Patients who have residual invasive carcinoma after the receipt of neoadjuvant chemotherapy for human epidermal growth factor receptor 2 (HER2)–negative breast cancer have poor prognoses. The benefit of adjuvant chemotherapy in these patients remains unclear. We randomly assigned 910 patients with HER2-negative residual invasive breast cancer after neoadjuvant chemotherapy (containing anthracycline, taxane, or both) to receive standard postsurgical treatment either with capecitabine or without (control). The primary end point was disease-free survival. Secondary end points included overall survival. The result of the prespecified interim analysis met the primary end point, so this trial was terminated early. The final analysis showed that disease-free survival was longer in the capecitabine group than in the control group (74.1% vs. 67.6% of the patients were alive and free from recurrence or second cancer at 5 years; hazard ratio for recurrence, second cancer, or death, 0.70; 95% confidence interval [CI], 0.53 to 0.92; P=0.01). Overall survival was longer in the capecitabine group than in the control group (89.2% vs. 83.6% of the patients were alive at 5 years; hazard ratio for death, 0.59; 95% CI, 0.39 to 0.90; P=0.01). Among patients with triple-negative disease, the rate of disease-free survival was 69.8% in the capecitabine group versus 56.1% in the control group (hazard ratio for recurrence, second cancer, or death, 0.58; 95% CI, 0.39 to 0.87), and the overall survival rate was 78.8% versus 70.3% (hazard ratio for death, 0.52; 95% CI, 0.30 to 0.90). The hand–foot syndrome, the most common adverse reaction to capecitabine, occurred in 73.4% of the patients in the capecitabine group. After standard neoadjuvant chemotherapy containing anthracycline, taxane, or both, the addition of adjuvant capecitabine therapy was safe and effective in prolonging disease-free survival and overall survival among patients with HER2-negative breast cancer who had residual invasive disease on pathological testing. (Funded by the Advanced Clinical Research Organization and the Japan Breast Cancer Research Group; CREATE-X UMIN Clinical Trials Registry number, UMIN000000843.)

To investigate immune escape during breast tumor progression, we analyzed the composition of leukocytes in normal breast tissues, ductal carcinoma in situ (DCIS), and invasive ductal carcinomas (IDC). We found significant tissue and tumor subtype-specific differences in multiple cell types including T cells and neutrophils. Gene expression profiling of CD45⁺CD3⁺ T cells demonstrated a decrease in CD8⁺ signatures in IDCs. Immunofluorescence analysis showed fewer activated GZMB⁺CD8⁺ T cells in IDC than in DCIS, including in matched DCIS and recurrent IDC. T-cell receptor clonotype diversity was significantly higher in DCIS than in IDCs. Immune checkpoint protein TIGIT-expressing T cells were more frequent in DCIS, whereas high PD-L1 expression and amplification of CD274 (encoding PD-L1) was only detected in triple-negative IDCs. Coamplification of a 17q12 chemokine cluster with ERBB2 subdivided HER2⁺ breast tumors into immunologically and clinically distinct subtypes. Our results show coevolution of cancer cells and the immune microenvironment during tumor progression. Significance: The design of effective cancer immunotherapies requires the understanding of mechanisms underlying immune escape during tumor progression. Here we demonstrate a switch to a less active tumor immune environment during the in situ to invasive breast carcinoma transition, and identify immune regulators and genomic alterations that shape tumor evolution. Cancer Discov; 7(10); 1098–115. ©2017 AACR. See related commentary by Speiser and Verdeil, p. 1062. This article is highlighted in the In This Issue feature, p. 1047

Purpose Breast cancer in very young women (age < 35 years) is uncommon and poorly understood. We sought to evaluate the prognosis and treatment response of these patients compared with women ages 35 to 50 years. Patients and Methods We analyzed data from 9,885 breast cancer patients age ≤ 50 years who were part of the Korean Breast Cancer Society registration program between 1992 and 2001. The overall survival (OS) and breast cancer-specific survival (BCSS) were compared between age groups. Results One thousand four hundred forty-four patients (14.6%) were younger than age 35 and 8,441 (85.4%) patients were between 35 and 50 years of age. Younger patients had significantly higher T-stage and higher lymph node positivity and lower hormone receptor expression than older patients. Younger patients had a greater probability of death than older patients, regardless of tumor size or lymph node status. The survival difference was significant for patients with positive or unknown hormone receptor status (P < .0001), but not for patients with negative hormone receptor status. In a multivariate analysis, the interaction term of young age and hormone receptor positivity was significant for OS and BCSS with a hazard ratio for OS of 2.13 (95% CI, 1.52 to 2.98). The significant survival benefit from adjuvant hormone therapy after chemotherapy observed in older patients (hazard ratio for OS, 0.61; 95% CI, 0.47 to 0.79; P = .001) could not be seen in younger patients (P > .05). Conclusion Younger patients (age < 35) showed worse prognosis than older patients (age, 35 to 50 years) only in the hormone receptor–unknown or hormone receptor–positive subgroups. Adjuvant tamoxifen therapy might provide less survival benefit when added to chemotherapy in very young breast cancer patients.

Adipocytes influence breast cancer behaviour via fatty acid release into the tumour microenvironment. Co-culturing human adipocytes and breast cancer cells increased CD36 expression, with fatty acid import into breast cancer cells. Genetic ablation of CD36 attenuates adipocyte-induced epithelial-mesenchymal transition (EMT) and stemness. We show a feedforward loop between CD36 and STAT3; where CD36 activates STAT3 signalling and STAT3 binds to the CD36 promoter, regulating its expression. CD36 expression results in metabolic reprogramming, with a shift towards fatty acid oxidation. CD36 inhibition induces de novo lipogenesis in breast cancer cells. Increased CD36 expression occurs with increased FABP4 expression. We showed that CD36 directly interacts with FABP4 to regulate fatty acid import, transport, and metabolism. CD36 and FABP4 inhibition induces apoptosis in tumour cells. These results indicate that CD36 mediates fatty acid import from adipocytes into cancer cells and activates signalling pathways that drive tumour progression. Targeting CD36 may have a potential for therapy, which will target the tumour microenvironment.

Ahn SG, et al. J Breast Cancer. 2016 Sep;19(3):223-230. https://doi.org/10.4048/jbc.2016.19.3.223

Low serum levels of adiponectin are a high risk factor for various types of cancer. Although adiponectin inhibits proliferation and metastasis of breast cancer cells, the underlying molecular mechanisms remain obscure. In this study, we show that adiponectin-activated AMPK reduces the invasiveness of MDA-MB-231 cells by stimulating dephosphorylation of AKT by increasing protein phosphatase 2A (PP2A) activity. Among the various regulatory B56 subunits, B56γ was directly phosphorylated by AMPK at Ser²⁹⁸ and Ser³³⁶, leading to an increase of PP2A activity through dephosphorylation of PP2Ac at Tyr³⁰⁷. We also show that both the blood levels of adiponectin and the tissue levels of PP2A activity were decreased in breast cancer patients and that the direct administration of adiponectin into tumor tissues stimulates PP2A activity. Taken together, these findings show that adiponectin, derived from adipocytes, negatively regulates the invasiveness of breast cancer cells by activating the tumor suppressor PP2A. [Cancer Res 2009;69(9):4018–26]