Clinical Study On The Recurrence Risk Of HR+/HER2+ Breast Cancer And The Pathology And Prognosis Of Its Single-hormone Receptor Positive Subtypes

Background: Breast cancer has become the most prevalent malignant tumor among women worldwide,whose health is seriously jeopardized.The co-expression of hormone receptor(HR)and human epidermal growth factor receptor-2(HER2)in breast cancer accounts for 10%-15% of the total patients.HR expression refers to the expression of estrogen receptor(ER)and/or progestogen receptor(PR).Theoretically,HR+/HER2+ breast cancer is sensitive to chemotherapy,targeted therapy,and endocrine therapy.However,reduced treatment sensitivity and poor prognosis of the patients are observed due to the interaction between the HR and HER2 signaling pathways.Therefore,determining the factors affecting the prognosis of HR+/HER2+ patients and stratifying the risk of newly diagnosed patients are important to favor precise treatment.Additionally,the PR expression should be consistent with ER,the upstream regulator.However,single HR-positive breast cancer is common in clinical practices,including ER+/PR-and ER-/PR+.Previous studies have suggested that single HR-positive breast cancer is a specific subtype with controversial clinical characteristics and prognosis,while its clinicopathological characteristics and prognosis are not fully investigated.Aims: 1.Exploring the independent risk factors affecting the recurrence and metastasis of HR+/HER2+ breast cancer and developing a predictive risk model to help establish treatment protocols.2.Exploring the clinicopathological and prognostic characteristics of single HRpositive breast cancer in HR+/HER2+breast cancer to provide references for individualized therapy.Methods: Part I: A retrospective analysis was performed on the newly diagnosed female patients with HR+/HER2+ breast cancer without recurrence and metastasis history from 01/01/2013 to 31/12/2019 in the breast surgery department of our hospital.They have been followed up with the recorded time and location of the first recurrence and metastasis.Independent risk factors affecting the recurrence and metastasis of patients were screened through COX analysis,and a risk prediction model was then established with disease-free survival(DFS)regarded as the primary endpoint of the study.Part II: The HR+/HER2+ cases included were further divided into ER+/PR+,ER+/PR-,and ER-/PR+ subgroups based on hormone receptor expression.The clinicopathological characteristics and prognosis were analyzed.Results: 434 HR+/HER2+ breast cancer patients were included,with a median follow-up time of 70.83 ± 1.21 months.Part I: 1.Advanced tumor stage of tumor(T2 vs T1,P=0.0273;T3 vs T1,P=0.0026),positive vascular tumor thrombus(P<0.0001),ER expression≤10%(P<0.0001),no targeted treatment(P<0.0001),increased preoperative CEA(P<0.0001),and increased CA153(P=0.0227)are independent risk factors for recurrence and metastasis of HR+/HER2+ breast cancer patients.2.A 1/3/5-year recurrence predictive risk model of HR+/HER2+ breast cancer was established according to tumor stage,the positivity of vascular cancer thrombus,ER expression,targeted treatment,and preoperative CEA and CA153 levels.Its efficacy was evaluated by using a time-dependent receiver operating characteristic(ROC)curve.The area under curve(AUC)is 0.91(95% CI: 0.86-0.97),0.83(95% CI: 0.76-0.89),and 0.81(95% CI: 0.75-0.87),respectively.3.The patients over 60,who received chemotherapy demonstrated higher DFS(HR=0.03,95% CI: 0.00-0.32,P=0.003).However,the DFS among the patients with negative small tumor lymph node was not significant,whether they received chemotherapy or not.(HR=1.57,95% CI: 0.11-21.67,P=0.736).Part II: The cohort included 434 HR+/HER2+ patients,which were subdivided into the ER+/PR+ group(n=288),the ER+/PR-group(n=93),and the ER-/PR+ group(n=53).1.Compared to the ER+/PR+ group,the ER+/PR-group demonstrated higher age(56.91± 9.08 vs 50.93±11.62 years old,P <0.001)and a higher proportion of postmenopausal patients(63.0% vs 47.6%,P <0.001).2.Compared to the ER+/PR+ group,the ER-/PR+ group demonstrated larger tumors(2.98±1.46 vs 2.53±1.27 cm,P=0.022),more positive axillary lymph nodes(P=0.044),and a higher proportion of vascular cancer thrombus(62.3% vs 29.2%,P <0.001).Compared to the ER+/PR-group,the ER-/PR+ group demonstrated lower onset age(50.55±10.64 vs 56.91± 9.08 years old,P <0.001),a lower proportion of postmenopausal patients(74.2% vs 43.4%,P <0.001),and higher positive rate of vascular cancer thrombus(62.3% vs 24.7%,P <0.001).3.Endocrine therapy significantly improved DFS in the ER+/PR+ and ER+/PR-groups(HR=0.27,95% CI: 0.15-0.48,P <0.001;HR=0.18,95% CI: 0.06-0.57,P =0.001),but not in the ER-/PR+ group(HR=0.58,95% CI: 0.20-1.69,P =0.313).4.There was no significant difference in the DFS among the ER+/PR+,ER+/PR-,and ER-/PR+ groups(P>0.05).Conclusion: 1.Advanced tumor stage,higher positive rate of vascular cancer thrombus,ER expression ≤10%,non-receiving targeted therapy,and abnormal preoperative CEA and CA153 levels are independent risk factors for recurrence and metastasis in HR+/HER2+ patients.2.The risk of recurrence and metastasis in HR+/HER2+ patients can be evaluated based on tumor stage,the positivity of vascular cancer thrombus,ER expression,targeted treatment,and preoperative CEA and CA153 levels.3.For the patients of HER2+ breast cancer,the proportions of older onset and postmenopausal patients are higher in the ER+/PR-group than the ER+/PR+ group and ER-/PR+ group.Compared to the ER+/PR+ group,the patients in the ER-/PR+ group are relatively insensitive to endocrine therapy,whose tumor was more invasive and characterized by larger size,higher positive rates of vascular cancer thrombus,and more lymph node metastases than the ER+/PR+ group.4.For the patients with HER2+ breast cancer,there was no significant difference in DFS among ER+/PR+,ER+/PR-and ER-/PR+ groups.