Impact of Complex Apoptotic Signaling Pathways on Cancer Cell Sensitivity to Therapy.

Anticancer drugs induce apoptotic and non-apoptotic cell death in various cancer types. The signaling pathways for anticancer drug-induced apoptotic cell death have been shown to differ between drug-sensitive and drug-resistant cells. In atypical multidrug-resistant leukemia cells, the c-Jun/activator protein 1 (AP-1)/p53 signaling pathway leading to apoptotic death is altered. Cancer cells treated with anticancer drugs undergo c-Jun/AP-1-mediated apoptotic death and are involved in c-Jun N-terminal kinase activation and growth arrest- and DNA damage-inducible gene 153 (Gadd153)/CCAAT/enhancer-binding protein homologous protein pathway induction, regardless of the p53 genotype. Gadd153 induction is associated with mitochondrial membrane permeabilization after anticancer drug treatment and involves a coupled endoplasmic reticulum stress response. The induction of apoptosis by anticancer drugs is mediated by the intrinsic pathway (cytochrome c, Cyt c) and subsequent activation of the caspase cascade via proapoptotic genes (e.g., Bax and Bcl-xS) and their interactions. Anticancer drug-induced apoptosis involves caspase-dependent and caspase-independent pathways and occurs via intrinsic and extrinsic pathways. The targeting of antiapoptotic genes such as Bcl-2 enhances anticancer drug efficacy. The modulation of apoptotic signaling by Bcl-xS transduction increases the sensitivity of multidrug resistance-related protein-overexpressing epidermoid carcinoma cells to anticancer drugs. The significance of autophagy in cancer therapy remains to be elucidated. In this review, we summarize current knowledge of cancer cell death-related signaling pathways and their alterations during anticancer drug treatment and discuss potential strategies to enhance treatment efficacy.

Breast cancer recurrence and survival rates in patients who underwent breast-conserving surgery under non-mechanically ventilated anesthesia.

BACKGROUND: Recurrence after primary treatment is an important obstacle to the curing of primary breast cancer. Less-immunosuppressive anesthetic techniques, such as local anesthesia with lidocaine, intravenous anesthesia (IVA) with propofol, and/or sedation with midazolam under spontaneous breathing may reduce breast cancer recurrence compared with standard general anesthesia techniques such as IVA and inhalation anesthesia with opioids under mechanical ventilation. AIM: The aim of this study was to analyze the factors involved in breast cancer recurrence in patients who underwent breast-conserving surgery (BCS) under non-mechanically ventilated anesthesia. METHODS: The study included 491 consecutive patients with stages 0-III breast cancer who underwent BCS/axillary lymph-node management with local anesthesia and IVA and/or sedation under non-mechanical ventilation between May 2008 and September 2021. Survival and recurrence were assessed by retrospective cohort analysis. RESULTS: The median follow-up period was 2565 days (range, 28-4834 days). The overall and breast cancer-specific survival rates were 92.9% and 95.6%, respectively. Twenty-one deaths, of which 11 were breast cancer-related, occurred. Disease recurred in 29 (5.9%) patients, of whom 15 patients received neoadjuvant chemotherapy (NAC) and 14 patients received adjuvant therapy (chemotherapy in 12 cases). The surgical procedure performed, but not other clinicopathological factors [recurrence site, P stage, tumor subtype, and disease-free interval (DFI)], differed between the NAC and adjuvant therapy groups. The DFI tended to be shorter in the NAC group than in the adjuvant therapy group. The pathological therapeutic effect grade after NAC was 1 in 12 patients and ≥2 in 3 patients. CONCLUSION: More than 50% (15/29) of patients with recurrence who underwent BCS were given NAC, but most patients did not respond to it. Similarly, adjuvant chemotherapy may not have contributed to the eradication of residual tumor cells after BCS. To reduce breast cancer recurrence in patients undergoing BCS, treatment strategies, especially for patients who do not respond to NAC or adjuvant chemotherapy, need to be developed. Non-mechanical ventilation anesthesia may also affect the incidence of breast cancer recurrence.

Outcomes in patients with non-invasive breast carcinoma.

BACKGROUND AND AIM: Non-invasive breast carcinoma is considered to be localized disease and is distinguished from invasive ductal and lobular carcinomas. The local recurrence of non-invasive carcinoma after surgery may lead to development of invasive carcinoma and promote distant metastasis, which worsens the prognosis for breast cancer mortality. The distant metastasis of non-invasive carcinoma may involve the ductal microvasculature without invasion. The outcomes of non-invasive breast carcinoma were examined in this retrospective cohort study. METHODS AND RESULTS: Of 872 primary breast cancers diagnosed at a single center between May 2008 and March 2022, 93 (10.6%) were found to be non-invasive carcinomas and were examined in this study. The breast cancer recurrence and survival rates of patients with non-invasive carcinoma were analyzed retrospectively. The median follow-up period was 1891 (range, 5-4804) days. All patients underwent surgical treatment [mastectomy with sentinel lymph node biopsy (SLNB) and partial mastectomy with or without SLNB, tumorectomy, and microdochectomy]. Postoperatively, radiation therapy was administered to 73 (78.4%) of the patients and endocrine therapy was administered to 64 (81.0%) of 79 patients with hormone-receptor positivity. Of 26 patients who underwent partial mastectomy with SLNB, 24 (92.3%) showed isolated tumor cells in the SLNs on one-step nucleic acid amplification. Local recurrence was observed in three (0.3%) patients; no distant metastasis was observed. One patient died of a noncancerous disease. The overall survival rate was 98.0% and the breast cancer-specific survival rate was 100.0%. CONCLUSIONS: Non-invasive breast carcinoma, like invasive breast carcinoma, causes local recurrence, but has a good prognosis without distant metastasis. The clinical significance of isolated tumor cells in the SLNs as a systemic component of non-invasive breast carcinoma remains to be elucidated.

Current Status and Prospects of Anesthesia and Breast Cancer: Does Anesthetic Technique Affect Recurrence and Survival Rates in Breast Cancer Surgery?

The relationship between the anesthetic technique and cancer recurrence has not yet been clarified in cancer surgery. Surgical stress and inhalation anesthesia suppress cell-mediated immunity (CMI), whereas intravenous (IV) anesthesia with propofol and regional anesthesia (RA) are known to be protective for CMI. Surgical stress, general anesthesia (GA) with inhalation anesthesia and opioids contribute to perioperative immunosuppression and may increase cancer recurrence and decrease survival. Surgical stress and GA activate the hypothalamic-pituitary-adrenal axis and release neuroendocrine mediators such as cortisol, catecholamines, and prostaglandin E2, which may reduce host defense immunity and promote distant metastasis. On the other hand, IV anesthesia with propofol and RA with paravertebral block or epidural anesthesia can weaken surgical stress and GA-induced immunosuppression and protect the host defense immunity. IV anesthesia with propofol and RA or in combination with GA may reduce cancer recurrence and improve patient survival compared to GA alone. We review the current status of the relationship between anesthesia and breast cancer recurrence using retrospective and prospective studies conducted with animal models and clinical samples, and discuss the future prospects for reducing breast cancer recurrence and improving survival rates in breast cancer surgery.

Current and Future Therapies for Immunogenic Cell Death and Related Molecules to Potentially Cure Primary Breast Cancer.

How primary breast cancer can be cured after (neo)adjuvant therapy remains unclear at the molecular level. Immune activation by anticancer agents may contribute to residual tumor cell eradication with postsurgical (neo)adjuvant chemotherapy. Chemotherapy-induced immunogenic cell death (ICD) may result in long-term immune activation with memory effector T cells, leading to a primary breast cancer cure. Anthracycline and taxane treatments cause ICD and immunogenic modulations, resulting in the activation of antitumor immunity through damage-associated molecular patterns (DAMPs), such as adenosine triphosphate, calreticulin, high mobility group box 1, heat shock proteins 70/90, and annexin A1. This response may eradicate residual tumor cells after surgical treatment. Although DAMP release is also implicated in tumor progression, metastasis, and drug resistance, thereby representing a double-edged sword, robust immune activation by anticancer agents and the subsequent acquisition of long-term antitumor immune memory can be essential components of the primary breast cancer cure. This review discusses the molecular mechanisms by which anticancer drugs induce ICD and immunogenic modifications for antitumor immunity and targeted anti-DAMP therapy. Our aim was to improve the understanding of how to eradicate residual tumor cells treated with anticancer drugs and cure primary breast cancer by enhancing antitumor immunity with immune checkpoint inhibitors and vaccines.

Clinical Perspectives in Addressing Unsolved Issues in (Neo)Adjuvant Therapy for Primary Breast Cancer.

The treatment of primary breast cancer has evolved over the past 50 years based on the concept that breast cancer is a systemic disease, with the escalation of adjuvant and neoadjuvant therapies and de-escalation of breast cancer surgery. Despite the development of these therapies, recurrence with distant metastasis during the 10 years after surgical treatment is observed, albeit infrequently. Recent advances in genomic analysis based on circulating tumor cells and circulating tumor DNA have enabled the development of targeted therapies based on genetic mutations in residual tumor cells. A paradigm shift involving the application of neoadjuvant chemotherapy (NAC) has enabled the prediction of treatment response and long-term prognoses; additional adjuvant chemotherapy targeting remaining tumor cells after NAC improves survival. The activation of antitumor immunity by anticancer agents may be involved in the eradication of residual tumor cells. Elucidation of the manner in which antitumor immunity is induced by anticancer agents and unknown factors, and the overcoming of drug resistance via the targeted eradication of residual tumor cells based on genomic profiles, will inevitably lead to the achievement of 0% distant recurrence and a complete cure for primary breast cancer.

Immune factors associated with the pathological and therapeutic effects of preoperative chemotherapy in patients with breast cancer.

Immune activation plays an important role in achieving the pathological and therapeutic effects of preoperative chemotherapy in patients with breast cancer. We evaluated how the immune response contributes to various therapeutic effects. This study was conducted on 43 patients with stages II-IV breast cancer who received preoperative chemotherapy followed by surgery. Peripheral natural killer (pNK) cell activity and the neutrophil-lymphocyte ratio, lymphocyte-monocyte ratio, and platelet-lymphocyte ratio (PLR) were assessed before and after chemotherapy. Tumor-infiltrating lymphocytes (TILs) and levels of 14 tumor microenvironmental factors, analyzed by next-generation sequencing, were assessed in formalin-fixed, paraffin-embedded sections of preoperative biopsy samples and surgical specimens. Univariate analysis showed that grade 2 (G2) and better therapeutic effects were significantly associated with human epidermal growth factor receptor 2 (HER-2)-positive cancer, lower PLRs, and higher NK cell and interleukin-6 levels after chemotherapy. The disappearance of axillary lymph-node metastasis was significantly associated with HER-2-positive cancer; increased pNK cell activity and lower PLRs and vascular endothelial growth factor (VEGF) levels after chemotherapy; and increased cytotoxic T lymphocyte antigen 4 (CTLA-4) levels in regulatory T cells (Tregs) and ≥5% TILs before chemotherapy. Multivariate analysis showed that G2 and better therapeutic effects tended to be associated with higher NK cell levels after chemotherapy (odds ratio = 1.02; 95% confidence interval, 0.99-1.05; P = 0.07). The activation of local and systemic immune responses by downregulation of immunosuppressive factors, such as VEGF and CTLA-4 in Tregs, had variable pathological and therapeutic effects after preoperative chemotherapy in patients with breast cancer.

Outpatient breast-conserving surgery for breast cancer: Use of local and intravenous anesthesia and/or sedation may reduce recurrence and improve survival.

The use of general anesthesia (GA) with inhalational anesthetics for breast cancer surgery may be associated with breast cancer recurrence and increased mortality due to the immunosuppressive effects of these drugs. Less-immunosuppressive anesthetic techniques may reduce breast cancer recurrence. We evaluated the feasibility, safety, and efficacy of outpatient breast-conserving surgery (BCS) for breast cancer in a breast clinic in terms of the anesthetic technique used, complications occurring, recurrence, and survival. Methods: The sample comprised 456 consecutive patients with stage 0-III breast cancer who underwent BCS/axillary lymph node (ALN) management using local and intravenous anesthesia and/or sedation between May 2008 and January 2020. Most patients received adjuvant chemotherapy and/or endocrine therapy and radiotherapy after surgery. Patient outcomes were evaluated retrospectively. Results: All patients recovered and were discharged after resting for 3-4 h postoperatively. No procedure-related severe complication or death occurred. Sixty-four complications (14.0%) were observed: 14 wound infections, 17 hematomas, and 33 axillary lymphoceles. The median follow-up period was 2259 days (range, 9-4190 days), during which disease recurrence was observed in 25 (5.4%) patients. The overall survival and breast cancer-specific survival rates were 92.3% and 94.7%, respectively. Conclusions: Outpatient surgery for breast cancer involving BCS and ALN management under local and intravenous anesthesia and/or sedation can be performed safely, without serious complication or death. Less-immunosuppressive anesthetic techniques with spontaneous breathing may reduce the recurrence of breast cancer and improve survival relative to GA.

Immune correlates of the differing pathological and therapeutic effects of neoadjuvant chemotherapy in breast cancer.

PURPOSE: To evaluate immune responses paralleling the pathological and therapeutic effects of neoadjuvant chemotherapy (NAC) in the tumor microenvironment of breast cancer. PATIENTS AND METHODS: 38 patients with stages II and III breast cancer received NAC followed by surgery in 2012-2018. Peripheral natural killer (pNK) cell activity, tumor-infiltrating lymphocytes (TILs), and levels of tumor microenvironmental factors were assessed before and after NAC. RESULTS: In univariate analysis, grade 2 (G2) and better therapeutic effects were significantly associated with high post-NAC levels of NK cells and interleukin-6, and tended to be associated with higher CD4, CD8 and CTLA-4 transcripts. Disappearance of axillary lymph node metastasis (Ax+) was significantly associated with 1) increased NK and pNK levels, 2) decreased vascular endothelial growth factor (VEGF) transcripts after NAC, 3) the presence of ≥5% TILs, and tended to be associated with higher CTLA-4 levels before NAC. Multivariate analysis showed that G2 and better therapeutic effects were significantly associated with higher NK levels after NAC (OR = 1.07, 95% CI 1.00-1.14; p = 0.0255), and that disappearance of Ax+ was significantly associated with the presence of ≥5% pre-NAC TILs (OR = 19.87, 95% CI 2.24-175.80; p = 0.0072). CONCLUSIONS: Increased NK cells after NAC, together with increased CD4+ and CD8+ T-cells, and decreased CTLA-4+ T cells and VEGF correlate with beneficial therapeutic effects. Systemic activation of pNK cell activity and the presence of pre-NAC TILs may improve the elimination of Ax + together with decreased immunosuppression by VEGF in tumors.

Correction to: Targeted therapy against Bcl-2-related proteins in breast cancer cells.

After the publication of this work [1] errors were noticed in Figs. 1a, 6a, and 8a-in which the ß-actin bands were mistakenly presented.

A potential role for peripheral natural killer cell activity induced by preoperative chemotherapy in breast cancer patients.

Tumor-infiltrating lymphocytes are an important prognostic factor after neoadjuvant chemotherapy (NAC) in patients with breast cancer. Natural killer (NK) cells play critical roles in antitumor immune surveillance. Here, we assessed the relationship between peripheral natural killer (pNK) cell activity, tumor microenvironmental factors (TMEFs), and the therapeutic efficacy of preoperative chemotherapy in patients with breast cancer. In a cohort of 39 patients diagnosed with stage II-IV breast cancer who received NAC, we measured pNK cell activity by chromium release assay and assessed TMEF levels by next-generation sequencing. Following NAC, pNK cell activity was increased in 24/39 patients but decreased in 15/39 patients. Increased pNK cell activity following preoperative chemotherapy was associated significantly with the disappearance of axillary lymph node metastasis (Ax+; p = 0.0235). Increased pNK cell activity remained significantly associated with the disappearance of Ax+ in multivariate logistic regression analysis (OR 5.41, 95% CI 1.19-24.52, p = 0.0283). A Grade 2 or higher effect of NAC was associated with high pre-NAC cytotoxic T lymphocyte-associated protein 4 (CTLA-4) levels (p = 0.0281) and elevated post-NAC NK (p = 0.0005) cells and transforming growth factor-beta (TGF-ß; p = 0.0350) levels. The disappearance of Ax+ was associated with high pre-NAC CTLA-4 levels (p = 0.0278) and elevated CD4 levels after NAC (p = 0.0250). The systemic activation of pNK cells after NAC may improve metastatic tumor elimination in patients with breast cancer owing to a release from local immunosuppression, and immune activation in the tumor microenvironment.

Outcomes of outpatient breast cancer surgery at a private breast clinic.

Advances in surgical and anesthetic techniques have allowed for outpatient treatment of breast cancer. We evaluated the feasibility, safety, efficacy, and surgical outcomes of outpatient surgery in 370 patients with breast cancer who underwent breast-conserving surgery (BCS)/axillar lymph node (ALN) management. There were no deaths or severe intraoperative complications, but 41 complications were observed and disease recurrence occurred in 18 patients. The cumulative overall survival rate was 95.2%. Outpatient surgery was well tolerated, feasible, and safe in patients receiving BCS/ALN management.

Effects of surgery and anesthetic choice on immunosuppression and cancer recurrence.

BACKGROUND: The relationship between surgery and anesthetic-induced immunosuppression and cancer recurrence remains unresolved. Surgery and anesthesia stimulate the hypothalamic-pituitary-adrenal (HPA) axis and sympathetic nervous system (SNS) to cause immunosuppression through several tumor-derived soluble factors. The potential impact of surgery and anesthesia on cancer recurrence was reviewed to provide guidance for cancer surgical treatment. METHODS: PubMed was searched up to December 31, 2016 using search terms such as, "anesthetic technique and cancer recurrence," "regional anesthesia and cancer recurrence," "local anesthesia and cancer recurrence," "anesthetic technique and immunosuppression," and "anesthetic technique and oncologic surgery." RESULTS: Surgery-induced stress responses and surgical manipulation enhance tumor metastasis via release of angiogenic factors and suppression of natural killer (NK) cells and cell-mediated immunity. Intravenous agents such as ketamine and thiopental suppress NK cell activity, whereas propofol does not. Ketamine induces T-lymphocyte apoptosis but midazolam does not affect cytotoxic T-lymphocytes. Volatile anesthetics suppress NK cell activity, induce T-lymphocyte apoptosis, and enhance angiogenesis through hypoxia inducible factor-1α (HIF-1α) activity. Opioids suppress NK cell activity and increase regulatory T cells. CONCLUSION: Local anesthetics such as lidocaine increase NK cell activity. Anesthetics such as propofol and locoregional anesthesia, which decrease surgery-induced neuroendocrine responses through HPA-axis and SNS suppression, may cause less immunosuppression and recurrence of certain types of cancer compared to volatile anesthetics and opioids.

Differences in immune response to anesthetics used for day surgery versus hospitalization surgery for breast cancer patients.

BACKGROUND: Surgery/anesthetic technique-stimulated immunosuppression may be associated with outcome for cancer patients. Here, the immune responses of patients undergoing day surgery versus hospitalization surgery for breast cancer were compared in a prospective study. METHODS: Between February 2012 and August 2014, 21 breast cancer patients underwent day surgery and 16 breast cancer patients underwent hospitalization surgery. The former group received lidocaine/propofol/pethidine, while propofol/systemic opioid- and sevoflurane/propofol/systemic opioid-based anesthesia were administered to the latter group. Surgical stress response was evaluated based on time of operation and amount of bleeding during operation. Immune function was assessed based on natural killer (NK) cell activity, CD4/8 T cell ratio, and cytokine levels of IL-6 and IL-10 that were detected before surgery, after surgery, and on the first postoperative day. RESULTS: Operation time did not differ between the two groups. Blood loss was significantly less for the hospitalization surgery group. No change in NK cell activity was observed for either group, although the CD4/8 T cell ratio increased transiently following day surgery. Levels of IL-6 increased significantly in both groups following surgery, and these levels tended to be higher in the hospitalization surgery group. One patient who underwent hospitalization surgery had higher levels of IL-10. CONCLUSIONS: There were few differences in immune response between the two groups, potentially since a majority of the hospitalization surgery patients received propofol-based anesthesia. We hypothesize that the use of volatile anesthetic/opioid analgesia in hospitalization surgery has a greater influence on immune function in breast cancer patients than local anesthetic/propofol-based anesthesia in day surgery.

Anesthetic technique and cancer recurrence in oncologic surgery: unraveling the puzzle.

Surgery/anesthetic technique-stimulated immunosuppression in the perioperative period might cause an increase in cancer-related mortality. Whether anesthetic technique can affect the outcomes of cancer patients remains inconclusive. This review discusses data from the available literature on anesthetic techniques applied in oncologic surgery, the long-term outcomes of anesthetic technique, and their relation to survival and cancer recurrence. Searches of the PubMed database up to June 30, 2016, were conducted to identify publications with the terms "anesthetic technique and cancer recurrence," "regional anesthesia and cancer recurrence," "local anesthesia and cancer recurrence," "anesthetic technique and immunosuppression," and "anesthetic technique and oncologic surgery." Surgery/anesthesia-stimulated activation of the hypothalamic-pituitary-adrenal (HPA) axis and the sympathetic nervous system (SNS) provides immunosuppression through several soluble factors. Volatile anesthetics and opioids suppress cell-mediated immunity (CMI) and promote the proliferation of cancer cells and angiogenesis, whereas propofol does not suppress CMI and inhibits tumor angiogenesis. Regional anesthesia (RA) protects CMI and diminishes the surgical neuroendocrine stress response by blocking afferent neural transmission that stimulates the HPA axis and SNS, decreasing the requirement for opioids and volatile anesthetics and thereby decreasing cancer recurrence. Preclinical and retrospective studies highlight a potential benefit of anesthetic technique in reducing cancer-related mortality and recurrence by attenuating immunosuppression following surgical treatment in patients with specific types of cancer. Several well-planned, prospective, randomized controlled trials (RCTs) are underway that may provide more conclusive and definitive results regarding the benefits of anesthetic technique on survival in oncologic surgery.

Anastrozole versus tamoxifen as adjuvant therapy for Japanese postmenopausal patients with hormone-responsive breast cancer: efficacy results of long-term follow-up data from the N-SAS BC 03 trial.

Aromatase inhibitors are superior to tamoxifen as adjuvant therapy in postmenopausal patients with hormone-responsive breast cancer. We report the follow-up efficacy results from the N-SAS BC 03 trial (UMIN CTRID: C000000056) where anastrozole was compared with tamoxifen as adjuvant therapy in postmenopausal Japanese patients with hormone-responsive early breast cancer. The full analysis set contained 696 patients (anastrozole arm, n = 345; tamoxifen arm, n = 351). The log-rank test was used to compare the two groups in terms of disease-free survival (DFS) and relapse-free survival (RFS); Kaplan-Meier estimates were calculated. The treatment effects were estimated by Cox's proportional hazards model. To examine time-varying effect of hazard ratios, we estimated time-varying hazard ratios at time t [HR(t)] using data from time t up to 12 months. After a median follow-up of 98.5 months, hazard ratios (95% CIs) were 0.90 (0.65-1.24; log-rank p = 0.526) for DFS and 0.83 (0.56-1.23; log-rank p = 0.344) for RFS. Hazard ratios (95% CIs) for DFS and RFS up to 36 months were 0.69 (0.40-1.17) and 0.54 (0.27-1.06) and those after 36 months were 1.06 (0.70-1.59) and 1.05 (0.64-1.73), respectively. Time-varying hazard ratios for both DFS and RFS showed that hazard ratios were initially in favor of anastrozole and approached 1.0 at around 36 months. Superior efficacy of anastrozole to tamoxifen suggested by the initial analysis was not confirmed in the present analysis after a long-term follow-up period. Advantage of anastrozole was the greatest immediately after switching from tamoxifen and then decreased thereafter.

Cancer immunoediting from immune surveillance to immune escape.

Cancer immune surveillance is considered to be an important host protection process to inhibit carcinogenesis and to maintain cellular homeostasis. In the interaction of host and tumour cells, three essential phases have been proposed: elimination, equilibrium and escape, which are designated the 'three E's'. Several immune effector cells and secreted cytokines play a critical role in pursuing each process. Nascent transformed cells can initially be eliminated by an innate immune response such as by natural killer cells. During tumour progression, even though an adaptive immune response can be provoked by antigen-specific T cells, immune selection produces tumour cell variants that lose major histocompatibility complex class I and II antigens and decreases amounts of tumour antigens in the equilibrium phase. Furthermore, tumour-derived soluble factors facilitate the escape from immune attack, allowing progression and metastasis. In this review, the central roles of effector cells and cytokines in tumour immunity, and the escape mechanisms of tumour cells during tumour progression are discussed.