Breast cancer and thyroid hormone signaling have been linked since the 1960s. Breast cancer patients have a higher incidence of thyroid cancer, and thyroid cancer patients have a higher incidence of breast cancer than would be predicted by chance alone, supporting a link between thyroid hormone signaling and breast malignancy. Despite many correlative studies, the role and mechanism of thyroid hormone signaling in mammary tumorigenesis has not been elucidated. Past studies have not comprehensively evaluated thyroid hormones (T3, T4) and thyroid stimulating hormone (TSH) levels with breast cancer status in the same individual. The results are further confounded by issues of temporality; studies have either assessed thyroid hormone levels before or after diagnosis, prohibiting conclusions regarding whether thyroid disruption is a cause or effect of breast cancer. In vitro models demonstrate that mammary cells have thyroid hormone receptors and respond to thyroid hormones; however these studies have not been extended to in vivo models. In the current study, we took a translational approach by combining data from cell culture, mouse models and breast cancer patients from the City of Hope Cancer Registry (CHCR). We used the murine MMTV-PyMT model of breast cancer and treated mice with the anti-thyroid drug PTU; lowering T4 levels and increasing TSH. These mice developed significantly larger mammary tumors than untreated animals or those treated with T4 (p= 0.0012 and p=0.0183, respectively). Next, we showed that MCF10a cells in vitro are sensitive to both T4 and TSH added to the culture medium. We hypothesize that even subtle perturbations in normal thyroid hormone levels can stimulate mammary cell growth, increasing risk of transformation. We extended these findings to a small pilot study of 879 invasive and 136 in situ female breast cancer patients with comprehensive thyroid hormone lab analyses in the CHCR (total=984). Pre-treatment results were available for 44 women. TSH was significantly elevated for invasive versus in situ patients (Pt-test =0.016), regardless of the timing of the test. Pre-treatment TSH levels were significantly increased as the severity of disease increased (Pt-test =0.026). Women diagnosed stage 1 disease with no recurrence had a mean TSH level of 1.68 ± 1.87 (Standard Deviation: SD), whereas women diagnosed with stage 1 disease who returned with metastasis had a mean of 2.64 ± 1.72 SD. In the same women, free T4 and total T4 levels were lower and T3 levels were higher (Pt-test< 0.05) in women with invasive versus in situ disease. These studies support the hypothesis that even minimally dysregulated thyroid hormone levels may increase the risk of breast cancer development and progression to aggressive disease. Many women over the age of 50 suffer from sub-clinical hypothyroidism, and our results suggest that sub-clinical hypothyroidism increases breast cancer risk and disease progression. Interestingly, our data indicate that as disease progresses, dependence on TSH lessens, and the most striking differences may be seen in early and low grade disease. Collectively, our data highlight a need to further investigate the role of sub-clinical hypothyroidism in breast cancer. Citation Format: Franco A, Jolly LA, Russell S, Goldstein L, DeHart J. The role of thyroid hormones in breast tumorigenesis: A translational study utilizing mouse models, cell culture and patient data. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P5-06-01.

Conclusions: STK11mut and KEAP1mut occur predominantly in NSCLC with SK11mut more frequent in KEAP1mut cases than vice versa. STK11mut and KEAP1mut tumors are similar in disease type, age, gender, alteration types, frequencies of co-alterations with KRAS, TP53, CDKN2A/B, SMARCA4 and numerous other genes. In addition, STK11mut and KEAP1mut tumors feature biomarkers predictive of ICPI benefit despite the likelihood of resistance and a paucity of targeted therapy opportunities.

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Introduction: RAS mutations in metastatic colorectal cancer (mCRC) are clearly associated with lack of benefit from anti-EGFR drugs. Recent data suggest that these mutations may affect the pattern of metastatic spread. The aim of our study was to investigate if KRAS mutant mCRC has a distinct pattern of metastatization. Methods: We conducted a retrospective study including patients with mCRC with KRAS mutational analysis performed between 2010 and 2012. Exon 2 KRAS mutations are routinely analyzed for treatment decision in our centre by therascreen® or cobas® assays. We excluded those patients with no clinical data available. SPSS was used for the statistical analysis. Results: 203 patients with clinical and molecular characterization by exon 2 KRAS mutation were included in the analysis. The median age was 63 years old and 142 patients (70%) were male. At the time of colorectal cancer diagnosis, 133 patients (65.5%) had advanced disease, and 70 patients (34.5%) were diagnosed with non-advanced CRC but tumor relapsed with distant metastasis. Tumors were located in the colon in 144 patients (70.9%), mainly in the sigma (76 patients, 37.4%). Regarding the metastatic sites, liver was the most common site of metastasis (124 patients, 61.1%). Fifty-seven patients had lung metastasis (28.1%), 32 patients (15.8%) had distant lymph nodes metastasis and 29 patients (14.3%) had peritoneal metastasis. Other distant metastasis sites were adrenal glands (1%), bone (2%), central nervous system (CNS) (0.5%) and ovary (3.9%). KRAS mutation was detected in 95 patients (46.8%). Median overall survival was 35.6 months, with no difference observed between KRAS mutant and KRAS wild-type tumors (29.6 months vs 40.8 months, p-value = 0.162). Lung metastases were more frequent in exon 2 KRAS mutant tumors (34.7% vs 22.2%, odds ratio = 3.92, p-value = 0.048), although this was more evident in rectal cancer. Metastases in liver, lymph nodes, adrenal glands, bone, peritoneum and ovary were not associated with KRAS mutational status. We have also observed that mutations in KRAS were related to a more extensive disease, metastases were more frequently present in 2 or more locations in KRAS mutant tumors (33.7% vs 21.3%, p-value = 0.048). Conclusion: Molecular features together with their clinical characteristics (more frequent lung metastasis and extended disease) suggest that the biology of these tumors is different from other genomically-defined groups. Nevertheless, KRAS mutation does not significantly impact survival in the metastatic setting.

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