Pathogenic mutations in ethnic Lebanese Arab patients with high risk for hereditary breast cancer

Background: Breast cancer accounts for 35-40% of cancer in women in Lebanese and Arab countries with 50% of patients (pts) diagnosed before age 50. Prevalence of pathogenic BRCA variants in high-risk pts is 5.6-20% (Abulkhair and El Saghir 2021). 7 BRCA1 and 7 BRCA2 pathogenic variants were found in 5.6% of 250 pts with high hereditary risk breast cancer using amplicon sequencing and MLPA (El Saghir 2015;Poulet 2016). We report results of Next Generation Sequencing (NGS) on selected cases based on Manchester Score. First report in ethnic Lebanese Arab pts. Method(s): Pts prospectively enrolled in 2009-2012. IRB approval secured. Pts signed informed consent. Data collected from medical records. Amplicon and MLPA was done on 250 patients. NGS was done on 100 cases with Manchester Score 14-56. DNAs of the 14 pts previously found to have a pathogenic variant (Manchester Score 10-59) were not re-sequenced. NGS on remaining 150 pts was not done due to Covid-19 pandemic and lack of additional funding. Result(s): NGS showed 7 pathogenic variants, 4 in PALB2 and 3 in ATM. No new BRCA variants were found. Two BRCA2 mutations noted by Amplicon/MLPA reported as VUS in 2015 are reclassified as pathogenic. Total BRCA2 pathogenic variants becomes 9. Total pathogenic variants 23. Risk of having hereditary breast cancer in pts with MS 10-59 is 20% (23/ 114), and at least 9.2% in the entire cohort (23/250). Age <=40 with family history (FH) carries 18.9% risk of harboring a pathogenic mutation while no FH, 1.4% (Table 1). All BRCA1 pts had triple negative and 7/9 BRCA2 pts had hormone receptor positive breast cancer. 4 unrelated pts shared the same c.1056_1057delGA PALB2 pathogenic variant thus we suggest this is a founder mutation in Lebanese Ethnic Arab population. Conclusion(s): Mutation rates in high hereditary risk pts with Manchester Score range 10-59 is 20%. Age <=40 with positive FH can be used to select pts for testing when resources are limited. Our data suggests that c.1056_1057delGA is a PALB2 founder mutation. No conflict of interest.Copyright © 2022 Elsevier Ltd. All rights reserved

Accelerated Partial Breast Irradiation (APBI) Using Five Daily Fractions: A Prospective, Phase II, Multi-Center Trial of Cosmetic Outcomes and Toxicity: Final Results

To report final results of a clinical trial of APBI using intensity modulated radiotherapy (IMRT) to deliver 27 Gy in 5 daily fractions following breast conserving surgery (BCS) prospectively designed to assess the efficacy and cosmetic outcomes of a 1-week, APBI regimen among women with early breast cancer. Women ≥ 50 years, with lymph node-negative, ER positive, HER-2 negative breast cancer or ductal carcinoma in situ (DCIS), ≤ 3cm diameter, following BCS with margins ≥ 2mm, and excellent or good baseline cosmesis received 27 Gy in 5 daily fractions to the seroma plus 1 cm CTV and 0.7 cm PTV margins. Clinical photographs, patient and provider cosmetic scores, breast fibrosis, telangiectasia and pain were collected prospectively, prior to RT and at 6 weeks, 1 and 2 years after RT. The primary endpoint was the proportion of women who retained Excellent or Good cosmesis at 2 years using the EORTC Cosmetic Rating System. Cosmetic failure was deterioration from Excellent or Good to Fair or Poor. A panel of 5 radiation oncologists independently assessed the cosmetic photographs. Secondary endpoints were rates and grades of breast fibrosis, telangiectasia, breast pain, ipsilateral breast tumor recurrence (IBRT), overall (OS), breast cancer-specific survival (BCSS) and subsequent mastectomy. Efficacy outcomes were assessed at clinic visits and by review of charts. ClinicalTrials.gov registration: NCT02681107. A total of 298 patients were treated between April 25, 2016, and October 31, 2019. At a median follow up of 48 months, the 4-year OS was 98.5% (95% CI 96.1% - 99.5%) and BCSS was 99.7% (95% CI 97.6% - 99.9%). The 4-year IBRT rate was 3.3% (95% CI 1.1% - 6.4%). There were 10 contralateral breast events for a 4-year rate of 3.9% (95% CI 2.2% - 6.9%). There were 10 ipsilateral and 6 contralateral mastectomies. Two patients died of unrelated causes prior to 2 years;79 patients declined in-clinic attendance due to COVID or competing comorbidities and 217 women had 2-year cosmetic photographs and clinical assessments performed. Consensus of the photo-panel cosmesis at baseline was: Excellent: n=116 (53%), Good: n=102 (47%), Fair: n=1 (0.5%) and Poor: n=0. Consensus overall cosmesis at 2 years was: Excellent: n= 141 (65%), Good: n=78 (35%), Fair: n=0 and Poor: n=0. Most patients had either improved (n=168;77%) or no change (n=43;20%) in cosmesis at 2-years. No patient had cosmetic failure but 6 (3%) had a change from Excellent to Good at 2 years. Most patients reported either no (79%) or mild (21%) pain, with no moderate or severe pain. Two patients (0.9%) had grade 2 fibrosis and 5 patients (2%) had visible telangiectasia that did not detract from overall cosmesis. APBI using 27 Gy in 5 fractions using a conformal IMRT technique, achieved excellent 2-year cosmesis with minimal toxicity. The IBRT risk was comparable to the contralateral new breast cancer risk and to local recurrence rates of recently published early breast cancer trials. [ FROM AUTHOR] Copyright of International Journal of Radiation Oncology, Biology, Physics is the property of Pergamon Press - An Imprint of Elsevier Science and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full . (Copyright applies to all s.)

Immunogenicity of SARS-CoV-2 vaccines in patients with breast cancer.

Purpose: To explore the immunogenicity of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccines in patients with breast cancer based on type of anticancer treatment. Methods: Patients with breast cancer had anti-spike antibody concentrations measured ⩾14 days after receiving a full SARS-CoV-2 vaccination series. The primary endpoint was IgA/G/M anti-spike antibody concentration. Multiple regression analysis was used to analyze log10-transformed antibody titer concentrations. Results: Between 29 April and 20 July 2021, 233 patients with breast cancer were enrolled, of whom 212 were eligible for the current analysis. Patients who received mRNA-1273 (Moderna) had the highest antibody concentrations [geometric mean concentration (GMC) in log10: 3.0 U/mL], compared to patients who received BNT162b2 (Pfizer) (GMC: 2.6 U/mL) (multiple regression adjusted p = 0.013) and Ad26.COV2.S (Johnson & Johnson/Janssen) (GMC: 2.6 U/mL) (p = 0.071). Patients receiving cytotoxic therapy had a significantly lower antibody titer GMC (2.5 U/mL) compared to patients on no therapy or endocrine therapy alone (3.0 U/mL) (p = 0.005). Patients on targeted therapies (GMC: 2.7 U/mL) also had a numerically lower GMC compared to patients not receiving therapy/on endocrine therapy alone, although this result was not significant (p = 0.364). Among patients who received an additional dose of vaccine (n = 31), 28 demonstrated an increased antibody response that ranged from 0.2 to >4.4 U/ mL. Conclusion: Most patients with breast cancer generate detectable anti-spike antibodies following SARS-CoV-2 vaccination, though systemic treatments and vaccine type impact level of response. Further studies are needed to better understand the clinical implications of different antibody levels, the effectiveness of additional SARS-CoV-2 vaccine doses, and the risk of breakthrough infections among patients with breast cancer.

Predictors of adherence to oral endocrine therapy in racial and ethnic minority patients with low socioeconomic status before and during the COVID-19 pandemic

Introduction: Medication adherence is important in ensuring the maximum effect of oral endocrine therapy (OET) in hormone receptor-positive breast cancer (HR+ BC) patients. Low medication adherence is more seen in racial and ethnic minority patients of lower socioeconomic status. COVID-19 pandemic has further introduced complexities that have impacted patients' medication-use behaviors. Our goal was to (1) assess the medication adherence to OET in racial and ethnic minority patients of lower socioeconomic status with HR+ BC and (2) assess the impact of the COVID-19 pandemic on their OET adherence. Patients and Methods: A retrospective, single-center study from September 2019 through September 2020 was conducted. The primary endpoint was adherence rate during the 6 months prior (September 2019-February 2020) and 6 months after (April 2020-September 2020) the COVID-19 pandemic started in the United States. The following three racial/ethnic groups were compared: Non-Hispanic White/Caucasian, Black/African American, and Hispanic/Latino. Chi-Square and Student's t-tests were used to compare the adherent and nonadherent groups. The secondary endpoint was to identify predictors of nonadherence to OET. Multivariable logistic regression model was used to assess predictors of S nonadherence. Results: Out of 270 patients, a total of 251 patients had a refill for an OET before COVID-19 with a mean proportion of days covered (PDC) of 0.72%. Of these, 140 (55.78%) were adherent and 111 (44.22%) were nonadherent. A total of 194 patients had a refill for an OET during COVID-19 with a mean PDC of 0.67%. Of these, 83 (42.78%) were adherent and 111 (57.22%) were nonadherent. A total of 187 patients had a refill for OET before and during the COVID-19 pandemic. There was a significant difference in the adherence before and during the pandemic when PDC was used as a continuous (p <0.0001, Student's paired t-test) or a categorical variable (p <0.0001, McNemar chi-square test). In a multivariate analysis of data before the pandemic, Black/African American and White/Caucasian were less likely to be adherent compared to Hispanic/Latino (Black/African American: odds ratio [OR], 0.36;95% confidence interval [CI], 0.18-0.723;White/Caucasian: OR, 0.25;95% CI, 0.074-0.853). Patients with diabetes mellitus (DM) were more likely to be adherent compared to patients without DM (OR, 2.364;95% CI, 1.199-4.662), and patients with hypertension (HTN) were less likely to be adherent compared to patients without HTN (OR, 0.481;95% CI, 0.236-0.981). Patients who were prescribed aromatase inhibitors were more likely to be adherent compared to patients that were prescribed tamoxifen (OR, 0.484;95% CI, 0.235-0.998). Patients diagnosed with invasive BC (stages 1-4) were more likely to be adherent compared to those diagnosed with non-invasive (in situ) tumors or ductal/lobular hyperplasia. During the pandemic, patients who used home delivery were more likely to be adherent compared to those who did not use home delivery (OR, 11.574;95% CI, 2.45-54.55). There was no significant difference in the proportion of patients using home delivery between different racial and ethnic groups. Conclusion: OET adherence was reduced during the COVID-19 pandemic in racial and ethnic minority patients with low socioeconomic status. Tamoxifen therapy, Black/African American, and White/Caucasian origin, not having DM, having HTN, and diagnosed with non-invasive BC were associated with OET nonadherence in patients before the COVID-19 pandemic. Whereas, not using home delivery for OET medications predicted nonadherence in patients during the COVID-19 pandemic.

Using Oncotype DX Breast Recurrence Score® (RS) assay to define the role of neoadjuvant endocrine therapy (NET) in early-stage hormone receptor positive (HR+) breast cancer (BC)

Background: Adjuvant endocrine therapy remains the standard of care for patients (pts) with early stage, HR+ BC who can safely omit chemotherapy based on RS results;however, the role of NET remains unclear. There are limited data regarding the optimal duration of treatment with NET and the ideal patient (pt) population for NET in terms of age and RS result. This question rose to critical importance amidst the COVID-19 pandemic, during which NET was utilized more broadly in attempts to delay surgery or chemotherapy while preserving optimal pt outcomes. This study re-examines the use of NET among a cohort of pts with HR+ BC randomized to NET or neoadjuvant chemotherapy (NCT) based on RS (performed on initial core biopsy specimens). Methods:Data were pooled from two independent studies performed at Emory's Winship Cancer Institute and Massey Cancer Center at Virginia Commonwealth University (VCU) from 2010-2012. These studies evaluated rates of clinical and pathologic complete response (pCR) among pts with early stage, HR+ BC assigned to treatment groups based on RS results. Pts with RS 0-10 received NET (Group (Grp) A), RS 11-24/25 (Emory 11-24 vs VCU 11-25) were randomized to NET (Grp B) or NCT (Grp SC), and those with RS 25/26-100 received NCT (Grp D). Associations between RS result, neoadjuvant therapy and pCR in the breast, lymph nodes (LN) and breast plus LN were evaluated using Fisher's exact test. Results:109 pts were included in this analysis. The Emory cohort was younger (median age 56 years (yrs) vs 63 yrs in VCU cohort) and more diverse (37.5% African American (AA) vs 18.6% AA in VCU cohort). The pts were predominantly post-menopausal (69.6% Emory vs 83.1% VCU). Nodal status among the Emory cohort was evenly divided with 50% N0 and 50% N+, while the majority of VCU pts were N0 (76.3% N0 vs 22.0% N+). Pts were grouped based on RS result: RS <11 (18% Emory vs 20.3% VCU), RS 11-24/25 (36% Emory vs 55.9% VCU) and RS 24/25 or higher (46% Emory vs 23.7% VCU). Pts with low RS result were older (median 64 yrs vs 59 yrs among RS > 24/25) with higher percentage of low-grade tumors (47.6% grade 1 vs 5.4% grade 1 among RS >24/25). With regard to pCR, there were no significant differences among pts with low or intermediate RS results, as no pts in these groups achieved pCR in the breast or breast + LN (Table). Pts with RS result 25/26-100 (Grp D) were the only pts shown to achieve pCR in breast + LN (18.9%, p= 0.0043 across groups). Notably, while pts on the Emory study received longer courses of NET (median 10 months vs 5.5 months), there were no significant differences in pCR across RS result subgroups noted between the two institutions. Conclusion:Our results demonstrate that the use of Oncotype DX Breast Recurrence Score® or other genomic assays in the neoadjuvant setting may help guide treatment decisions when considering the use of NET versus NCT. Pt age and length of endocrine therapy as well as pt preferences should be considered when determining neoadjuvant treatment plans. There are currently ongoing studies evaluating the use of NET with CDK4/6 inhibitors that will offer further insight into optimal neoadjuvant treatment strategies in HR+ BC. Subsequent phase III evaluation of the role of genomic assays in the neoadjuvant setting is feasible and may help determine whether NET + CDK 4/6 inhibitors could replace NCT for pts with higher RS values.

Adjuvant decision making in the era of limited nodal information

The increasing use of pre-operative systemic therapy has resulted in more limited information about axillary lymph node status, both from the impact of systemic therapy itself as well as from less extensive axillary surgery. Decisions about the use of adjuvant endocrine therapy have not been majorly affected, but information on the presence and number of involved lymph nodes can have a significant influence on the use of adjuvant chemotherapy and HER-2 targeted therapies. In addition, lymph node information can also impact decisions around radiation therapy, making multidisciplinary discussions highly relevant when planning therapy. Patients with hormone receptor positive breast cancer may be treated with pre-operative endocrine therapy. This strategy was often used in early stage breast cancer during the COVID pandemic due to delays in surgery. Although an effective approach, pre-operative endocrine therapy may impact nodal status at surgery, information which is important when deciding on the use of OncotypeDX testing in premenopausal women. Similarly, in postmenopausal women, the presence and number of lymph nodes involved is a critical factor in determining the appropriateness of OncotypeDx testing. This nodal information may be lost in the setting of pre-operative therapy and would alter decisions regarding adjuvant chemotherapy. For patients with HER2 positive breast cancer, the presence of nodal disease remains critical for adjuvant decision making. In the situation of small (up to 3 cm) node negative cancers, up front surgery is preferred, because pathologic confirmation of the tumor size and node negative status may make patients eligible for a de-escalated approach of adjuvant paclitaxel and trastuzumab. Patients with more advanced HER2 positive disease are good candidates for preoperative chemotherapy and HER2 targeted therapy. If they have residual disease at surgery, they can be offered trastuzumab emtansine, which was shown in the KATHERINE trial to improve outcomes. In both situations, accurate information about the presence of disease in the axillary lymph nodes determines the most effective treatment approach. Finally, accurate information about nodal status is also relevant to decisions in patients with triple negative breast cancer. Patients who are treated with pre-operative chemotherapy and have residual disease in either the breast or axillary lymph nodes may be offered adjuvant capecitabine, based on the CREATE-X study, which indicated improved survival outcomes in those patients with residual disease who received adjuvant capecitabine. As in HER2 positive breast cancer, the presence of residual disease (including in the lymph nodes) after preoperative therapy will influence the adjuvant therapy recommendation. Thus, when considering de-escalation approaches in axillary management, the impact on systemic therapy decision making must be carefully considered, as these additional adjuvant therapies may improve survival for patients. Conflict of Interest: No significant relationships.

Bridging Endocrine Therapy for HR+/HER2- Resectable Breast Cancer: Is it Safe?

BACKGROUND: The COVID-19 pandemic has required new treatment paradigms to limit exposures and optimize hospital resources, including the use of neoadjuvant endocrine therapy (NAET) as bridging therapy for HR+/HER2-invasive tumors and DCIS. While this approach has been used in locally advanced disease, it is unclear how it may affect outcomes in resectable HR+/HER2- tumors. METHODS: Women ≥18 years diagnosed with in situ (Tis) or non-metastatic HR+/HER2- breast cancer from March-May 2019 and 2020 were included. Fisher's exact test and two-sample t test were used to compare baseline characteristics and surgical outcomes between strata. Sub-analysis was performed between patients who received primary surgery vs a bridging NAET approach. RESULTS: Despite similar clinical characteristics, patients in 2019 were more likely to have a surgery-first approach (75% vs 42%, P-value = .0007), receive surgery sooner (22 vs 29 days, P-value < .001), and within 60 days from diagnosis date (100% vs 85%, P-value = .0301). Neoadjuvant endocrine therapy was a more prevalent approach in 2020 (48% vs 7%, P-value < .0001). Rates of clinical to pathologic up-staging remained consistent across primary surgery vs bridging NAET subgroups (P-value = .9253). DISCUSSION: Pandemic-driven treatment protocols provide a unique opportunity to assess the utility of bridging endocrine therapy for resectable HR+/HER2- tumors. Differences in clinical and pathologic staging were similar across groups and did not appear to be affected by receipt of NAET. Our limited cohort demonstrates this strategic therapeutic avenue can optimize health care utilization and may be a reasonable approach when delaying surgery is preferred.