Precision medicine: PI3K targeting in advanced breast cancer

Correction to: Non-contrast MRI for breast screening: preliminary study on detectability of benign and malignant lesions in women with dense breasts In the original version of the article, the image of Figure 2 was erroneously duplicated as Figure 4. The correct version of Figure 4 is given below. The original article has been corrected.

Letter regarding Sopik V et al. entitled “Impact of microinvasion on breast cancer mortality in women with ductal carcinoma in situ”

The potential role of neutrophil trogocytosis and G-CSF in the loss of HER2 expression

Rationale for evaluating breast cancers of Lynch syndrome patients for mismatch repair gene expression Abstract Background Lynch Syndrome (LS) patients harbor germline mutations in one of several mismatch repair (MMR) genes and are predisposed to the development of colon and endometrial cancers and multiple other cancers types as well. Tumors related to LS are characterized by deficient protein expression of one or more MMR genes (dMMR) and/or demonstrate high microsatellite instability (MSI-H) (Win et al. in Breast Cancer Res 15(2):R27, 2013). The National Comprehensive Cancer Network (NCCN) Guideline states that there have been “suggestions” of increased risk of breast cancer in diagnosed LS patients, but does not endorse “increased screening above-average-risk breast cancer screening recommendations” for patients with LS (Provenzale et al. in J Natl Compr Cancer Netw 14(8):1010–1030, 2019). Results This report describes a molecularly diagnosed LS patient who developed a dMMR breast cancer. Conclusions Sporadic dMMR breast cancers are extremely rare (Davies et al. in Cancer Res 77:4755–4762, 2017). It seems reasonable to conclude that identifying a dMMR breast cancer in a patient with known LS strongly suggests that her LS is breast cancer-predisposing. LS patients with dMMR breast cancers might therefore be considered for above-average breast cancer screening for the development of additional breast cancers. Also, the FDA recently granted approval of checkpoint inhibitor therapy for all metastatic dMMR solid malignancies (Lemery et al. in N Engl J Med 377:1409–1412, 2017). MMR expression assays in metastatic breast cancers of LS patients would represent a more focused approach to identifying patients with breast cancers who are potentially eligible for checkpoint inhibitor therapy than would be universal MMR testing of all metastatic breast cancers.

In BRCA mutation carriers breast conserving surgery may not be the best choice

Agreement between molecular subtyping and surrogate subtype classification: a contemporary population-based study of ER-positive/HER2-negative primary breast cancer Abstract Purpose Oestrogen receptor-positive (ER+) and human epidermal receptor 2-negative (HER2–) breast cancers are classified as Luminal A or B based on gene expression, but immunohistochemical markers are used for surrogate subtyping. The aims of this study were to examine the agreement between molecular subtyping (MS) and surrogate subtyping and to identify subgroups consisting mainly of Luminal A or B tumours. Methods The cohort consisted of 2063 patients diagnosed between 2013–2017, with primary ER+/HER2– breast cancer, analysed by RNA sequencing. Surrogate subtyping was performed according to three algorithms (St. Gallen 2013, Maisonneuve and our proposed Grade-based classification). Agreement (%) and kappa statistics (κ) were used as concordance measures and ROC analysis for luminal distinction. Ki67, progesterone receptor (PR) and histological grade (HG) were further investigated as surrogate markers. Results The agreement rates between the MS and St. Gallen 2013, Maisonneuve and Grade-based classifications were 62% (κ = 0.30), 66% (κ = 0.35) and 70% (κ = 0.41), respectively. PR did not contribute to distinguishing Luminal A from B tumours (auROC = 0.56). By classifying HG1-2 tumours as Luminal A-like and HG3 as Luminal B-like, agreement with MS was 80% (κ = 0.46). Moreover, by combining HG and Ki67 status, a large subgroup of patients (51% of the cohort) having > 90% Luminal A tumours could be identified. Conclusions Agreement between MS and surrogate classifications was generally poor. However, a post hoc analysis showed that a combination of HG and Ki67 could identify patients very likely to have Luminal A tumours according to MS.

Utilization, duration, and outcomes of neoadjuvant endocrine therapy in the United States Abstract Purpose To evaluate if real-world utilization of neoadjuvant endocrine therapy (NET) is associated with similar rates of response and breast conservation surgery (BCS) compared to neoadjuvant chemotherapy (NAC). Methods Our population-based assessment used the National Cancer Data Base to identify women diagnosed with stage II–III, hormone receptor (HR)-positive BC who underwent surgery and received endocrine therapy from 2004 to 2014. Women were categorized by receipt of NET, NAC or no neoadjuvant therapy. We used logistic regression to assess differences in outcomes between therapies using inverse propensity score weighting to adjust for potential selection bias. Results In our sample of 211,986 women, 6584 received NET, 52,310 received NAC, and 153,092 did not receive any neoadjuvant therapy. After adjusting for multiple relevant covariates and cofounders, there was no significant difference between NET and NAC with regard to BCS [odds ratio (OR) 0.91; 95% confidence interval (CI) (0.82–1.01)]; however, women who received NET were significantly less likely to achieve pCR [OR 0.34; 95% CI (0.23–0.51)] or a decrease in T stage [OR 0.39; CI (0.34–0.44)] compared to women treated with NAC. Patients who received NET for ≥ 3 months had higher odds of BCS (OR 1.59; 95% CI 1.46–1.73) and downstaging (OR 1.79; 95% CI 1.63–1.97) compared to patients who did not receive neoadjuvant therapy. Conclusions Women who received NET had similar rates of BCS compared to women who received NAC. Those who received NET for longer treatment durations had increased odds of BCS and downstaging compared to women who did not receive neoadjuvant therapy.

Multi-targeted kinase inhibition alleviates mTOR inhibitor resistance in triple-negative breast cancer Abstract Purpose Owing to its genetic heterogeneity and acquired resistance, triple-negative breast cancer (TNBC) is not responsive to single-targeted therapy, causing disproportional cancer-related death worldwide. Combined targeted therapy strategies to block interactive oncogenic signaling networks are being explored for effective treatment of the refractory TNBC subtype. Methods A broad kinase inhibitor screen was applied to profile the proliferative responses of TNBC cells, revealing resistance of TNBC cells to inhibition of the mammalian target of rapamycin (mTOR). A systematic drug combination screen was subsequently performed to identify that AEE788, an inhibitor targeting multiple receptor tyrosine kinases (RTKs) EGFR/HER2 and VEGFR, synergizes with selective mTOR inhibitor rapamycin as well as its analogs (rapalogs) temsirolimus and everolimus to inhibit TNBC cell proliferation. Results The combination treatment with AEE788 and rapalog effectively inhibits phosphorylation of mTOR and 4EBP1, relieves mTOR inhibition-mediated upregulation of cyclin D1, and maintains suppression of AKT and ERK signaling, thereby sensitizing TNBC cells to the rapalogs. siRNA validation of cheminformatics-based predicted AEE788 targets has further revealed the mTOR interactive RPS6K members (RPS6KA3, RPS6KA6, RPS6KB1, and RPS6KL1) as synthetic lethal targets for rapalog combination treatment. Conclusions mTOR signaling is highly activated in TNBC tumors. As single rapalog treatment is insufficient to block mTOR signaling in rapalog-resistant TNBC cells, our results thus provide a potential multi-kinase inhibitor combinatorial strategy to overcome mTOR-targeted therapy resistance in TNBC cells.

Prognostic and clinicopathological value of PD-L1 expression in primary breast cancer: a meta-analysis Abstract Purpose To evaluate the association between PD-L1 expression (PD-L1+) and clinicopathological characteristics and effect on prognosis in primary breast cancer (PBC). Methods A systematic search of the PubMed, Web of Science, and Embase databases was conducted in November 2018. Studies detecting PD-L1 using immunohistochemistry, and concerning its prognostic or clinicopathological significance in PBC were included. The HR with 95% CI for survival, and the events for clinicopathological features were pooled. Results Forty-seven studies were included, with a total of 14,367 PBC patients. PD-L1+ tumor cells (TCs) were associated with ductal carcinomas, large tumor size, histological Grade 3 tumors, high Ki-67, ER and PR negative, and triple-negative breast cancer; and also, related to high tumor-infiltrating lymphocytes (TILs) and PD-1 expression. PD-L1+ TCs were significantly associated with shorter disease-free survival (DFS, HR = 1.43, 95% CI 1.21–1.70, P < 0.0001) and overall survival (OS, HR = 1.58, 95% CI 1.14–2.20, P = 0.006). And the HRs of PD-L1+ TCs on DFS and OS were higher (1.48 and 1.70, respectively) and homogeneous when using whole tissue section, compared with tumor microarrays. However, PD-L1+ TILs related to better DFS (HR = 0.45, 95% CI 0.28–0.73, P = 0.001) and OS (HR = 0.41, 95% CI 0.27–0.63, P < 0.0001). Conclusion PD-L1 expression on TCs associates with high-risk clinicopathological parameters and poor prognosis in PBC patients, while PD-L1+ TILs may relate to a better survival. Comprehensive assessment of TCs and TILs is required when evaluating the clinical relevance of PD-L1 expression in future studies.