Neoadjuvant endocrine treatment (NAE) for estrogen receptor (ER)-positive/human epidermal growth factor receptor 2 (HER2)-negative primary breast cancer improves the surgical outcome, and its therapeutic response is useful for predicting prognosis. The indication for NAE is patients who have highly hormone-sensitive breast cancer. The optimal treatment duration depends on the required endpoint. In the case of tumor reduction or introduction to breast-conserving surgery (BCS), a treatment period of at least 6 months is required. Several clinical trials are underway to develop treatment strategies based on shortterm responsiveness to NAE to improve the prognosis of hormone receptor (HR)-positive/HER2-negative breast cancer. This article outlines the current status of NAE and new treatment strategies based on the responsiveness during NAE or clinical and biological feature on residual tumor after NAE.
Background Cowden syndrome is a rare autosomal-dominant disease with a high risk of malignant tumors of the breast, commonly caused by germline mutations in the PTEN gene. Most breast cancers related to Cowden syndrome showed typically a slow-growing and favorable clinical course. Here, we report a progressive case of triple-negative breast cancer in a patient who was diagnosed with Cowden syndrome. Case presentation A 35-year-old female with breast cancer was referred to our hospital. Histopathological examination of the tumor showed that it was triple-negative breast cancer with high proliferation marker. Preoperative positron emission tomography-computed tomography showed abnormal uptake in the left cerebellar hemisphere in addition to the right breast and axillary lymph node. Brain T2-weighted magnetic resonance imaging revealed hyperintense bands in the left cerebellar hemisphere lesion, which demonstrated a “tiger-stripe” appearance. The patient’s mother had died of endometrial cancer. Subsequently, she underwent genetic testing, leading to a diagnosis of Cowden syndrome with a pathogenic variant c.823_840del.18 at exon 8 in PTEN. She was treated with neoadjuvant chemotherapy of eribulin and cyclophosphamide followed by adriamycin and cyclophosphamide. However, her tumors increased after these treatments. She was immediately surgically treated and received adjuvant chemotherapy of capecitabine. Unfortunately, the cancer recurred in the lung nine months after surgery. We then administered paclitaxel and bevacizumab therapy, but the disease rapidly progressed. Consequently, the patient died due to breast cancer about three months after recurrence. Conclusion We report an aggressive case of cancer with Cowden syndrome which was resistant to standard chemotherapy. Alteration of the phosphatidylinositol-3 kinase/Akt/mammalian target of rapamycin pathway due to inactivating PTEN protein may be associated with chemoresistance and serves as a candidate for therapeutic intervention in PTEN-related cancers.
Purpose: We previously published that the expression levels of 5 genes (ADCK2, CUL2, FAM13A, KRAS, LILRA2) related to tumor shrinkage by neoadjuvant endocrine therapy (NAET) were identified though the gene expression profiles (Goto-Yamaguchi L et al, Breast Cancer Res Treat. 72:353-362,2018). In this study, we examined whether expression levels of these 5 genes were associated with prognosis in patients with ER-positive/HER2-negative operable breast cancer. Methods: Formalin-fixed paraffin embedded tumor tissues before systemic treatment were provided by 273 patients with ER-positive/HER2-negative operable breast cancer receiving standard of care at our institute from June 2000 to January 2011. We examined gene expression levels of these 5 genes determined by real time-quantitative PCR using RNA extracted from the tumor samples. We analyzed the prognostic impact of these 5 genes in terms of relapse-free survival (RFS) and breast cancer-specific survival (BCSS). We also study the relationship between 5 genes expression and clinic-pathological factors. Results: Median follow-up time was 106 months. Among 5 genes, high expression levels of ADCK2 and CUL2 were significantly related with poor PFS (log-rank test, ADCK2: p=0.022, CUL2: p0.045) but not BCSS. On the other hand, high levels of FAM13A expression were significantly poor BCSS (log-rank test, p=0.042) but not RFS. Expression of KRAS and LILRA2 were not any correlation with prognosis. Multivariate analysis in terms of RFS revealed that ADCK2 was an independent prognostic factor (HR 2.26, 95%CI 1.04 to 5.07, p = 0.038). In addition, multivariate analysis in terms of BCSS revealed that FAM13A (HR 15.6, 95%CI 2.36 to 316.0, p = 0.0029), nodal status (HR 8.22, 95%CI 1.57 to 62.9, p=0.012) and PgR (HR 0.14, 95%CI 0.0068 to 0.93, p=0.042) were independent prognostic factors. Expression of ADCK2 and CUL2 were not associated with any clinic-pathological factors such as menopausal status, tumor size, nodal status, expression levels of ER and PgR, nuclear grade and ki67 labeling index. FAM13A expression was positively correlated with ki67 labeling index (chi-square test, p=0.0007). Conclusion: Despite the genes associated with tumor shrinkage by NAET, ADCK2, CUL2 and FAM13A among the genes were positively correlated with poor prognosis. This paradoxical phenomenon showed that endpoint of short-term endocrine therapy such as tumor shrinkage may not be reflect that of long-term endocrine therapy such as PFS and BCSS. Citation Format: Lisa Goto-Yamaguchi, Mutsuko Ibusuki-Yamamoto, Masako Takeno, Yositaka Fujiki, Mai Tomiguchi, Aiko Sueta, Yutaka Yamamoto. Expression levels of some genes associated with tumor shrinkage by neoadjuvant endocrine therapy were paradoxically related with poor prognosis in patients with ER-positive/HER2-negative operable breast cancer [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P2-11-17.
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