The Crystal Structures of the Hydrates of Copper Formate.' Part I. Copper Formate Tetrahydrate

@IAC

AKT1[low] quiescent cancer cells persist after neoadjuvant chemotherapy in triple negative breast cancer

Background: Absence of pathologic complete response (pCR) to neoadjuvant chemotherapy (NACT) correlates with poor long-term survival in patients with triple negative breast cancer (TNBC). These incomplete treatment responses are likely determined by mechanisms that enable cancer cells to resist being killed. However, the detailed characterization of a drug-resistant cancer cell state in residual TNBC tissue after NACT has remained elusive. AKT1(low) quiescent cancer cells (QCCs) are a quiescent, epigenetically plastic, and chemotherapy-resistant subpopulation initially identified in experimental cancer models. Here, we asked whether QCCs exist in primary tumors from patients with TNBC and persist after treatment with NACT. Methods: We obtained pre-treatment biopsy, post-treatment mastectomy, and metastatic specimens from a retrospective cohort of TNBC patients treated with NACT at Massachusetts General Hospital (n = 25). Using quantitative automated immunofluorescence microscopy, QCCs were identified as AKT(low)/H3K9me2(low)/HES1(high) cancer cells using prespecified immunofluorescence intensity thresholds. QCCs were represented in 2D and 3D digital tumor maps and QCC percentage (QCC-P) and QCC cluster index (QCC-CI) were determined for each sample. Results: We showed that QCCs exist as non-random and heterogeneously distributed clusters within primary breast tumors. In addition, these QCC clusters persist after treatment with multi-agent, multi-cycle, neoadjuvant chemotherapy in both residual primary tumors and nodal and distant metastases in patients with triple negative breast cancer. Conclusions: These first-in-human data potentially qualify AKT1(low) quiescent cancer cells as a non-genetic cell state that persists after neoadjuvant chemotherapy in triple negative breast cancer patients and warrants further study

The Crystal Structures of the Hydrates of Copper Formate.' Part II. Copper Formate Di hydrate

@IAC

AKT1[low] quiescent cancer cells persist after neoadjuvant chemotherapy in triple negative breast cancer

Background: Absence of pathologic complete response (pCR) to neoadjuvant chemotherapy (NACT) correlates with poor long-term survival in patients with triple negative breast cancer (TNBC). These incomplete treatment responses are likely determined by mechanisms that enable cancer cells to resist being killed. However, the detailed characterization of a drug-resistant cancer cell state in residual TNBC tissue after NACT has remained elusive. AKT1(low) quiescent cancer cells (QCCs) are a quiescent, epigenetically plastic, and chemotherapy-resistant subpopulation initially identified in experimental cancer models. Here, we asked whether QCCs exist in primary tumors from patients with TNBC and persist after treatment with NACT. Methods: We obtained pre-treatment biopsy, post-treatment mastectomy, and metastatic specimens from a retrospective cohort of TNBC patients treated with NACT at Massachusetts General Hospital (n = 25). Using quantitative automated immunofluorescence microscopy, QCCs were identified as AKT(low)/H3K9me2(low)/HES1(high) cancer cells using prespecified immunofluorescence intensity thresholds. QCCs were represented in 2D and 3D digital tumor maps and QCC percentage (QCC-P) and QCC cluster index (QCC-CI) were determined for each sample. Results: We showed that QCCs exist as non-random and heterogeneously distributed clusters within primary breast tumors. In addition, these QCC clusters persist after treatment with multi-agent, multi-cycle, neoadjuvant chemotherapy in both residual primary tumors and nodal and distant metastases in patients with triple negative breast cancer. Conclusions: These first-in-human data potentially qualify AKT1(low) quiescent cancer cells as a non-genetic cell state that persists after neoadjuvant chemotherapy in triple negative breast cancer patients and warrants further study

Additional file 1: of AKT1low quiescent cancer cells persist after neoadjuvant chemotherapy in triple negative breast cancer

S2 Antibody target specificity is unaffected by sequence of primary antibody application. Merged (right) and single color (left) confocal microscopy images at × 60 of an untreated primary TNBC tumor stained in an alternate sequence: pan-AKT ➔ H3K9me2 ➔ HES1 (c.f. standard sequence of H3K9me2 ➔ pan-AKT ➔ HES1) demonstrating consistent cytoplasmic pan-AKT (green) and HES1 (red) staining and nuclear H3K9me2 (yellow) staining in an example QCC (white arrows). (PDF 3624 kb