Trastuzumab emtansine(T-DM1)has been approved for the treatment of HER2-positive breast cancer.However,the efficacy of T-DM1 for patients after failure of pyrotinib and/or trastuzumab plus pertuzumab has not been clea...Trastuzumab emtansine(T-DM1)has been approved for the treatment of HER2-positive breast cancer.However,the efficacy of T-DM1 for patients after failure of pyrotinib and/or trastuzumab plus pertuzumab has not been clear.Additionally,no biomarker has been reported to predict the effect of T-DM1.In this multicenter phase Ⅱ trial(NCT06125834),36 participants with HER2-positive metastatic breast cancer were enrolled to receive T-DM1 therapy on a 21-day cycle until progression or unacceptable toxicity.The primary endpoint was the objective response rate(ORR).The secondary endpoints included the disease control rate(DCR),clinical benefit rate(CBR),progression-free survival(PFS),and toxicity.The primary endpoint was an ORR of 47.2%(17/36,95%CI 30.4–64.5).The treatment exhibited a manageable toxicity profile.The DCR was 66.7%(24/36,95%CI 49.0–81.4),and the CBR was 50.0%(18/36,95%CI 32.9–67.1).The median PFS was 6.6(95%CI 5.2-NA)months.Single-cell RNA sequencing revealed that the low cell cycle activity of cancer cells,activated macrophages and CD8+T cells was associated with the good efficacy of T-DM1,which was validated in a neoadjuvant cohort.This study suggests that T-DM1 is effective with a measurable safety profile in patients with metastatic HER2-positive breast cancer after failure of pyrotinib and/or trastuzumab plus pertuzumab.Our preliminary findings suggest potential biomarkers that may help predict T-DM1 efficacy,generating hypotheses for novel therapeutic targets that may address T-DM1 resistance.展开更多
Metastasis is the major cause of cancer-related death,and lymph node is the most common site of metastasis in breast cancer.However,the alterations that happen in tumor-draining lymph nodes(TDLNs)to form a premetastat...Metastasis is the major cause of cancer-related death,and lymph node is the most common site of metastasis in breast cancer.However,the alterations that happen in tumor-draining lymph nodes(TDLNs)to form a premetastatic microenvironment are largely unknown.Here,we first report the dynamic changes in size and immune status of TDLNs before metastasis in breast cancer.With the progression of tumor,the TDLN is first enlarged and immune-activated at early stage that contains specific antitumor immunity against metastasis.The TDLN is then contracted and immunosuppressed at late stage before finally getting metastasized.Mechanistically,B and follicular helper T(Tfh)cells parallelly expand and contract to determine the size of TDLN.The activation status and specific antitumor immunity of CD8+T cells in the TDLN are determined by interleukin-21(IL-21)produced by Tfh cells,thus showing parallel changes.The turn from activated enlargement to suppressed contraction is due to the spontaneous contraction of germinal centers mediated by follicular regulatory T cells.On the basis of the B-Tfh-IL-21-CD8^(+)T cell axis,we prove that targeting the axis could activate TDLNs to resist metastasis.Together,our findings identify the dynamic alterations and regulatory mechanisms of premetastatic TDLNs of breast cancer and provide new strategies to inhibit lymph node metastasis.展开更多
基金supported in part by the National Natural Science Foundation of China(81771953,82172683,and 82303710)the Natural Science Foundation of Jiangsu Province(BK20230017)+8 种基金Jiangsu Province Capability Improvement Project through Science,Technology and Education(Jiangsu Provincial Medical Key Discipline,ZDXK202222)Jiangsu Province Excellent Postdoctoral Program(2023ZB006)a project funded by Jiangsu Provincial Science and Technology Department(BE2022807)the JieBangGuaShuai Project for High-Level Hospital Construction of Jiangsu Province Hospital(CZ1420240211)Wujieping Medical Foundation(320.6750.2023-18-1 and 320.6750.2022-19-90)a project funded by Jiangsu Postgraduate Practice and Innovation Plan(JX10214028)Beijing Science and Technology Innovation Medical Development Foundation(KC2021-ZZ-0010-3)Postgraduate Research&Practice Innovation Program of Jiangsu Province(SJCX24_0791)a project funded by the Priority Academic Program Development of Jiangsu Higher Education Institutions.
文摘Trastuzumab emtansine(T-DM1)has been approved for the treatment of HER2-positive breast cancer.However,the efficacy of T-DM1 for patients after failure of pyrotinib and/or trastuzumab plus pertuzumab has not been clear.Additionally,no biomarker has been reported to predict the effect of T-DM1.In this multicenter phase Ⅱ trial(NCT06125834),36 participants with HER2-positive metastatic breast cancer were enrolled to receive T-DM1 therapy on a 21-day cycle until progression or unacceptable toxicity.The primary endpoint was the objective response rate(ORR).The secondary endpoints included the disease control rate(DCR),clinical benefit rate(CBR),progression-free survival(PFS),and toxicity.The primary endpoint was an ORR of 47.2%(17/36,95%CI 30.4–64.5).The treatment exhibited a manageable toxicity profile.The DCR was 66.7%(24/36,95%CI 49.0–81.4),and the CBR was 50.0%(18/36,95%CI 32.9–67.1).The median PFS was 6.6(95%CI 5.2-NA)months.Single-cell RNA sequencing revealed that the low cell cycle activity of cancer cells,activated macrophages and CD8+T cells was associated with the good efficacy of T-DM1,which was validated in a neoadjuvant cohort.This study suggests that T-DM1 is effective with a measurable safety profile in patients with metastatic HER2-positive breast cancer after failure of pyrotinib and/or trastuzumab plus pertuzumab.Our preliminary findings suggest potential biomarkers that may help predict T-DM1 efficacy,generating hypotheses for novel therapeutic targets that may address T-DM1 resistance.
基金supported in part by the National Natural Science Foundation of China(81771953 and 82172683)a project funded by Jiangsu Provincial Science and Technology Department(BE2022807).
文摘Metastasis is the major cause of cancer-related death,and lymph node is the most common site of metastasis in breast cancer.However,the alterations that happen in tumor-draining lymph nodes(TDLNs)to form a premetastatic microenvironment are largely unknown.Here,we first report the dynamic changes in size and immune status of TDLNs before metastasis in breast cancer.With the progression of tumor,the TDLN is first enlarged and immune-activated at early stage that contains specific antitumor immunity against metastasis.The TDLN is then contracted and immunosuppressed at late stage before finally getting metastasized.Mechanistically,B and follicular helper T(Tfh)cells parallelly expand and contract to determine the size of TDLN.The activation status and specific antitumor immunity of CD8+T cells in the TDLN are determined by interleukin-21(IL-21)produced by Tfh cells,thus showing parallel changes.The turn from activated enlargement to suppressed contraction is due to the spontaneous contraction of germinal centers mediated by follicular regulatory T cells.On the basis of the B-Tfh-IL-21-CD8^(+)T cell axis,we prove that targeting the axis could activate TDLNs to resist metastasis.Together,our findings identify the dynamic alterations and regulatory mechanisms of premetastatic TDLNs of breast cancer and provide new strategies to inhibit lymph node metastasis.
