasis [42]. These findings support serum peptidomics as a promising biomarker-discovery approach, but they do not yet establish its value for clinical risk stratification or prediction of therapeutic response; larger cohorts and independent validation are required [42].
6. Therapeutic Strategies in Feline Mammary Carcinoma
Surgical excision remains the primary cornerstone of treatment for feline mammary tumors, as aggressive intervention is typically required to address the high rate of malignancy. Bilateral mastectomy is generally recommended because feline mammary tumors are frequently multifocal and aggressive [6,11] (Figure 3). Despite this, achieving complete surgical margins remains a persistent challenge, particularly in cases of ulcerated or infiltrative tumors where local recurrence is frequent [8,19].
Given these surgical limitations and the relative scarcity of comprehensive clinicopathological data compared to canine mammary oncology, precise histopathological classification and staging are essential for effective postoperative management [3,25,28]. Standardizing feline staging may improve prognostic assessment and facilitate more reproducible comparative studies [25,28]. Ultimately, a unified diagnostic approach is vital for overcoming the current limitations of cytotoxic therapies and improving long-term outcomes for feline patients.
6.1. Targeted and Comparative Therapeutic Strategies
Evidence for conventional chemotherapy in FMC remains limited and heterogeneous [19,43], encouraging investigation of targeted approaches. These strategies focus on growth factor receptors and immune regulatory pathways that shape the tumor microenvironment.
6.1.1. Tyrosine Kinase Inhibitors (TKIs) and Clinical Response
Interest in TKIs is driven by the documented expression of receptors such as VEGFR (vascular endothelial growth factor receptor), PDGFR (platelet-derived growth factor receptor), and KIT in feline mammary carcinoma [20,21].
Toceranib phosphate, a multi-target TKI, has demonstrated a clinical benefit rate of 64.7% in cats with macroscopic mammary adenocarcinoma [21]. In the prospective toceranib study, objective responses were reported in a subset of cats, with a median overall survival of 145 days [21]. A notable observation in these trials is “biological discordance,” where primary tumors respond to treatment while distant metastases progress. The discordant responses observed between primary tumors and metastases highlight the potential importance of interlesional biological heterogeneity, although the mechanisms were not established by that study.
Beyond toceranib, Lapatinib, a dual inhibitor of EGFR (epidermal growth factor receptor) and HER2, has shown potent antiproliferative effects in feline cell lines [20]. However, pharmacokinetic studies indicate that cats require optimized dosing due to lower systemic exposure compared to dogs or humans.
6.1.2. Comparative Advances in Immunotherapy
Modern oncology categorizes tumors as immunologically “hot” (inflamed), “excluded,” or “cold” (immune-desert), a distinction that dictates responsiveness to immunotherapy [44,45,46]. Because selected FMCs show hormone receptor-negative/triple-negative phenotypes and immune checkpoint alterations, FMC may provide a complementary system for investigating tumor–immune interactions relevant to aggressive mammary cancer [10,16,17,18].
The therapeutic landscape is currently centered on immune checkpoint inhibitors (ICI). Beyond the PD-1/PD-L1 axis, several emerging targets have been identified in both species:
LAG-3: An inhibitory receptor co-expressed on exhausted T cells. Its blockade, often combined with PD-1 inhibitors, shows synergistic potential in reversing T-cell exhaustion [45,46].
VISTA: An immune-regulatory checkpoint that has been investigated in aggressive feline mammary carcinoma subtypes and proposed as a potential therapeutic target [18].
TIM-3: A regulator of innate immunity whose expression in FMC paradoxically correlates with clinical outcomes, mirroring human TNBC data [37].
CTLA-4: A fundamental regulator of T-cell activation. Its soluble isoform has been detected in both human and feline serum, serving as a potential non-invasive biomarker [38].
6.2. Future Directions: Multimodal Integration
The potential integration of TKIs with immune-modulatory strategies represents a hypothesis for future FMC studies. While current studies are often limited by small sample sizes and variable protocols, the observed activity of these agents supports further investigation, but does not establish comparative efficacy [16,18,20,21,37,38].
Moving forward, larger randomized trials are essential to define the optimal role of these therapies, particularly in the adjuvant setting for microscopic disease. Harmonized diagnostic frameworks could facilitate more rigorous comparative studies and evaluation of personalized approaches, while clinical benefit in either species remains to be established [6,7].
7. Feline Mammary Carcinoma and Human Breast Cancer: A Comparative Oncology Perspective
The comparative interest in FMC is based on the occurrence of several clinicopathological and molecular features that overlap with those described in human breast cancer. These include aggressive invasive behavior, lymphatic and distant dissemination, alterations in hormone receptor expression, HER2-associated signaling, proliferative activity, tumor–immune interactions, and dysregulation of pathways involved in tumor progression [5,12,14,15,16,17,18]. However, these similarities should be interpreted at the level of specific biological processes rather than as evidence of complete biological or molecular equivalence. In particular, the immunohistochemical phenotypes described in FMC should not be considered direct substitutes for the molecularly defined subtypes of human breast cancer.
7.1. Clinicopathological Convergence
FMC is characterized by a high proportion of malignant tumors and frequent invasive growth, while tumor size, histological grade, lymphovascular invasion, and lymph-node involvement have been investigated as prognostic factors [5,7,8,25,30]. Several histological patterns have been described in feline mammary carcinomas, including tubulopapillary, solid, cribriform, and invasive micropapillary patterns [5,9]. Invasive micropapillary carcinoma is of particular comparative interest because its histological architecture and propensity for lymphatic dissemination have parallels in human breast carcinoma [9]. Nevertheless, morphological similarity alone does not establish equivalence between feline histological entities and the considerably more extensive classification used in human breast pathology.
Histological grading has been investigated as a prognostic tool in FMC, with several studies reporting associations between higher grade, increased proliferative activity, and poorer outcome [7,8,30]. However, the prognostic performance of individual grading systems has varied among studies, and differences in methodology have complicated direct comparison of published cohorts [5,7,26]. These limitations are relevant when FMC is considered from a comparative oncology perspective because reproducible pathological classification is a prerequisite for meaningful cross-species comparisons.
Tumor burden and regional lymph-node involvement also represent areas of clinicopathological convergence. Larger primary tumors and lymph-node metastasis are generally associated with more advanced disease and poorer outcome in cats [5,7,8,25,30]. Similar variables constitute established components of human breast cancer staging. Thus, these parameters may provide useful common clinical endpoints for comparative studies, although staging systems and treatment implications remain species-specific.
The spontaneous development of FMC in immunocompetent animals is a potential comparative advantage. Unlike experimentally induced tumors or conventional cell-line xenografts, naturally occurring FMC develops within an intact host and is influenced by the tumor microenvironment, immune system, stromal interactions, and naturally occurring metastatic processes [12,17]. This feature may be particularly informative for studying tumor progression and host–tumor interactions. However, spontaneous development should not be interpreted as evidence that FMC reproduces the complete biological spectrum of human breast cancer.
7.2. Hormone Receptors, HER2, and Phenotype-Based Molecular Classification
Immunohistochemical evaluation of estrogen receptor (ER), progesterone receptor (PR), HER2, cytokeratins, and Ki-67 has been widely used to characterize FMC [14,15,16,17,18,31,35]. Compared with human breast cancer, feline mammary carcinomas show a relatively high frequency of hormone receptor-negative tumors, particularly among aggressive carcinomas [5,12,14,15]. This feature has prompted investigation of FMC as a potential comparative system for selected hormone receptor-negative and basal-like human breast cancers [12].
Feline mammary carcinomas can be grouped using IHC-based surrogate phenotypes analogous to those applied clinically in human breast cancer. Soares et al. identified luminal A, luminal B, HER2-positive, and triple-negative/basal-like phenotypes in feline mammary carcinomas and reported differences in survival between these groups [14,15]. In particular, triple-negative/basal-like tumors were associated with shorter survival and disease-free intervals in the studied cohorts [15]. These findings support the biological heterogeneity of FMC and provide a rationale for comparative investigation of aggressive mammary tumor phenotypes.
Nevertheless, the term “triple-negative” requires particular caution in a comparative context. In human breast cancer, TNBC is defined clinically by the absence of ER, PR, and HER2 expression but represents a heterogeneous group of tumors with distinct transcriptional, genomic, and biological characteristics [47]. Therefore, an ER−/PR−/HER2− feline tumor may be regarded as a phenotypic analogue of human TNBC, but receptor negativity alone does not demonstrate molecular equivalence to any specific human TNBC subtype. Comparative gene-expression analyses have identified similarities between feline mammary carcinomas and human TNBC [48], supporting further investigation, but these observations remain insufficient to establish that FMC reproduces the full molecular heterogeneity of human TNBC.
HER2 provides another important example of both biological convergence and methodological limitation. HER2 expression has been detected in feline mammary carcinomas, and feline HER2 has been investigated at both the protein and gene levels [18,20,39]. However, reported frequencies of HER2 positivity have varied considerably between studies. Soares et al. demonstrated that HER2 assessment in FMC requires optimized IHC and in situ hybridization methodologies and emphasized the inconsistency of previously available data [49]. Similarly, Rasotto et al. detected HER2 overexpression in only 5.5% of feline mammary carcinomas using an optimized IHC protocol [49]. These findings indicate that differences in antibodies, staining protocols, scoring criteria, and analytical thresholds may substantially influence the reported prevalence of HER2-positive FMC.
This methodological issue is particularly important because HER2 testing is highly standardized in human breast cancer, where validated IHC and in situ hybridization criteria are used to determine eligibility for HER2-directed treatment [50]. Consequently, the detection of HER2 expression in feline tumors should be interpreted as evidence of a potentially conserved biological pathway rather than as direct evidence that feline HER2-positive tumors are equivalent to human HER2-positive breast cancer.
7.3. Proliferation, Invasion, and Metastatic Progression
Proliferative activity is another area of convergence between FMC and human breast cancer. Ki-67 expression has been investigated extensively in feline mammary tumors and has been associated with histological grade and clinical outcome in several studies [31,35]. However, reported cut-off values and the strength of prognostic associations have varied among studies, and the absence of standardized methodology remains an important limitation [5,26,31,35]. Accordingly, Ki-67 may be considered a promising prognostic marker in FMC, but feline-specific thresholds should not be directly extrapolated from human breast cancer.
The invasive and metastatic behavior of FMC provides a further opportunity for comparative investigation. Feline mammary carcinomas may exhibit lymphovascular invasion, regional lymph-node metastasis, and distant dissemination, particularly to the lungs [5,8,15,25]. The presence of invasive micropapillary morphology has also been associated with lymphatic involvement [9]. These features make naturally occurring FMC potentially informative for studying mechanisms of tumor dissemination.
At the molecular level, epithelial-to-mesenchymal transition (EMT)-associated processes have been investigated in feline mammary carcinoma [33,34,41]. The co-expression of epithelial and mesenchymal markers has been described in feline tumors, consistent with phenotypic plasticity associated with invasion and metastasis. EMT is also extensively studied in human breast cancer as a biological process contributing to tumor-cell plasticity, invasion, and resistance [33,34]. Nevertheless, the presence of EMT-associated markers in FMC should not be interpreted as proof that identical EMT programs operate in the same manner across species.
7.4. Tumor Microenvironment and Immune Regulation
The tumor microenvironment (TME) represents a further area of comparative interest. Studies of FMC have identified tumor-infiltrating lymphocytes and other immune-cell populations, together with alterations in immune checkpoint pathways [16,17,18]. Nascimento et al. characterized the landscape of tumor-infiltrating immune cells in FMC and demonstrated associations between immune-cell composition, pathological characteristics, and clinical behavior [17]. Similarly, PD-1/PD-L1 expression has been investigated in feline mammary carcinoma, including in HER2-positive and triple-negative/normal-like phenotypes [17]. VISTA and TIM-3 have also been proposed as potential immune-regulatory targets in feline mammary carcinoma [18,37].
These observations provide a biological rationale for comparative investigation of tumor–immune interactions. However, the presence of homologous immune checkpoint pathways does not establish that immune checkpoint inhibitors will have equivalent activity in cats and humans. Differences in ligand expression, receptor biology, immune-cell composition, antibody cross-reactivity, pharmacokinetics, and treatment exposure may influence therapeutic responses. Therefore, feline immune checkpoint studies should currently be regarded as hypothesis-generating and complementary to human experimental and clinical research.
The spontaneous development of FMC in immunocompetent hosts may nevertheless provide an opportunity to study tumor–immune interactions under naturally occurring disease conditions [17]. This may be particularly relevant for understanding the relationship between tumor phenotype, immune-cell infiltration, metastatic progression, and treatment response. Prospective studies incorporating standardized pathological, immunological, and clinical endpoints will be necessary to determine the extent to which these findings can be translated across species.
7.5. Molecular and Omics-Based Convergence
Recent transcriptomic, proteomic, phosphoproteomic, and peptidomic studies have expanded the molecular characterization of FMC [14,40,41,42]. Transcriptomic profiling has identified candidate biomarkers and druggable pathways related to metabolism and cell-cycle regulation [12], while phosphoproteomic analyses have identified alterations in proteins involved in cell-cycle control, signaling, metabolism, and other processes associated with tumor progression [41]. Tissue proteomic studies have further identified protein signatures associated with metastatic status and histopathological characteristics [40], and serum peptidomic analyses have identified candidate signatures distinguishing metastatic from non-metastatic FMC [42].
These approaches may provide a useful basis for comparative hypothesis generation. For example, several proteins and signaling pathways identified in feline tumors have recognized roles in human breast cancer. However, pathway overlap should be interpreted cautiously. Identification of a conserved protein or signaling pathway does not establish that its regulation, biological importance, or therapeutic response is identical in the two species.
The comparative value of omics approaches will therefore depend on cross-species validation rather than on the identification of isolated molecular similarities. Future studies should ideally compare feline and human tumors using harmonized analytical pipelines, predefined biological questions, sufficiently powered cohorts, and clinically relevant endpoints.
7.6. Therapeutic and Translational Relevance
The therapeutic landscape represents an important component of comparative oncology. Surgery remains the principal treatment for FMC, whereas human breast cancer management incorporates surgery, radiotherapy, chemotherapy, endocrine therapy, HER2-directed treatment, immunotherapy, and other targeted approaches according to tumor subtype and stage [5,19]. Systemic treatment studies in cats have generally involved smaller cohorts than those available in human oncology, and evidence for adjuvant systemic treatment remains comparatively limited [19,21,43].
Targeted therapies have nevertheless received increasing attention. Tyrosine kinase inhibitors targeting pathways involving HER2, EGFR, VEGFR, PDGFR, and related receptors have demonstrated antiproliferative activity in feline mammary carcinoma models [20]. Toceranib has also been investigated clinically in cats with macroscopic mammary adenocarcinoma, providing preliminary evidence of biological and clinical activity [21]. These studies illustrate how naturally occurring feline tumors may contribute to comparative therapeutic research.
However, activity of a targeted agent in feline cell lines or clinical patients should not be interpreted as evidence of equivalent efficacy in human breast cancer. Drug pharmacokinetics, target expression, receptor structure, tissue penetration, toxicity, and resistance mechanisms may differ substantially between species. Similarly, evidence that trastuzumab or other HER2-directed approaches interact with feline HER2 in experimental systems supports biological investigation but does not establish clinical equivalence [39].
The most appropriate translational framework is therefore bidirectional and hypothesis-driven. FMC may contribute to the investigation of naturally occurring tumor progression, therapeutic response, resistance, and tumor–host interactions, while findings from human oncology can inform candidate biomarkers and therapeutic strategies for feline disease. This complementary approach avoids treating FMC as a substitute for human breast cancer while recognizing its potential value for selected comparative questions.
7.7. Limitations of FMC as a Comparative Model
Several limitations should be considered when interpreting FMC as a comparative model of human breast cancer. First, feline molecular classification remains less standardized than human breast cancer classification. IHC-based surrogate phenotypes are useful for describing biological heterogeneity, but they do not capture the full genomic and transcriptomic diversity of human breast cancer [14,15,47].
Second, methodological heterogeneity remains a major limitation of the feline literature. Differences in tissue processing, antibodies, IHC protocols, scoring criteria, molecular assays, staging systems, and clinical endpoints complicate comparison among studies [5,26]. This problem is particularly evident for HER2 and Ki-67, for which different analytical approaches may generate substantially different results [31,35,49].
Third, many studies of FMC are retrospective and include relatively small cohorts. As emphasized by Zappulli et al., the retrospective nature of much of the available evidence and the lack of methodological standardization reduce the strength of prognostic conclusions and limit comparability between studies [5]. Similar limitations apply to exploratory omics studies, which require validation in independent cohorts before candidate biomarkers can be considered clinically useful.
Fourth, the clinical management of mammary carcinoma differs markedly between cats and humans. Human breast cancer benefits from standardized screening, multidisciplinary staging, prospective clinical trials, and validated systemic therapies. In cats, surgery remains the main therapeutic intervention and evidence supporting systemic and targeted treatments is more limited [19,21,43]. Consequently, treatment response and survival outcomes cannot be directly compared without accounting for these differences.
Finally, the comparative relevance of FMC is unlikely to be uniform across all human breast cancer subtypes. The available evidence suggests particular interest in aggressive, hormone receptor-negative, basal-like, and selected HER2-associated phenotypes [12,14,15,16,17,18]. This does not mean that FMC reproduces the entire biological spectrum of human breast cancer. Instead, its value may be greatest for specific questions concerning aggressive tumor biology, metastatic progression, tumor–immune interactions, biomarker development, and therapeutic response.
Taken together, the available evidence supports the use of FMC as a complementary comparative oncology system rather than as a direct surrogate for human breast cancer. Naturally occurring feline tumors may provide information that is difficult to reproduce in conventional experimental systems, particularly regarding tumor development in an immunocompetent host, spontaneous metastatic progression, and naturally occurring tumor–host interactions. However, translational conclusions should be based on validated molecular and clinical endpoints rather than on phenotypic similarity alone. Standardized pathological and molecular definitions, harmonized methodologies, adequately powered multicenter cohorts, prospective clinical studies, and independent cross-species validation will be required to define the precise translational contribution of FMC to breast cancer research.
The main areas of clinicopathological, molecular, immune, and biomarker convergence between feline mammary carcinoma and human breast cancer, together with their principal translational limitations, are summarized in Figure 4 and Table 4.
8. Conclusions
Feline mammary carcinoma is an aggressive neoplasm in cats, with frequent local invasion, lymph-node involvement, and distant metastatic progression. Surgery remains the principal treatment, while histopathological grading, clinical staging, and immunohistochemical assessment provide important prognostic information. Recent transcriptomic, proteomic, phosphoproteomic, and serum peptidomic studies have expanded the characterization of FMC and identified candidate biomarkers and signaling pathways. Selected clinicopathological, molecular, and immune features overlap with those described in human breast cancer, particularly in aggressive hormone receptor-negative and selected HER2-associated phenotypes. However, these similarities do not establish biological equivalence. Differences in molecular classification, analytical methods, treatment standards, cohort size, and clinical validation currently limit direct translational inference. FMC is therefore best considered a complementary, question-specific comparative oncology system that may contribute to studies of aggressive tumor biology, metastasis, tumor–host interactions, biomarker discovery, and therapeutic response. Targeted and immunomodulatory approaches remain areas of investigation, but most feline evidence is preliminary. Future studies should prioritize standardized pathological and molecular definitions, harmonized methodologies, adequately powered prospective cohorts, and independent cross-species validation to clarify the specific translational contribution of FMC to human breast cancer research.