Faculty Bibliography

BACKGROUND:Growing evidence suggests that the tumor immune microenvironment influences breast cancer development and prognosis. Density of tumor-infiltrating lymphocytes (TILs) within invasive breast cancer is correlated with response to therapy, especially in triple-negative disease. The clinical relevance and outcomes of TILs within ductal carcinoma in situ (DCIS) are less understood. METHODS:Our institutional database of 668 patients with pure DCIS from 2010 to 2018 was queried. TILs were evaluated by International TILs Working Group guidelines. Percentage of TILs was assessed from the densest focus (hotspot) in one high-power field of stroma touching the basement membrane. Statistical methods included cluster analyses (to define sparse versus dense TILs), logistic, and Cox regression models. RESULTS:Sixty-nine patients with DCIS and TILs were evaluated, of whom 54 (78%) were treated by breast-conserving surgery. Thirteen (19%) patients had ipsilateral recurrence. Each recurrence (n = 13) was matched to four controls (n = 56) based on date of surgery. Median follow-up was 6.7 years. TILs were defined as sparse (< 45%) or dense (≥ 45%). Dense TILs were associated with younger age (p = 0.045), larger tumor size (p < 0.001), high nuclear grade (p = 0.010), comedo histology (p = 0.033), necrosis (p = 0.027), estrogen receptor (ER) negativity (p = 0.037), and ipsilateral recurrence (p = 0.001). Nine patients with dense TILs had mean time to recurrence of 73.5 months compared with four patients with sparse TILs with mean time to recurrence of 97.9 months (p = 0.003). CONCLUSIONS:Dense TILs were significantly associated with age, tumor size, nuclear grade, comedo histology, necrosis, and ER status and was a significant predictor of recurrence in patients with pure DCIS.

Background/Objective: Growing evidence suggests that tumor immune-microenvironment influences breast cancer carcinogenesis and prognosis. Density of tumor-infiltrating lymphocytes (TILs) within invasive breast cancer correlates with response to therapy, especially in triple-negative disease. The clinical relevance and outcomes of TILs within ductal carcinoma in situ (DCIS) is less understood.
Method(s): Our institutional database was queried for pure DCIS from 2010-2018 (n=668). Local recurrences (n=13) were matched 1:4 to patients without recurrence. TILs were evaluated by the International TILs Working Group Guidelines. Percentage of TILs was assessed from the densest focus in 1 high-power field of stroma touching the basement membrane. Statistical methods included cluster analyses, logistic, and Cox regression models.
Result(s): Sixty-nine patients, including the 13 recurrences were evaluated. Fifty-four (78%) were treated by breast-conserving surgery (BCS). The median follow-up was 6.7 years. TILs were defined as sparse (<45%) and dense (>=45%). Dense TILs was associated with younger age (p=0.045), larger tumor size (p<0.001), high nuclear grade (p<0.001), comedo histology (p=0.016), necrosis (p=0.038), and recurrence (p=0.001). Nine patients with dense TILs had a mean time to recurrence of 74 months compared to 4 patients with sparse TILs who had a mean time to recurrence of 93 months (p=0.044) (Figure).
Conclusion(s): We found that dense TILs in DCIS was significantly associated with age, tumor size, grade, and histology. Most importantly, dense TILs are a significant predictor of recurrence in patients with DCIS, which underlies the prognostic importance of the immune microenvironment of early breast cancers. (Figure Presented)

Adaptive resistance to MEK inhibitors (MEK-Is) typically occurs via induction of genes for different receptor tyrosine kinases (RTKs) and/or their ligands, even in tumors of the same histotype, making combination strategies challenging. SHP2 (PTPN11) is required for RAS/ERK pathway activation by most RTKs, and might provide a common resistance node. We found that combining the SHP2 inhibitor SHP099 with a MEK-I inhibited the proliferation of multiple cancer cell lines in vitro. PTPN11 knockdown/MEK-I treatment had similar effects, while expressing SHP099 binding-defective PTPN11 mutants conferred resistance, demonstrating that SHP099 is on-target. SHP099/trametinib was highly efficacious in xenograft and/or genetically engineered models of KRAS-mutant pancreas, lung, and ovarian cancer and in wild type RAS-expressing triple negative breast cancer. SHP099 inhibited activation of KRAS mutants with residual GTPase activity, impeded SOS/RAS/MEK/ERK1/2 reactivation in response to MEK-Is and blocked ERK1/2-dependent transcriptional programs. We conclude that SHP099/MEK-I combinations could have therapeutic utility in multiple malignancies.