Pertuzumab

Background: Approval to pertuzumab as part of a complete treatment regimen for patients with early stage breast cancer (EBC) before surgery (neoadjuvant setting) was granted by the FDA in September 2013. Since then, the relevance of neoadjuvant treatment in Her2 overexpressing breast cancer has increased considerably. This for instance has been emphasized by the results of the Neosphere Study, in which dual blockade of Her2 was combined with docetaxel as chemotherapy backbone and resulted in favorable pCR rates. But it is likely, that anthracyclines could play an important role in enhancing the effectiveness of the above mentioned treatment. However, there is only little data about the cardiac safety of this combination. The use of liposomal doxorubicin might be a valuable alternative with low cardiotoxicity, as it has been shown in comparable publications without the use of pertuzumab. Therefore we report pCR-rate and cardiac safety of a single arm, retrospective, multicenter analysis of neoadjuvant treatment for Her2 positive EBC with liposomal doxorubicin, docetaxel, trastuzumab and pertuzumab. Methods: In this study 42 women with Her2 positive EBC were investigated in 4 oncological departments in Austria. 41 patients were treated with liposomal doxorubicin (50 mg/m2), docetaxel (75 mg/m2) concurrent with trastuzumab and pertuzumab in standard dosage for 6 cycles as neoadjuvant therapy. One patient refused to receive a chemotherapy but agreed to be treated with combined antibody therapy alone. All patients were free of cardiovascular disease and had a left ventricular ejection fraction (LVEF) of ≥ 50%. Cardiac function was measured by LVEF and was examined at regular intervals (cycles 0-3, cycle 6, FU). Clinical response was evaluated by diagnostic breast imaging after cycles 3 and 6. All patients underwent surgery after neoadjuvant chemotherapy. The absence of any residual invasive cancer in the breast and axilla was defined as pathological complete response (pCR). Median follow up was 1.3 years. Results: Median age of the patients was 49 years. After 6 cycles of treatment the pCR rate was 76.2%. In this cohort a negative estrogen-and/or progesteron receptor was predictive for pCR (p<0.001). These patients achieved pCR in 95.2%. The antibody only treatment in one case also resulted in a pCR. No patient progressed during treatment. Only one of the patients (2,4%) suffered symptomatic heart failure after surgery. The patient initially presented with an LVEF of 16%. Conclusions: In this multicenter analysis we observed a considerably high rate of pCR in HER2-positive EBC treated with liposomal doxorubicin, docetaxel, trastuzumab and pertuzumab. Especially the group of hormone receptor negative patients showed a remarkable response rate. The addition of liposomal doxorubicin entails a very favorable cardiotoxicity profile. This regimen is a safe treatment option in patients with HER-2 positive breast cancer. Citation Format: Egle D, Hubalek M, Hager C, Poyßl C, Lang A, Jäger T, Volgger B, Abdel-Azim S, Tiechl J, Angerer J, Marth C. Efficacy and cardiac safety in neoadjuvant treatment of Her2 positive breast cancer with concomitant nonpegylated liposomal doxorubicin, docetaxel and dual blockade with trastuzumab and pertuzumab: A retrospective analysis. [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 P4-14-11.

5-year analysis of neoadjuvant pertuzumab and trastuzumab in patients with locally advanced, inflammatory, or early-stage HER2-positive breast cancer (NeoSphere): a multicentre, open-label, phase 2 randomised trial

Background: Women undergoing treatment for breast cancer experience both disease- and treatment-related symptoms. Remote symptom management programs allow real time symptom documentation, earlier intervention, and opportunities to improve quality of life and decrease symptom burden. This study describes patient-reported outcomes (PROs) in women undergoing treatment for early stage and metastatic breast cancer. Methods: Women with breast cancer using Carevive’s remote symptom management (RSM) program completed weekly surveys to assess the presence of 14 common symptoms over 16 weeks. Symptoms assessed were anxiety, decreased appetite, fatigue, general pain, mouth sores, muscle pain, nausea, vomiting, numbness, sadness, shortness of breath, diarrhea, constipation, and insomnia. When a symptom was reported, additional questions were asked regarding symptom severity, frequency, and interference using the National Cancer Society’s Patient Reported Outcomes-Common Terminology Criteria for Adverse Events (PRO-CTCAE). The PRO-CTCAE produced composite scores, which classified each symptom reporting event as mild, moderate-severe, or severe. A mild symptom classification generates an electronic care plan with recommendations for symptom management; moderate-severe and severe classifications trigger an alert to the care team. Descriptive analyses summarize PROs for early stage and metastatic patients. Symptom burden was assessed by calculating the frequency distribution of each patient’s highest reported composite score for each symptom by month (Table 1). Results: Between September 2020 and April 2022, 280 women enrolled in the RSM program; 201 of these women had complete staging information for analysis. 80% (n=160) had early stage (0-III) and 20% (n=41) had metastatic (IV) disease. 32% (n=64) were less than 50 years old and 68% (n=137) were age 50 or older. 58% (n=116) were hormone receptor (HR) positive/HER2 negative, 22% (n=45) HR+ or -/HER2+ and 19% (n=39) HR-/HER2-. In Month 1, patients with metastatic disease most frequently reported moderate to severe symptoms for general pain (51%), nausea (32%), decreased appetite (22%), and diarrhea (29%). In Month 1, patients with early stage disease most frequently reported moderate to severe symptoms for general pain (32%) and diarrhea (28%). In Month 1, general pain was the most frequently reported symptom for both early stage (34%) and metastatic (51%) groups. In both groups over 16 weeks, nausea, diarrhea, and constipation were among the five most reported symptoms along with muscle pain for early stage patients and shortness of breath for metastatic patients. The frequency of all symptoms decreased over 16 weeks, but there remained cases of moderate-severe and severe symptom intensity through Week 16 for several symptoms. Conclusion: Women with metastatic and early stage breast cancer both report severe symptoms during treatment. Early stage patients may have different symptom profiles and unmet needs not captured by common PROs. Future work should further evaluate symptom profiles of early stage patients to understand how to best use PRO monitoring in the curative intent setting. Percentage of Moderate-Severe and Severe Symptom Reports By Month and Symptom for Women with Early Stage and Metastatic Breast Cancer MO=Month Citation Format: Tara Kaufmann, Aaron Galaznik, Nicholas Coombs, Gabrielle B. Rocque. Patient-Reported Symptom Burden in Women Undergoing Treatment for Early Stage and Metastatic Breast Cancer [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P5-07-12.

ABSTRACTIntroduction: Despite the advances in the treatment of HER2-positive breast cancer, resistance to actual chemotherapeutic regimens eventually occurs. Neratinib, an orally available pan-inhibitor of the ERBB family, represents an interesting new option for early-stage HER2-positive breast cancer.Areas covered: In this article, the development of neratinib, with a special focus on its potential value in the treatment of early-stage HER2-positive breast cancer, has been reviewed. For this purpose, a literature search was conducted, including preclinical studies, early-phase trials in advanced cancer with neratinib in monotherapy and in combination, and phase II and large phase III trials in the early setting. Management of neratinib-induced toxicity, future perspectives for the drug, and ongoing trials are also discussed in this review.Expert commentary: Neratinib is emerging as a promising oral drug for the treatment of HER2-positive breast cancer. Although FDA and EMA approval is derived from the extended adjuvant treatment, this setting may not be the ideal scenario to obtain the beneficial effects of neratinib. Confirmatory data in the neoadjuvant setting and subgroup analysis from the ExTENET trial might bring some light into the best setting for neratinib therapy. Data from confirmatory trials in the metastatic setting are also required.

Exemestane (Aromasin) is an orally active steroidal irreversible inactivator of the aromatase enzyme indicated as an adjuvant treatment in postmenopausal women with estrogen receptor-positive early-stage breast cancer following 2-3 years of adjuvant treatment with tamoxifen, and for the treatment of advanced breast cancer in postmenopausal women whose disease has progressed following tamoxifen or other antiestrogen therapy. Exemestane is effective for the treatment of postmenopausal women with early-stage or advanced breast cancer. In early-stage disease, switching to exemestane for 2-3 years after 2-3 years of adjuvant tamoxifen treatment was more effective in prolonging disease-free survival than continuing tamoxifen therapy, although it was not associated with an overall survival benefit, except in those with estrogen receptor-positive or unknown receptor status disease when nodal status, hormone replacement therapy (HRT) and chemotherapy use were adjusted for. Moreover, preliminary data suggest that the efficacy of exemestane is generally no different to that of tamoxifen in the primary adjuvant treatment of early-stage breast cancer, although exemestane may be better in prolonging the time to distant recurrence. In advanced disease, exemestane showed equivalent efficacy to megestrol in patients with disease refractory to tamoxifen and an efficacy not significantly different from that of fulvestrant in those refractory to a nonsteroidal aromatase inhibitor. Available data, some of which are limited, suggest exemestane is also effective in the first-line hormonal treatment of advanced breast cancer in postmenopausal women. Exemestane is generally well tolerated, although the potential bone fracture risk of the drug requires further investigation. Results from directly comparative trials indicating the efficacy, tolerability and bone fracture risk of exemestane relative to third-generation aromatase inhibitors and other agents in both early-stage and advanced disease, as well as the optimal sequence of endocrine therapies, are awaited with interest. In the meantime, switching to exemestane should be considered in postmenopausal women who have received 2-3 years of adjuvant tamoxifen treatment for early-stage breast cancer, and is an emerging treatment option for postmenopausal women with advanced breast cancer refractory to one or more antiestrogen therapies.

524 Background: One year of adjuvant trastuzumab in combination with chemotherapy is the standard of care in early-stage HER2 positive breast cancer. Existing data on shortening trastuzumab treatment show conflicting results. Methods: A search of PubMed and conferences identified randomized trials that compared abbreviated trastuzumab therapy to one year of treatment in early-stage HER2 positive breast cancer. Hazard ratios (HRs) and 95% confidence intervals (CI) were extracted for disease free survival (DFS) and overall survival (OS). Data on the number of DFS and distant relapse events were also collected as were the number of patients at risk in each group. Subgroup analyses evaluated the effect of nodal involvement, estrogen receptor (ER) expression and the duration of abbreviated trastuzumab (9-12 weeks versus 6 months). Odds ratios (ORs) and 95% CI were computed for pre-specified cardiotoxicity events including cardiac dysfunction and congestive heart failure (CHF). Results: Analysis included 6 trials comprising 11603 patients. In most studies adjuvant chemotherapy included anthracyclines and taxanes. Shorter trastuzumab treatment was associated with worse DFS (HR = 1.14, 95% CI 1.05-1.25, p = 0.002) and OS (HR = 1.15, 95% CI 1.02-1.29. p = 0.02). The effect on DFS was not influenced by ER status (p for the subgroup difference = 0.23), nodal involvement (p = 0.44) or the different duration of trastuzumab in the experimental arm (p = 0.08). In absolute terms, after an estimated median follow-up of 71 months, shorter treatment with trastuzumab was associated with an absolute increase in DFS events of 2.3%. Shorter trastuzumab treatment was associated with lower odds of cardiac dysfunction (OR = 0.67, 95% CI 0.55-0.81, p < 0.001) and CHF (OR = 0.66, 95% CI 0.50-0.86, p = 0.003). Conclusions: Compared to one year, shorter duration of adjuvant trastuzumab is associated with significantly worse DFS and OS, despite favorable cardiotoxicity profile. One year of trastuzumab should remain the standard adjuvant treatment in early-stage HER2 positive breast cancer with appropriate cardiac monitoring.

Background: Neoadjuvant pertuzumab (P)+trastuzumab (H)+standard chemotherapy (CT) significantly increases pathologic complete response (pCR) rates v H+CT. However, anti-HER2 therapy following anthracyclines can cause heart failure, and data are limited or lacking on combining P+H after epirubicin or doxorubicin. We report cardiac and overall safety as well as total pCR (tpCR) rates with widely used but understudied anthracycline-containing regimens. Methods: BERENICE (NCT02132949), a non-randomized, open-label, phase II study, enrolled patients (pts) with centrally confirmed HER2-positive, locally advanced, inflammatory, or early-stage, unilateral, and invasive breast cancer, Eastern Cooperative Oncology Group performance status ≤1, and baseline left ventricular ejection fraction (LVEF) ≥55%. In the neoadjuvant period, Cohort A pts received four q2w dose-dense doxorubicin+cyclophosphamide cycles (60 mg/m2/600 mg/m2 with granulocyte-colony stimulating factor support as needed) followed by 12 qw paclitaxel doses (80 mg/m2) + four q3w P+H cycles (P 840 mg, then 420 mg; H 8mg/kg, then 6 mg/kg). Cohort B received four q3w fluorouracil/epirubicin/cyclophosphamide cycles (500 mg/m2/100 mg/m2/600 mg/m2) followed by four q3w docetaxel cycles (75 mg/m2 escalated to 100 mg/m2) + four q3w P+H cycles. Surgery was performed after cycle 8 for both cohorts. The primary objective was to evaluate cardiac safety during the neoadjuvant period, assessed by incidence of 1) New York Heart Association (NYHA) Class III/IV heart failure and 2) significant LVEF declines (≥10% from baseline with a value of <50%). Secondary objectives included assessments of adverse event (AE) rates and tpCR (ypT0/Tis ypN0; NX was considered non-tpCR). Results are descriptive; no statistical hypothesis testing was planned. Results: Four hundred one pts were enrolled between Jul 2014–Aug 2015. Clinical cutoff was Mar 3, 2016. Demographics and baseline characteristics were generally balanced between cohorts; 64.3% v 61.7% of pts had centrally confirmed hormone receptor (HR)-positive disease and 95.0% v 93.0% had T1–T3 primary tumors. Three pts in Cohort A and none in Cohort B experienced NYHA Class III/IV heart failure during neoadjuvant treatment (table). Thirteen pts in Cohort A v four in Cohort B had significant LVEF declines (table). One Cohort B pt's LVEF decline was prior to anti-HER2 treatment. AE and serious AE (SAE) rates were well balanced between cohorts. The most common AEs were nausea, diarrhea, and alopecia. The most common SAE was febrile neutropenia. tpCR rates were similar between cohorts (table). Neoadjuvant periodCohort ACohort BSafety: Pts, n (%)N=199N=198NYHA Class III/IV heart failure3 (1.5%)0Significant LVEF decline13 (6.5%)4 (2.0%)tpCR (ypT0/Tis ypN0): Pts, n/N (%) Intention-to-treat123/199 (61.8%)122/201 (60.7%)HR-positive66/128 (51.6%)71/124 (57.3%)HR-negative53/65 (81.5%)51/75 (68.0%) Conclusion: Cardiac and general safety of the two anthracycline-containing regimens in BERENICE were as expected and were consistent with the known P+H+CT profiles. Both regimens were active, and tpCR rates were high. Citation Format: Swain SM, Ewer MS, Viale G, Delaloge S, Ferrero JM, Verrill M, Colomer R, Vieira C, Werner TL, Douthwaite H, Bradley D, Waldron-Lynch M, Eng-Wong J, Dang C. Primary analysis of BERENICE: A phase II cardiac safety study of pertuzumab, trastuzumab, and neoadjuvant anthracycline-based chemotherapy in patients with locally advanced, inflammatory, or early-stage, unilateral, and invasive HER2-positive breast cancer [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P4-21-41.

Breast cancer is the most common cancer and the second leading cause of cancer death in American women. It was the second most common cancer in the world in 2002, with more than 1 million new cases. Despite advances in early detection and the understanding of the molecular bases of breast cancer biology, about 30% of patients with early-stage breast cancer have recurrent disease. To offer more effective and less toxic treatment, selecting therapies requires considering the patient and the clinical and molecular characteristics of the tumor. Systemic treatment of breast cancer includes cytotoxic, hormonal, and immunotherapeutic agents. These medications are used in the adjuvant, neoadjuvant, and metastatic settings. In general, systemic agents are active at the beginning of therapy in 90% of primary breast cancers and 50% of metastases. However, after a variable period of time, progression occurs. At that point, resistance to therapy is not only common but expected. Herein we review general mechanisms of drug resistance, including multidrug resistance by P-glyucoprotein and the multidrug resistance protein family in association with specific agents and their metabolism, emergence of refractory tumors associated with multiple resistance mechanisms, and resistance factors unique to host-tumor-drug interactions. Important anticancer agents specific to breast cancer are described.

The role of radiation therapy in the management of primary breast cancer

Background: Scientific evidence strongly indicates that locoregional control in early-stage breast cancer (BC) by lumpectomy with radiation therapy or by mastectomy yields similar disease-free survival (DFS) and overall survival (OS). A recent retrospective review of a Danish prospective database demonstrated strong favorable interaction between radiotherapy (RT) and all BC subtypes that contain high amount of tumor infiltrating lymphocytes (TILs). Objective: We aim to compare DFS and OS in patients with early-stage HER2-positive BC, whose tumors demonstrate high involvement by TILs after locoregional treatment by either mastectomy or lumpectomy and whole breast radiotherapy. Methods: We retrospectively reviewed the charts and histopathology slides of patients with HER2-positive BC with clinical stage T1-T2 N0, who were treated in our center between January 2009 and December 2018. Locoregional management included either mastectomy (no radiation group) or lumpectomy with whole breast irradiation (radiation group). Stromal TILs were estimated using hematoxylin-eosin staining, according to the recommendations of the TILs working group 2014. This was performed by 3 independent pathologists who were blinded to the clinical course of the patients. A competing risk model, Kaplan-Meier analysis and multivariate Cox regression analysis were used to estimate correlations between TILs and clinical outcomes. Results: A total of 110 charts were reviewed and 99 were included in the final analysis. Patients were dichotomized into groups of “low-TILs” and “high-TILs” using a 40% cut off. Approximately 25% of patients (26/99) were “high-TILs” and around 50% of the “high-TILs” and “low-TILs” patients received RT. In all groups, around 90% of patients received chemotherapy and anti-HER2 therapy. All hormone receptor-positive patients received adjuvant endocrine therapy. While RT did not result in significant DFS or OS advantage in the low-TILs group, patients with high-TILs had significant improvement of DFS and OS with the addition of RT. Table 1 depict the 5-year DFS and 5-year OS in "high-TILs" and "low-TILs" groups in relation to RT, respectively. Conclusion: In this retrospective analysis, our findings indicate that in high-TILs early-stage HER2-positive BC, RT was associated with significant improvement of 5-year DFS and OS. The exact mechanism is not well understood. However, this observation is important and warrants confirmation in prospective clinical trials. 5-year DFS5-year OSHigh TILsLow TILsHigh TILsLow TILsRT group100%90%100%83%No RT group65%90%72%93%p-value0.0270.960.0250.184 Citation Format: Jason A Mouabbi, Momal Chand, Ramen Sakhi, Ishaq A Asghar, Daniel Ockner, Tarik Hadid, Carrie L Dul, Mothaffar F Rimawi, Amer Aref. Radiation therapy improves survival in early-stage HER2-positive breast cancer with high-level of tumor infiltrating lymphocytes [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS15-01.

Introduction Trastuzumab emtansine (T-DM1) is an antibody–drug conjugate comprising trastuzumab, a stable linker, and DM1 (a microtubule inhibitor). T-DM1 prolonged PFS and OS compared with standard therapy in a phase 3 study in patients with human epidermal growth factor receptor 2 (HER2)–positive metastatic breast cancer (MBC) previously treated with trastuzumab and a taxane and was well tolerated (Verma, NEJM 2012). When combined with docetaxel (D) or pertuzumab (P), T-DM1 antitumor activity was enhanced in preclinical models of HER2-positive breast cancer (Lewis-Phillips, AACR 2008; Fields, AACR 2010). The feasibility of combining T-DM1 with D±P in patients with HER2-positive MBC and early-stage breast cancer (EBC) was demonstrated in phase 1b of study BP22572, in which the maximum tolerated doses (MTDs) were defined (Martin, SABCS 2012). Here we report on patients with EBC who were treated at the MTDs in phases 1b and 2a of the study. Methods BP22572 is a phase 1b/2a open-label, multicenter study evaluating neoadjuvant T-DM1 with D±P in patients with centrally confirmed HER2-positive EBC (clinical stage IIa–IIIc) who have not received prior anticancer therapy. Patients with EBC were treated for up to 6 cycles at the doses specified in the Table. Results Recruitment into the neoadjuvant cohorts was completed in November 2012; the data cutoff date for analyses presented here was May 2, 2013. A total of 70 patients were treated with the combinations (median age, 51.5 years [range, 34–76]). Grade 3/4 adverse events (AEs) were reported for 51 (72.9%) patients; those occurring in >1 patient are shown in the Table. One patient in the T-DM1 + D 100 mg/m2 cohort experienced grade 5 pneumonitis shortly after an episode of neutropenic fever. As of the data cutoff date, all patients had received neoadjuvant treatment, but not all had undergone surgery. Pathologic complete response (pCR; ypT0/is ypN0, absence of invasive disease or in situ disease only in the breast and negative axillary nodes) was achieved in 40 of 70 treated patients (preliminary pCR rate, 57.1%). Grade 3/4 AEs occurring in >1 patientAE, n (%)All patients (N = 70)T-DM1 3.6 mg/kg + D 75 mg/m2 q3w (n = 15)T-DM1 3.6 mg/kg + D 100 mg/m2 q3w (with G-CSF) (n = 22)T-DM1 3.6 mg/kg + D 60 mg/m2 + P 840 mg LD, then 420 mg q3w (n = 11)T-DM1 3.6 mg/kg + D 75 mg/m2 + P 840 mg LD, then 420 mg q3w (with G-CSF) (n = 22)Neutropenia21 (30)7 (47)2 (9)7 (64)5 (23)Thrombocytopenia14 (20)2 (13)6 (27)—6 (27)ALT increased11 (16)3 (20)3 (14)3 (27)2 (9)Asthenia6 (9)2 (13)2 (9)1 (9)1 (5)AST increased5 (7)2 (13)1 (5)—2 (9)Lymphopenia3 (4)—2 (9)—1 (5)Mucosal inflammation3 (4)—2 (9)—1 (5)Anemia2 (3)—1 (5)—1 (5)Febrile neutropenia2 (3)—1 (5)—1 (5)Leukopenia2 (3)1 (7)—1 (9)—Diarrhea2 (3)——1 (9)1 (5) Conclusions Grade 3/4 AE profiles were consistent with the known safety profiles of the 3 agents in patients with MBC. There was 1 grade 5 event (pneumonitis) in the T-DM1 + D 100 mg/m2 cohort. Preliminary pCR data are encouraging. Final safety and efficacy data from all patients in phase 2a of the study will be available for the presentation. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P4-12-07.

BACKGROUND: HER2-positive breast cancers, which accounts for 20% of breast cancers, is associated with aggressive clinical behavior and inferior survival. The approval of HER2 targeted therapy has changed the landscape of this disease and has reduced disease recurrence by 50% and has improved survival by 33%. (1) However, cardiotoxicity is a well-recognized adverse event associated with HER2-targeted therapies. Adjuvant trastuzumab emtansine (TDM1) is the current standard of care for patients with residual breast cancer after neoadjuvant HER2-targeted therapy. TDM1 is associated with a risk of cardiotoxicity defined as a decline in left ventricular ejection fraction (LVEF). In a pooled analysis of data from seven metastatic breast cancer trials with TDM1, the incidence of cardiac events such as congestive heart failure (CHF), cardiac ischemia, cardiac arrhythmia or grade 1/2 LVEF drop was 3.37%. Adjuvant breast radiation (RT) is routinely offered for patients at high risk for recurrence. Breast RT is also associated with long-term increased risk of cardiac disease more than 10 years after RT. The HERA trial which studied use of adjuvant trastuzumab showed that rates of cardiotoxicity were higher in patients receiving concurrent RT with trastuzumab (left sided > right sided breast cancer) compared to those who did not receive adjuvant RT, although not statistically significant. In the multivariate analysis, no treatment or baseline cardiovascular risk factors were strongly correlated with LVEF, but radiation therapy showed a borderline correlation (adjusted HR, 1.258; 95% CI, 1.00-1.58; P = .049). The risk of cardiotoxicity with concurrent TDM1 and RT has not been well studied. With increasing use of TDM1 in the adjuvant setting, it is important to understand the cardiotoxic effects of combination therapy in early-stage breast cancer. METHODS: We undertook a review of our clinical database to identify patients who received adjuvant TDM1 with concurrent RT for Stage I-III breast cancer from 1/2020 to 01/2022. Clinical parameters including age, date of diagnosis, history of cardiac disorders, echocardiogram findings, radiation dose, final pathologic stage and molecular subtypes of cancer were extracted. All patients had ejection fraction to monitor cardiac fraction. Global longitudinal strain (GLS), which is a more sensitive and reproducible indicator of cardiac dysfunction than LVEF, was also collected, if available. RESULTS: Of 32 patients identified in our retrospective analysis, two patients (6%) developed a drop in ejection fraction post radiation. Median age of patients was 57y. Majority of the patients were Caucasian (44%) followed by Hispanic (28%). 19 (60%) patients had right sided breast cancers and 13(40%) patients had left sided cancers. The mean pre-radiation ejection fraction was 60% and post radiation was 61%. Using paired t-testing, there was no statically significant difference in ejection fraction after radiation (p=0.343). Comparative GLS measurements were available for 16 patients and there was no statical difference with concurrent radiation (p=0.18). All patients tolerated radiation with mostly grade 2 skin dermatitis except four patients who had grade 3 skin dermatitis. One patient had to discontinue radiation early given grade 3 skin dermatitis. CONCLUSION: This institutional review of 32 patients suggests that adjuvant TDM1 with concurrent RT did not result in a significant change in ejection fraction or GLS. Most patients tolerated radiation without significant skin toxicities. One of the limitations of the study is the small sample size. A larger study should look at more broader conclusions; however this data has strong clinical implications. Cardiac Parameters pre and post RT Citation Format: Faheem Farooq, Dillon Cason, Nisha Ohri, Shicha Kumar, Allison Grann, Anna Litvak, Shridar Ganesan, Bruce G. Haffty, Deborah Toppmeyer, Coral Omene, Mridula A. George. Evaluating the risk of cardiotoxicity associated with concurrent trastuzumab emtansine (TDM1) and radiation therapy in patients with early-stage HER2 positive breast cancer [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P5-07-08.

Objective: To develop a non-invasive diagnostic assay for breast cancer. Methods: Breast cancer patients and non-cancerous donors were recruited. Cancer or benign non-cancerous tissues and peripheral blood were collected. The study was designed to have a training group and a validation group. The training group included cancer tissue and blood samples from 6 patients with breast cancer and 34 healthy donors, and the validation group including 40 patients with breast cancer and 11 with benign breast disease. Methylation capture sequencing and exome capture sequencing with an oncology panel were performed on the tissue samples. Based on these result, a liquid phase capture assay was designed to cover coding sequences of 340 genes as well as over 1000 common SNPs and more than 2000 differentially methylated sites in breast cancer tissues. NGS was performed with cfDNA from patients with breast cancer and healthy donors. Mutation abundance measurement based on population genetic statistics, methylation haplotype analysis based on machine learning model, and Gaussian decomposition based on spatial localization of nucleosomes were developed to calculate cancer specific genetic and epigenetic features. Results: We identified a major epigenetic landscape shift of breast cancer tissues from normal tissues or benign non-cancerous hyperplasia. Breast cancer tissues processed specific methylated haplotypes those absent in benign noncancerous or normal breast tissues. Prevalent nucleosomal shifts across the genome in breast cancer were identified, suggesting possible scenario of a global epigenetic switch. Using Gaussian mixture model and non-negative matrix factorization, we found a large number of breast cancer specific nucleosome spatial localization signals carried by cfDNA. Based on the uncovered epigenetic features, we trained a machine learning computational model to identify patients with breast cancer from those with benign disease and healthy donors. The model predicts nucleosomal fraction of malignancy for breast cancer originated signal. With the model, we uncovered nucleosomal spatial distribution in cfDNA associated with tumor burden and staging. In a Her2-positive early stage breast cancer patient, the tumor specific shift of nucleosome in cfDNA on a germline pathogenic mutation of ATR became unmeasurable after treatment with trastuzumab. The model archieved 100% accuracy (6/6 positive, and 34/34 negative) in the training group consisting 6 cancer pateints, 3 of which were patients with early stage (T1) breast cancer. In the validation group, the sensitivity, specificity and accuracy were 0.810 (33/40), 1.000 (11/11) and 0.862 (44/51). Conclusions: In this study, we developed a new non-invasive diagnostic assay for breast cancer based on decomposition of nucleosome spatial distribution in cfDNA sequencing. The model showed satisfactory diagnostic sensitivity and specificity in distinguishing early stage breast cancer patients from benign, non-cancerous donor. Further large cohort evaluation is necessary to confirm their potential in clinical applications. Key Words: Breast cancer; cfDNA; cancer specific nucleosome prediction; machine learning Citation Format: Wanyan Tang, Xin Zhou, Haiwei Zhang, Chuang Ge, Huiqing Yu, Weiqi Nian, Yi Zhang. A non-invasive diagnostic assay of early stage 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 P5-01-18.

Objective: To assess psychosocial morbidity in women with breast cancer and to compare the differential rates between women with early stage and advanced disease. Method: In this report, 303 women with early stage breast cancer, psychiatrically assessed at baseline (as part of a study of cognitive-existential group therapy during adjuvant chemotherapy), are compared with 200 women with advanced breast cancer (similarly assessed in a trial of supportive-expressive group therapy). A structured psychiatric interview plus self-report measures were used to assess psychiatric morbidity, quality of life and cognitive attitude to cancer. Results: The early stage patients, whose mean age was 46 years, were on average 3 months post-surgery and had an overall prevalence of DSM-IV psychiatric diagnosis of 45%. The metastatic patients, whose mean age was 51 years, were on average 63 months post-primary diagnosis and had an overall prevalence of DSM-IV diagnosis of 42%; the difference between the two rates was not statistically significant. Of women with early stage breast cancer, 36.7% had mood disorders, 9.6% suffering from major depression and 27.1% from minor depression. In the metastatic sample 31% had mood disorders, 6.5% having major depression and 24.5% with minor depression. Anxiety disorders were present in 8.6% of the early stage group and 6% of women with advanced disease. Fatigue, a past history of depression, and cognitive attitudes of helplessness, hopelessness or resignation were significantly associated with depression in both groups. The women from the metastatic sample were significantly less distressed by hair loss but more dissatisfied with body image, and had higher rates of lymphoedema and hot flushes than the early stage women. Conclusions: The rates of psychosocial distress are high, and similar, across patients with both early and advanced stage breast cancer, although the illness related causes of distress are different. These data present a challenge to clinical services to provide a comprehensive range of support services to ameliorate this distress.

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