Changes in HER2 status and survival outcomes in patients with non-pathological complete response after neoadjuvant targeted treatment.

To study the changes in human epidermal growth factor receptor 2 (HER2) expression in patients with HER2-positive breast cancer before and after neoadjuvant treatment. The clinicopathologic data of 499 patients with HER2-positive breast cancer who completed neoadjuvant treatment and surgery at the Fourth Hospital of Hebei Medical University from 2018 to 2021 were retrospectively analyzed. According to the new adjuvant regimen, 298 patients were divided into the trastuzumab + pertuzumab combined chemotherapy group (dual target group), and 201 patients were divided into the trastuzumab combined chemotherapy group (single target group).The effect of different neoadjuvant regimens on HER2 status was analyzed by comparing HER2 expression before and after treatment. A total of 255 of 499 neoadjuvant patients with HER2-positive breast cancer achieved a pathological complete response (pCR). pCR was achieved in 60.07% (179/298) of the dual target group and 37.81% (76/201) of the single target group, and the difference was statistically significant (χ² = 23.795, P < .001). Among 244 cases of HER2-positive breast cancer that did not reach pCR (non-pCR), there was a certain negative conversion rate of HER2 expression after neoadjuvant treatment, and the overall negative conversion rate was 13.11% (32/244). The negative conversion rates of the dual target group was 17.65% (21/119) and single target group was 8.80% (11/125), (χ² = 4.188, P = .041). The DFS of 499 patients in the pCR group was 98.43% (251/255), which was significantly higher than that in the non-pCR group 92.21% (225/244), (χ² = 8.536, P = .003). Only 2 (0.20%) of 32 patients with negative HER2 had recurrence and metastasis. Neoadjuvant treatment had an effect on the expression status of HER2, especially in the dual target group. For patients with negative HER2, the optimal treatment strategy remains to be explored, but continued anti-HER2 treatment is still recommended.

Elevated Sera IL-6 and NK-T Cells Associated With Increased Pathological Complete Response in HER2-positive Breast Cancer With Carboplatin-based Neoadjuvant Therapy.

Context: Neoadjuvant therapy is the primary treatment for stage II to III breast cancer (BC). The heterogeneity of BC challenges the identification of effective neoadjuvant regimens and of the related sensitive populations. Objective: The study intended to explore the predictive role of inflammatory cytokines, immune-cell subsets, and tumor-infiltrating lymphocytes (TILs) for the accomplishment of the pathological complete response (pCR) after a neoadjuvant regimen. Design: The research team conducted a phase II, single-armed, open-label trial. Setting: The study took place at the Fourth Hospital of Hebei Medical University in Shijiazhuang, Hebei, China. Participants: Participants were 42 patients at the hospital receiving treatment for human epidermal growth factor receptor 2 (HER2)-positive breast cancer (BC) between November 2018 and October 2021. Intervention: Participants received neoadjuvant therapy of six cycles of docetaxel, carboplatin, and trastuzumab (TCbH). Outcome Measures: The research team: (1) measured 13 cytokines and immune-cell populations in peripheral blood prior to neoadjuvant therapy administration; (2) measured TILs in tumor tissues; (3) analyzed correlations among biomarkers and pCR. Results: Of the 42 participants, 18 achieved pCR (42.9%) after the neoadjuvant therapy, with 37 having an overall response rate (ORR) of 88.1%. All participants experienced at least one short-term adverse event. The most common toxicity was leukopenia, with 33 participants (78.6%), while no cardiovascular dysfunction occurred. Compared with the non-pCR group, the pCR group had higher serum levels of tumor necrosis factor alpha (TNF-ɑ), with P = .013; interleukin 6 (IL-6), with P = .025; and IL-18, with P = .0004. Univariate analysis showed that IL-6 (OR, 3.429; 95% CI,1.838-6.396; P = .0001) had a significant correlation with pCR. Participants in the pCR group had a higher level of natural killer T (NK-T) cells (P = .009) and a lower ratio of cluster of differentiation 4 (CD4):CD8 (P = .0014) before neoadjuvant therapy. Univariate analysis linked a high population of NK-T cells (OR, 0.204; 95% CI,0.052-0.808; P = .018), a low CD4:CD8 ratio (OR, 10.500; 95% CI, 2.475-44.545; P = .001), and TILs expression (OR, 0.192; 95% CI, 0.051-0.731; P = .013) to pCR. Conclusions: Immunological factors, including IL-6, NK-T cells, CD4+ T versus CD8+ T ratio, and TILs expression were significant predictors for response to TCbH neoadjuvant therapy with carboplatin.

PDPN positive CAFs contribute to HER2 positive breast cancer resistance to trastuzumab by inhibiting antibody-dependent NK cell-mediated cytotoxicity.

Trastuzumab is a humanized monoclonal antibody, and has been clinical employed to treat human epidermal growth factor receptor 2 (HER2) positive breast cancer. However, drug resistance to trastuzumab remains a challenge due to the generally uncharacterized interactive immune responses within the tumor tissue. In this study, by means of single-cell sequencing, we identified a novel podoplanin-positive (PDPN+) cancer-associated fibroblasts (CAFs) subset, which was enriched in trastuzumab resistant tumor tissues. Furthermore, we found that PDPN+ CAFs promote resistance to trastuzumab in HER2+ breast cancer by secreting immunosuppressive factors indoleamine 2,3-dioxygenase 1 (IDO1) as well as tryptophan 2,3-dioxygenase 2 (TDO2), thereby suppressing antibody-dependent cell-mediated cytotoxicity (ADCC), which was mediated by functional NK cells. A dual inhibitor IDO/TDO-IN-3 simultaneously targeting IDO1 and TDO2 showed a promising effect on reversing PDPN+ CAFs-induced suppression of NK cells mediated ADCC. Collectively, a novel subset of PDPN+ CAFs was identified in this study, which induced trastuzumab resistance in breast cancer of HER2+ status via inhibiting ADCC immune response mediated by NK cells, hinting that PDPN+ CAFs could be a novel target of treatment to increase the sensitivity of HER2+ breast cancer to trastuzumab.

Real-world study of trastuzumab and pertuzumab combined with chemotherapy in neoadjuvant treatment for patients with HER2-positive breast cancer.

Clinical trials have shown that trastuzumab (H) and pertuzumab (P) combined with chemotherapy as neoadjuvant therapy increased pathological complete response (pCR) rate of patients with human epidermal growth factor receptor 2 (HER2)-positive breast cancer. However, date in China in the real world are currently limited. Clinical data from patients with HER2-positive breast cancer who received HP combined with chemotherapy as neoadjuvant therapy at 2 institutions from March 2019 to February 2022 were retrospectively analyzed. Adverse reactions were evaluated using CTCAE version 5.0. The primary endpoint was total pathologic complete response (tpCR; ypT0/isypN0), and the secondary endpoints were breast pathologic complete response (bpCR; ypT0/is) and axillary pathologic complete response (apCR; ypN0). Factors influencing tpCR were also analyzed. A total of 302 patients were included in the analysis, of which 145 were treated with H + P + taxane + carboplatin (TcbHP), 94 with H + P + taxane (THP) and 63 with sequential anthracycline and cyclophosphamide, followed by H + P + taxane (AC-THP). The overall tpCR rate was 64.9%, and those of TcbHP, THP, and AC-THP were 73.1%, 52.1%, and 65.1%, respectively. The tpCR rate of the hormone receptor (HR) negative group (80.3%) was higher than that of the HR positive group (52.1%). The overall bpCR rate was 73.5% and the apCR rate was 75.8%. In the univariate analysis, HR, HER2 status and treatment regimen were related factors that affected tpCR. In the multivariate analysis, HR, HER2 status and treatment regimen were independent predictors of tpCR (P < .001, P < .001 and P = .009). The levels 3 and 4 toxicities rates of TcbHP were slightly higher than those of THP and AC-THP. HP combined with chemotherapy has achieved a high pCR rate. The TcbHP regimen had the highest pCR. HR-negative tumors demonstrated a higher pCR. HR, HER2 status and treatment regimen were independent predictors of tpCR. The adverse reactions are controllable.

Clinicopathologic characteristics and prognosis of glycogen-rich clear cell carcinoma of the breast.

Glycogen-rich clear cell carcinoma (GRCC) of the breast is a rare type of breast carcinoma. Knowledge about the characteristics of this type is fragmentary, and the prognosis is on debate. In this study, we aimed to summarize the clinical, pathologic, and biologic characteristics of GRCC of the breast and analyze the survival. We reviewed the cases of breast cancer in our hospital between January 1999 and December 2009 and identified 28 patients as GRCC of the breast. The routine hematoxylin-eosin staining, periodic acid-Schiff (PAS) staining, and diastase PAS staining were performed on the tumor tissues. The expression of estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER-2), Ki67 and P53 were evaluated by immunohistochemistry. Tumors with a HER-2 score of 2+ were confirmed by fluorescent in situ hybridization test. Each GRCC case, who had complete follow-up data, was compared with four cases of usual invasive ductal carcinomas as controls in the same database and matched with age, year of diagnosis, tumor size, nodal status, and immunophenotype. The chi-squared test and the Fisher's exact test were used to compare the characteristics of GRCC cases and controls. The univariate analysis was used to study the prognosis, and Kaplan-Meier method was used to compare the survival of two groups. The clinicopathologic and imaging features were analyzed in the GRCC cases. Tumor sizes ranged from 0.8 to 7.5 cm (mean, 3.2 cm). Thirteen cases (46.4%) had positive lymph nodes. The positivity of ER and PR was 61.5% (16 of 26). HER-2 was positive for three cases (12%). The positivity of Ki67 and P53 were 87.5% and 45.8%, respectively. Twenty-four cases were followed up from 19 to 158 months. The prognosis of GRCC of the breast was significantly related with the number of positive lymph nodes (p < 0.001), and patients with more than 10 positive lymph nodes were at high risk of recurrence or metastasis. There was no significant difference in overall survival (p = 0.547), and disease-free survival (p = 0.900) between GRCC of the breast and the usual invasive ductal carcinomas. GRCC of the breast may not have a worse survival.

[Differences and clinical significance of receptor expression between primary and locally recurrent breast tumor tissues].

OBJECTIVE: To compare the difference of receptor expression between primary and locally recurrent breast tumor tissues, and analyze their impact on survival of the patients. METHODS: The expression of estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor-2 (HER-2) of primary and locally recurrent breast tumor tissues of 70 breast cancer patients were analyzed by immunohistochemistry or fluorescence in situ hybridization. The impact of the differences on overall survival (OS) and post-recurrence survival (PRS) of the patients was analyzed. RESULTS: The effective discrepancy rates between primary and locally recurrent breast cancer tissues were 26.1% (18/69) for ER, 50.0% (34/68) for PR, and 10.3%(4/39) for HER-2 expressions. In the 60 cases who had complete follow-up data, 23 patients (38.3%) died and the median overall survival was 107 months (11-288 months). The 3-, 5- and 10-year overall survival rates were 84.3%, 71.6% and 45.7%, respectively. Kaplan-Meier survival analysis showed that the changes of ER expression had significant impact on the OS (P = 0.001) and PRS (P < 0.001), but PR had no significant effect on OS (P = 0.416) and PRS (P = 0.056). However, the OS and PRS for patients with PR⁺ locally recurrent tumors were better than that of PR⁻ patients regardless of the primary tumor PR status. The expression of HER-2 had no significant effect on the OS (P = 0.840) and PRS (P = 0.544) of the patients. CONCLUSIONS: An expression discrepancy of ER, PR and HER-2 exists between primary and locally recurrent breast cancer tissues, it significantly affects the survival of the patients. Re-evaluation of the expressions of ER, PR and HER-2 receptor in locally recurrent breast tumor tissue is beneficial for their therapy and prognosis.

[Mammographic and pathological features of triple-negative breast cancer].

OBJECTIVE: To retrospectively evaluate the mammographic imaging findings and pathologic changes of the so-called "triple-negative" breast cancer (ER(-)/PR(-)/HER-2(-) breast cancer), and to compare them with the ER(+)/PR(+)/HER-2(-) and ER(-)/PR(-)/HER-2(+) breast cancer patients. METHODS: Five hundred cases of breast cancer treated in Cancer Institute and Hospital of Tianjin University from January to June of 2010 were included in this study. There were 112 cases of triple-negative breast cancer, 310 cases of ER(+)/PR(+)/HER-2(-) breast cancer, and 78 cases of ER(-)/PR(-)/HER-2(+) breast cancer. Their pathological and mammographic data were reviewed and analyzed. The pathological and mammographic features of the three groups were compared. RESULTS: Compared with the ER(+)/PR(+)/HER-2(-) breast cancer group, the triple-negative group had a higher histological grade (P < 0.001). Compared with the ER(+)/PR(+)/HER-2(-) and ER(-)/PR(-)/HER-2(+) groups, the triple-negative group was more likely to have a tumor mass (simple mass accounted for 58.0%, and tumor mass with calcification accounted for 19.6%). Moreover, compared with the ER(+)/PR(+)/HER-2(-) group (47.1% vs. 9.8%, P = 0.032)and the ER(-)/PR(-)/HER-2(+) group (47.1% vs. 0, P = 0.028), the tumor mass of triple-negative cancer was more likely to have a smooth margin. Triple-negative breast cancer seldom represented as calcification (simple calcification only accounted for 13.4%, and a mass with calcification accounted for 19.6%), and most of them were benign calcification (70.3%), significantly higher than that in the ER(+)/PR(+)/HER-2(-) group (23.1%, P = 0.002) and ER(-)/PR(-)/HER-2(+) group (10.2%, P < 0.001). CONCLUSIONS: Different types of breast cancer have different biological characteristics and mammographic features. Analysis of the mammographic features may help us to predict the type of breast cancer and its prognosis, and to select an optimal treatment plan for patients with different types of breast cancer.