Jiani Hu

Unraveling the clinicopathological features driving the emergence of ESR1 mutations in metastatic breast cancer

AbstractESR1 mutations were recently found to be an important mechanism of endocrine resistance in ER-positive (ERu2009+u2009) metastatic breast cancer. To determine the clinicopathological features driving the emergence of the ESR1 mutations we studied plasma cfDNA and detailed clinical data collected from patients with metastatic breast cancer. Droplet Digital PCR was performed for the detection of the most common ESR1 mutations and PIK3CA mutations. Among the patients with ERu2009+u2009/HER2- disease, ESR1 mutations were detected in 30% of the patients. There were no associations between the pathological features of the primary disease or time to distant recurrence and the emergence of ESR1 mutations in metastatic disease. The prevalence of the ESR1 mutations was significantly associated with prior treatment with an aromatase inhibitor in the adjuvant or metastatic setting. The prevalence of the ESR1 mutations was also positively associated with prior fulvestrant treatment. Conversely, the prevalence of ESR1 mutations was lower after treatment with a CDK4/6 inhibitor. There were no significant associations between specific systemic treatments and the prevalence of PIK3CA mutations. These results support the evolution of the ESR1 mutations under the selective pressure of treatment with aromatase inhibitors in the adjuvant and metastatic settings and have important implications in the optimization of adjuvant and metastatic treatment in ERu2009+u2009breast cancer.Genetics: Drug treatment spurs new resistance mutationsTreatment with aromatase inhibitors, a class of drugs that suppress the synthesis of estrogen, can drive the evolution of mutations in the estrogen receptor gene ESR1, leading to tumor resistance against hormone therapies. To better understand the emergence of ESR1 mutations, Rinath Jeselsohn from the Dana-Farber Cancer Institute u2028in Boston, Massachusetts, USA, and coworkers tested tumor DNA contained within blood samples from 155 women with metastatic breast cancer. They found ESR1 mutations rarely in women with any molecular subtype of cancer other than estrogen receptor-positive disease. Nothing about the primary tumor predicted who would develop ESR1 mutations; however, treatment with an aromatase inhibitor was associated with mutations arising. The findings highlight the need to develop therapeutic regimens that reduce the selective pressure for ESR1 mutations and/or target these mutations directly.

Correction to: Margins in Breast-Conserving Surgery After Neoadjuvant Therapy

In the original article, there is an error in Jungeun Choi’s affiliation. It is corrected as reflected here.

Multidisciplinary Management of the Axilla in Patients with cT1-T2 N0 Breast Cancer Undergoing Primary Mastectomy: Results from a Prospective Single-Institution Series

BackgroundThe after mapping of the axilla: radiotherapy or surgery (AMAROS) trial concluded that for patients with cT1-2 N0 breast cancer and one or two positive sentinel lymph nodes (SLNs), axillary radiotherapy (AxRT) provides equivalent locoregional control and a lower incidence of lymphedema compared with axillary lymph node dissection (ALND). The study prospectively assessed how often ALND could be replaced by AxRT in a consecutive cohort of patients undergoing mastectomy for cT1-2 N0 breast cancer.MethodsIn November 2015, our multidisciplinary group agreed to omit routine intraoperative SLN evaluation for cT1-2 N0 patients undergoing upfront mastectomy and potentially eligible for postmastectomy radiation therapy (PMRT), including those 60xa0years of age or younger and those older than 60xa0years with high-risk features. Patients with one or two positive SLNs on final pathology were reviewed to determine whether PMRT including the full axilla was an appropriate alternative to ALND.ResultsFrom November 2015 to December 2016, 154 patients met the study criteria, and 114 (74%) formed the final study cohort. Intraoperative SLN evaluation was omitted for 76 patients (67%). Of these patients, 20 (26%) had one or two positive SLNs, and 14 of these patients received PMRTu2009+u2009AxRT as an alternative to ALND. Three patients returned for ALND, and three patients were observed. On univariate analysis, tumor size, LVI, number of positive lymph nodes, and receipt of chemotherapy were associated with receipt of PMRT.ConclusionsFor the majority of patients with one or two positive SLNs, ALND was avoided in favor of PMRTu2009+u2009AxRT. With appropriate multidisciplinary strategies, intraoperative evaluation of the SLN and immediate ALND can be avoided for patients meeting the AMAROS criteria and eligible for PMRT.

The Potential Impact of AMAROS on the Management of the Axilla in Patients with Clinical T1-2N0 Breast Cancer Undergoing Primary Total Mastectomy

BackgroundRecent trials have demonstrated that axillary observation or axillary radiation therapy (AxRT) is equivalent to axillary node dissection (ALND) for patients with one or two positive sentinel lymph nodes (SLNs). These strategies have been widely adopted for patients having breast conservation. This report demonstrates the potential impact of the AMAROS trial on axillary therapy in a retrospective cohort of mastectomy patients.MethodsPatients undergoing primary mastectomy for cT1-2N0 breast cancer who had one or two positive SLNs were identified from institutional databases (2005–2015). Locoregional management strategies were evaluated, and variables predictive of the use of postmastectomy radiation therapy (PMRT) were identified.ResultsAmong 2594 mastectomies, 193 (7%) met the AMAROS eligibility criteria. The median patient age was 50xa0years (range 22–83xa0years). Locoregional treatment consisted of ALNDu2009+u2009PMRT for 102 patients (53%), ALND alone for 66 patients (34%), PMRT alone for 11 patients (6%), and observation for 14 patients (7%). Overall, 59 ALND patients (35%) had additional positive nodes. In the multivariate analysis, age younger than 50xa0years (odds ratio [OR] 3.55; 95% confidence interval [CI] 1.57–8.45), lymphovascular invasion (LVI) (OR 5.78; 95% CI 2.53–4.78), macrometastases (OR 3.99; 95% CI 1.54–10.97), and extracapsular extension (OR 11.66; 95% CI 2.55–88.34) were associated with receipt of PMRT.ConclusionIn this cohort of AMAROS-eligible patients, 168 (87%) underwent ALND, 102 (61%) of whom also received PMRT, suggesting that AxRT could have been used instead of ALND for a significant number of patients. Preoperative factors associated with the receipt of PMRT, such as young age and LVI, may be useful for defining a multidisciplinary decision-making framework for axillary management in this population.

Margins in Breast-Conserving Surgery After Neoadjuvant Therapy

BackgroundOptimal margin width for breast-conserving therapy (BCT) after neoadjuvant chemotherapy (NAC) is unknown. We sought to determine the impact of margin width on local recurrence and survival after NAC and BCT.MethodsPatients treated with NAC and BCT for stage I–III breast cancer from 2002 to 2014 were identified. Multivariate Cox regression was performed to determine the relationship between margin width and local recurrence free-survival (LRFS), disease-free survival (DFS), and overall survival (OS).ResultsA total of 382 patients were included. Median age was 51xa0years [range 22–79], median tumor size 3.0xa0cm [range 0.6–11.0], and receptor subtypes included 144 (37.7%) HR−/HER2−, 47 (12.3%) HR−/HER2+, 118 (30.9%) HR+/HER2−, and 70 (18.3%) HR+/HER2+. Breast pathologic complete response (pCR) was achieved in 105 (27.5%) patients. Final margin status was positive in 8 (2.1%) patients,u2009≤u20091xa0mm in 65 (17.0%), 1.1–2xa0mm in 30 (7.9%), andu2009>u20092xa0mm in 174 (45.5%). The 5-year LRFS was 96.3% (95% CI 94.0–98.6), DFS was 85.5% (95% CI 81.8–90.7), and OS was 90.8% (95% CI 87.4–94.2). There was no difference in LRFS, DFS, or OS for marginsu2009≤u20092 versusu2009>u20092xa0mm, and no difference in DFS or OS for marginsu2009≤u20091 versusu2009>u20091xa0mm. HR+ subtype (pu2009=u20090.04) and pCR (pu2009=u20090.03) were correlated with favorable DFS and node negativity (pu2009<u20090.001) with favorable DFS and OS.ConclusionsIn this cohort treated with NAC and BCT, there was no association between margin width and LRFS, DFS, or OS. Although further studies are needed, the excellent long-term outcomes demonstrated in patients with close (≤u20092xa0mm) margins following NAC suggest that a margin of “no-ink-on-tumor” may be acceptable in appropriately selected patients.

Implementation of a Venous Thromboembolism Prophylaxis Protocol Using the Caprini Risk Assessment Model in Patients Undergoing Mastectomy

BackgroundGuidelines for venous thromboembolism (VTE) prophylaxis are not well-established for breast surgery patients. An individualized VTE prophylaxis protocol using the Caprini score was adopted at our institution for patients undergoing mastectomyu2009±u2009implant-based reconstruction. In this study, we report our experience during the first year of implementation.MethodsIn August 2016, we adopted a VTE prophylaxis protocol for patients undergoing mastectomyu2009±u2009implant-based reconstruction. We used the Caprini score, a validated risk assessment tool for VTE, to determine each patient’s perioperative prophylaxis regimen. Detailed chart review was performed to record patient and treatment details, the Caprini score, pharmacologic VTE prophylaxis administration, and 30-day incidence of VTE and bleeding complications. We performed univariate analysis to identify factors associated with protocol compliance.ResultsOverall, 522 patients met the inclusion criteria. Median age was 51xa0years, 486 (93.1%) patients had malignancy, 234 (44.8%) underwent bilateral mastectomy, and 350 (67.0%) underwent reconstruction. Caprini scores ranged from 2 to 11, with 431 (82.6%) patients having a score from 5 to 7. Overall protocol compliance was 60.5%, and was associated with bilateral mastectomy (pu2009=u20090.02), reconstruction (pu2009=u20090.03), and longer procedures (pu2009<u20090.001). The rate of VTE was 0.2% (95% confidence interval [CI] 0.03–1.1%), rate of reoperation for hematoma was 2.7% (95% CI 1.6–4.5%), and rate of blood transfusion was 0.4% (95% CI 0.1–1.4%).ConclusionsThe implementation of an individualized VTE prophylaxis protocol for patients undergoing mastectomyu2009±u2009implant-based reconstruction is safe and feasible. Despite a high-risk cohort, the incidence of VTE was very low and bleeding complications were consistent with reported rates for breast surgery. Continued evaluation of this strategy is warranted.

Abstract 4950: The emergence of ESR1 mutations is associated with aromatase inhibitor and fulvestrant therapy

Introduction: In recent studies, constitutively active recurrent ESR1 ligand binding mutations (LBD) were found in about 20% of metastatic (met) HR+ breast cancers ( BRCAs) and rarely in primary HR+ cancers. In our previous work, we analyzed clinical tissue samples and detected an association between the number of prior endocrine treatments and the prevalence of these mutations, suggesting the emergence of the ESR1 mutations under the selective pressure of endocrine treatment. More recently, the LBD ESR1 mutations were successfully detected in plasma cell free (cf)DNA in patients with met HR+ disease. The presence of mutant ESR1 cfDNA was found to be prognostic. Here we sought to study the association between endocrine treatments in the adjuvant (adj) and met settings and the prevalence of cfDNA ESR1 and PIK3CA mutations in patients with met HR+ BRCA. Methods: Plasma samples and detailed clinical data were collected from patients with met BRCA through the Collection of Specimens and Clinical Data program of the Breast Oncology Center at the Dana Farber Cancer Institute. Droplet Digital PCR was used for the detection of the most common ESR1 LBD mutations (E380Q, Y537C, Y537N, Y537S and D538G) and the 3 most common PIK3CA mutations (E542K, E545K and H1047R) in cfDNA. Fisher’s Exact Test was used for statistical analysis. Results: Plasma samples were collected from 155 patients with met BRCA. ESR1 mutations were found in 30.1% of the patients with HR+/HER2- negative disease (34/113). PIK3CA mutations were detected in 31.8% of patients with HR+/HER2- disease. The majority of the patients had either newly diagnosed met disease or progressive met disease at the time of the blood draw. 14 patients had stable met disease and among these patients, only 1 of these patients was found to have an ESR1 mutation and no PIK3CA mutations were detected. The majority of patients with ESR1 mutations (88%) and PIK3CA mutations (75%) had progressive disease. Patients that received an aromatase inhibitor (AI) either in the adj or met setting had a higher prevalence of ESR1 mutations compared to patients that had no AI treatment, regardless of whether or not they received tamoxifen (TAM) (prevalence was 32% for adj AI only, 40.4% AI in met only, No AI and no TAM 7.1% and TAM but no AI 6.7%). In addition fulvestrant treatment in the met setting was significantly associated with ESR1 mutations (odds ratio 3.38, p-value Conclusions: Analysis of cfDNA can successfully detect ESR1 and PIK3CA mutations in newly diagnosed or progressive met BRCA patients and the emergence of the ESR1 mutations is associated with AI and fulvestrant treatment. These results support the serial monitoring of ESR1 mutations in cfDNA in met disease and highlight the need to study new agents to target these mutations. Citation Format: Yanan Kuang, Bilal Siddiqui, Jiani Hu, William T. Barry, Nancy U. Lin, Nikhil Wagle, Paul Kirschmeier, Pasi A. Janne, Cloud Paweletz, Ian Krop, Eric P. Winer, Myles Brown, Rinath Jeselsohn. The emergence of ESR1 mutations is associated with aromatase inhibitor and fulvestrant therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4950. doi:10.1158/1538-7445.AM2017-4950