目的：

      提供我国创新药物通过国家药品价格谈判纳入基本医疗保险前后，人类表皮生长因子受体2 (human epidermal growth factor receptor2, HER2) 阳性乳腺癌女性患者拒绝医生推荐治疗方案情况和变化的证据，探究影响HER2阳性乳腺癌患者拒绝医生推荐治疗方案的关键因素，以期有针对地提高我国难治性乳腺癌的治疗率，促进癌症治疗的公平可及，为优化创新药物公共保障政策提供循证决策依据。

方法：

      基于2014年至2020年在我国福建省肿瘤医院确诊为HER2阳性的1 332名女性乳腺癌患者的电子病历信息，采用描述性统计，分析患者社会人口学信息和临床资料，了解患者确诊后拒绝主诊医生推荐治疗方案的经历（包括手术治疗、化疗、放疗、靶向治疗、内分泌治疗）。采用二元多因素逻辑回归模型分析患者拒绝主诊医生推荐治疗方案的影响因素。通过半结构化访谈，对患者进行电话随访，进一步补充医院电子病历信息系统无法直接获得，但又与拒绝医生推荐治疗方案行为相关的信息，进一步分析可能影响患者拒绝医生推荐治疗方案的原因，并提出降低患者拒绝治疗率、促进提高癌症患者生存率的有针对性的政策建议。

结果：

      1 332例HER2阳性乳腺癌女性患者中，有327（24.55%）例患者的诊疗记录有拒绝医生推荐治疗方案的经历。居民医保参保患者中有拒绝医生推荐治疗方案经历患者的比例（30.18%）高于职工医保参保患者中的比例（18.31%）。肿瘤确诊分期为局部晚期（Stage Ⅲ）的患者中有拒绝医生推荐治疗方案经历的比例（29.71%）高于早期（Stage I,II）患者中的比例（21.41%）。327例有拒绝医生推荐治疗方案经历的患者中，有142例（43.43%）是因为经济因素，206例（63.00%）拒绝了靶向治疗方案。在治疗过程中要求返回当地治疗均为异地就医的早期（Stage Ⅰ,Ⅱ）患者。HER2阳性乳腺癌患者拒绝医生推荐治疗方案的多因素logistic回归分析结果显示，2017年底前确诊 (OR=0.64, 95%CI:0.45～0.91, P=0.01)、居民医保 (OR=2.43, 95%CI:1.77～3.35，P≤0.001) 和肿瘤分期为局部晚期Stage Ⅲ (OR=1.55, 95%CI:1.20～2.01，P≤0.001) 的患者拒绝医生推荐乳腺癌相关治疗的可能性更高。（2017年9月首个HER2阳性乳腺癌靶向治疗药物纳入当地医保）

      327位有拒绝医生推荐治疗方案经历的患者中，经电话随访到了93位患者，其中生存患者为76位（81.72%），死亡患者为17位（18.28%）。76位随访到的生存患者中，2017年底前确诊的比例为61.84%，明显均低于17位死亡患者中在2017年底前确诊的比例（82.35%）。通过进一步随访发现，41位（53.95%）生存患者拒绝的是靶向治疗，拒绝医生推荐治疗方案的原因主要包括经济因素（16位，21.05%）和异地治疗（15位，19.74%）。将近60%的生存患者表示自己的家庭因为进行乳腺癌相关的治疗承受了较大的经济压力。增加经济压力的原因包括（1）疾病治疗层面：治疗相关费用较高、治疗周期过长；（2）家庭层面：家有老小负担、家庭劳动力不足、家中有多人重病、农民家庭、无稳定收入；（3）社会保障和支持层面：无退休金、无医保、异地报销比例和额度有限。减轻经济压力的原因包括靶向药的降费、医保报销、有退休金，均为社会保障和支持层面。患者主要来自乡村（57位，75%）。在提供了教育程度和家庭年收入的患者中，65.45%的患者的教育程度为小学及以下，87.50%的患者家庭年收入在10万以内。超过一半的生存患者（35位，46.05%）在曾经拒绝医生推荐治疗方案后未接受任何其他治疗。

结论：

       研究发现HER2阳性乳腺癌患者拒绝医生推荐治疗方案的比例仍然较高，因经济原因而拒绝靶向治疗的问题更为突出。基本医疗保险福利的差异导致医疗保障不全面的患者经济负担更重。此外，研究还发现欠发达地区患者在寻求有质量保证的癌症治疗时存在困难和挑战。为了促进患者利用创新抗癌药物进行规范化诊疗，还应提高居民医保参保患者的公共保障水平，完善乡村群众等弱势群体的兜底性保障，加强向全人群传播科学的规范化癌症治疗知识，提升各地区和各级医疗机构的整体癌症诊疗能力和质量，实现肿瘤诊疗均质化，从而推动我国全面提高肿瘤生存率。

Objective：

There is a need to update the status and changes of refusal of physician recommended treatment among HER2-positive breast cancer patients in China, taking into account recent developments about innovative drugs are included in the basic medical insurance through national drug price negotiation. This study analyzed the influencing factors of refusal of physician recommended treatment in HER2-positive breast cancer patients. This study expects to specifically enhance the treatment rate of HER2-positive breast cancer in China, promote equitable access to cancer treatment, and provide evidence-based for optimizing public coverage policies for innovative drugs.

Methods：

This retrospective study included female breast cancer patients diagnosed as HER2-positive and received treatment at Fujian Cancer Hospital in southern China between 2014 and 2020. We collected socio-demographic information and relevant clinical data, understanding patients' experience of refusing treatments recommended by physician after diagnosis (Including surgery, chemotherapy, radiotherapy, targeted therapy, endocrine therapy). Multivariate analysis was conducted using a binary logistic regression model to analyze the influencing factors of refusal of physician recommended treatment in HER2-positive breast cancer patients. Patients were followed up by telephone through semi-structured interviews to further supplement information not directly available in the hospital information system but relevant to treatment refusal behavior. Telephone follow-up allows for further analysis of the reasons that may influence patients' refusal of physician recommended treatment and for targeted policy recommendations to reduce the rate of patient treatment refusal and to improved survival rates for cancer patients.

Results：

（1）Among 1,332 female patients with HER2-positive breast cancer, 327 (24.55%) had records of refusing breast cancer-related treatments recommended by physician. The proportion of patients with treatment refusal experience among residents covered by medical insurance (30.18%) was higher than that among employees covered by medical insurance (18.31%). The proportion of patients refusing treatment among those diagnosed with advanced-stage (Stage Ⅲ) tumors (29.71%) was higher than that among patients with early-stage (Stage I, II) tumors (21.41%).Among the 327 patients with treatment refusal experience, 142 (43.43%) refused treatment due to economic factors, and 206 (63.00%) refused targeted therapy. Patients who requested back to local treatment during the treatment process were early-stage (Stage I, II) patients living in another location. Multifactor logistic regression analysis of HER2 positive breast cancer patients refusing treatment showed that patients diagnosed before the end of 2017 (OR=0.64, 95% CI: 0.45-0.91, P=0.01), those covered by resident medical insurance (OR=2.43, 95% CI: 1.77-3.35, P≤0.001), and those with advanced-stage tumors (Stage Ⅲ) (OR=1.55, 95% CI: 1.20-2.01, P≤0.001) were more likely to refuse breast cancer-related treatments recommended by physician. (The first HER2 positive breast cancer targeted therapy drug was included in local medical insurance in September 2017).

（2）Among the 327 patients with treatment refusal experience, 93 were followed up by telephone, with 76 (81.72%) being survival patients and 17 (18.28%) being deceased. Among the 76 survival patients, the proportion diagnosed before the end of 2017 was 61.84%, significantly lower than the proportion of the 17 deceased patients diagnosed before the end of 2017 (82.35%). Through follow-up, it was found that 41 (53.95%) of the surviving patients refused targeted therapy, mainly due to economic factors (16, 21.05%) and treatment in another location (15, 19.74%). Nearly 60% of surviving patients stated that their families had experienced significant financial pressure due to breast cancer-related treatments. Reasons for increased economic pressure include (1) disease treatment aspect: higher treatment-related costs and long treatment cycles; (2) family aspect: burden of old and young children in the family, insufficient family labor, multiple serious illnesses in the family, farmers' families, and lack of stable income; and (3) social security and support aspect: lack of retirement pension, lack of health insurance, and limited reimbursement rates and amounts in different places. Reasons for reducing financial pressure include the reduction in the cost of targeted drugs, reimbursement by health insurance and the availability of a pension, which all at social security and support aspect. Most patients came from rural areas (57, 75%). Among patients with provided education levels and family incomes, 65.45% had an education level of primary school or below, and 87.50% had a family income of less than 100,000 RMB. More than half of the surviving patients (35, 46.05%) did not receive any other treatment after refusing treatment previously.

Conclusions：

This study reveals a high rate of refusal of physician recommended treatment among HER2-positive breast cancer patients, and the problem of refusing targeted treatments for economic reasons is even more prominent. The disparity in public health insurance benefits resulted in a heavier economic burden for patients with less comprehensive benefits. Furthermore, the study identified challenges faced by patients seeking quality-assured cancer therapy in underdeveloped regions in China. In order to promote standardized treatment of patients with innovative anticancer drugs, we should also improve the level of public protection for patients enrolled in the residents' health insurance, improve the safety net protection for vulnerable groups such as the rural population, strengthen the dissemination of scientific knowledge of standardized cancer treatment to the whole population, enhance the overall cancer diagnosis and treatment capacity and quality of medical institutions at all levels and in all regions, and achieve the homogenization of tumor diagnosis and treatment, so as to promote the overall improvement of the tumor Survival rate of tumor.