HER2-neu Positive Breast Cancer Research Articles

The Role of Digital Pathology in The Assessment of PD-L1 Expression in HER2-neu Positive Breast Cancer

The Role of Digital Pathology in The Assessment of PD-L1 Expression in HER2-neu Positive Breast Cancer

Trastuzumab-Related Cardiotoxicity in Adjuvant Setting: A Real-World Scenario.

Rachana Chennamaneni Trastuzumab, a humanized monoclonal antibody, significantly improves outcomes in HER 2-neu positive breast cancer. The incidence of cardiotoxicity with trastuzumab is approximately 8 to 10%. This study was designed to analyze the incidence and risk factors associated with trastuzumab-related cardiotoxicity in real-world settings. This was a single institutional retrospective analysis of the incidence of trastuzumab-related cardiotoxicity in nonmetastatic HER 2-positive, invasive breast cancer from January 2013 to December 2018. Trastuzumab-related cardiotoxicity was defined as symptomatic heart failure or asymptomatic decline in left ventricular ejection fraction (LVEF) by more than or equal to 10% or LVEF less than 50%. Risk factors analyzed were higher body mass index (≥30 kg/m 2 ), history of diabetes, hypertension, cardiac disease, left-sided radiotherapy (RT), and prior exposure to anthracyclines. Out of the 246 patients diagnosed with early stage HER 2-positive breast cancer, 117 (47.5%) received trastuzumab and constituted the study population. Trastuzumab-related cardiotoxicity was seen in a total of 16 (13.6%) patients. Eleven (9.4%) patients had an asymptomatic decline, while symptomatic LV dysfunction was seen in five (4.2%) patients. The median baseline ejection fraction was 65% (range, 56-72). The median time to development of cardiotoxicity was 18.5 weeks (range, 3-52) and the median trastuzumab cycle for cardiotoxicity was 6 (range, 2-16). Ten (62.5%) patients were rechallenged with trastuzumab following which one patient developed an asymptomatic decline in ejection fraction and one patient developed symptomatic heart failure. Cardiac-related mortality was seen in one (0.85%) patient. Left-sided RT to chest ( p = 0.012) and presence of more than or equal to two risk factors ( p = 0.01) had significant impact on incidence of cardiotoxicity. Approximately 14% developed trastuzumab-related cardiotoxicity that was slightly higher compared with that seen in clinical trials. Left-sided RT to chest and presence of two or more risk factors had significant impact on development of cardiotoxicity.

Metformin with neoadjuvant chemotherapy in localized triple negative and HER2neu-positive breast cancer: A prospective phase 2 open label randomised controlled trial (McBETH).

TPS631 Background: Repurposing of drugs in cancer is an attractive strategy and metformin has long been an agent with promising yet unproven activity in breast cancer. Despite some recent studies showing inadequate efficacy in adjuvant setting, there is a lack of well powered studies in neo-adjuvant setting in localised breast cancer. Few past studies suggest that metformin may have anticancer effects in the subsets of Her2 neu positive as well as Triple negative breast cancer (TNBC). We initiated this study to investigate if metformin in combination with standard neo-adjuvant chemotherapy is effective in improving pathological complete response rates in these subsets among localised breast cancers. Methods: This is an investigator initiated randomised, open label, parallel-group superiority trial. All non diabetic localised chemo-naïve breast cancer patients aged ≥18 years planned for neo-adjuvant chemotherapy will be randomly allocated (stratified by HER 2 positive and TNBC) to receive standard neo-adjuvant chemotherapy with or without metformin (850mg twice daily) till the day of surgery. The patients will be followed up until the surgery. The primary objective of this study is to compare the pathological complete response rates(ypT0ypN0) in each arm. The secondary objectives are to compare pathological complete response rates in predefined subsets of HER2 positive and triple negative breast cancer, clinical response rates in each arm, patient reported outcomes in each arm (ESAS-r Scale), breast conservation surgery rates in each arm, incidence and severity of adverse events in both arms. Trial statistical design: Planned accrual is total 242 patients including 10% drop out rate. It is a superiority design with an absolute improvement of 11% in pathological complete response from a baseline of 33% in the standard arm. Conduct to date: study activation: May 2022. Enrolment: 116 subjects. Clinical trial information: REF/2022/05/054208.

Incidence of trastuzumab-induced cardiotoxicity and impact of body mass index in patients with breast cancer: Results from a Saudi tertiary cancer center.

The effect of BMI as a risk factor in trastuzumab-induced cardiotoxicity in Saudi patients with HER2-neu positive breast cancer treated with trastuzumab and anthracyclines is not fully understood. The present study retrospectively evaluated the overall incidence of cardiotoxicity and the effect of BMI as a risk factor for cardiotoxicity. A retrospective study performed between 2011 and 2015 of patients with Her2-neu positive early breast cancer who were treated with either a combination of trastuzumab and anthracycline or a combination of trastuzumab with non-anthracycline or hormonal treatment in the adjuvant settings was carried out. The incidence of cardiotoxicity and the effect of BMI, hypertension and diabetes mellitus as risk factors for cardiotoxicity were assessed. Cardiotoxicity was measured using a drop in the ejection fraction of >10 percentage points to a left ventricular ejection fraction of <50%. The present cohort included 105 patients diagnosed with stage I and II breast cancer. The mean age of the present cohort was 47.5±1.0 years (range, 25-76 years), the mean height was 153.9±14.1 cm (range, 126-170 cm), the mean body weight was 75.7±15.6 kg (range, 40-143 kg) and the mean BMI was 31.3±5.8 (range, 18-49). Cardiotoxicity was detected in 21.9% of the cohort. The BMI was calculated for 81 patients who were treated with a combination of trastuzumab and anthracycline. Cardiotoxicity was detected in 3 out of 9 patients with a BMI <25, in 9 out of 23 patients with a BMI between 25 and 29, and in 6 patients with a BMI >30. There was a significant association between cardiotoxicity and BMI (P=0.03). No significant association between age, hypertension and diabetes and cardiotoxicity was identified. In conclusion, compared with global cohorts, the present results revealed a higher incidence of cardiotoxicity among Saudi patients with HER2-neu positive early breast cancer treated with trastuzumab combinations in adjuvant settings. Increased BMI was significantly associated with cardiotoxicity.

Efficacy and Safety of Lapatinib in Elderly Egyptian Patients with Her2 neu Positive Metastatic Breast Cancer

Introduction: The efficacy and safety of the lapatinib based treatment remain challenging in elderly patients with her2neu positive metastatic breast cancer (MBC). Lapatinib exhibits a good overall tolerance, but no study has yet been dedicated to elderly women. The present study is a real-world study that aimed to determine the efficacy and tolerability of the lapatinib-based treatment in the first line setting in Egyptian patients with HER2neu positive MBC who cannot get access to trastuzumab. Patients and Methods: In this retrospective study, 60 elderly patients (⩾ 65 years) with her2neu positive MBC and treatment naïve were included. All patients were treated with the combination of lapatinib (1,250 mg/day, continuously) and chemotherapy (either capecitabine 2,000 mg/m2 on days 1–14 of a 21-day cycle or weekly taxol 80 mg/m2), or lapatinib (1,250 mg/day, continuously) and hormonal treatment. Data on demographics, clinical outcome, and toxicity were collected form the patients’ medical records for descriptive analyses. Results: The median follow-up was 23.5 months (range 11–36 months). Most of the patients were hormone receptor positive (70%). About 28% of the patients had multiple sites of metastasis while 16 patients (26.7%) had bone only metastasis and 11 patients (18.3%) had lung only metastasis. Most of our patients (63.3%) had no associated comorbidities. An overall response rate of 61.7% was achieved, including 2 complete responses (3.3%), and 13 partial responses (21.7%). Median progression-free survival was 15.9 months (95% confidence interval (CI) 13.56- 18.33), and the median overall survival was 19.9 months (95% CI 17.8-21.9). Most common grade 1-2 side effects were diarrhea (43.3%), followed by hand-foot syndrome (35%), and skin rash (13.3%). Grade 3–4 toxicities were identified as hand-foot syndrome (10%), diarrhea (6.6%).There were no symptomatic cardiac events. Tolerability data show that 45% of patients needed a lapatinib dose reduction, and 30% a treatment interruption due to toxicity, while treatment discontinuation occurred in 18.3% of the cases. Conclusion: Lapatinib based therapy in elderly patients with her2neu positive MBC was effective. However, it was not well tolerated especially when combined with chemotherapy.

Changing trends in HER-2 neu positive breast cancers in women: A study by a medical student and his preceptor.

e12509 Background: Breast cancer affects 3.5 million women in the United States with 155, 000 women living with metastatic breast cancer in the US with 40,290 deaths every year. In particular, HER-2 NEU positive lesions are aggressively malignant, with increased recurrence and decreased survival but good response to Herceptin. This study reviews trends of breast cancers and looks in depth into prognostic indicators, in HER-2 NEU positive breast cancers. Methods: Anonymized medical data including demographics and tumor characteristics from San Antonio Regional Hospital’s (SARH) tumor registry database were collected from 2015-2017. Inclusion criteria included female patients with a diagnosis of invasive breast cancers. Data was stratified according to age at diagnosis, race of the patient, histologic grade, size of the tumor, lymph node status, HER-2 NEU status and stage (pathologic and clinical). Results: From 2015 to 2017 we identified 371 patients with invasive breast cancers. The percentages of HER-2 NEU positive patients in these years was 15.7%, 16.0%, and 9.4% in 2015, 2016 and 2017 respectively. This represented a 6.6% drop in HER-2 NEU positive patients from 2016 to 2017. We then looked at all HER-2 NEU positive breast cancers. In 2017, 71% of patients with HER-2 NEU positive tumors presented with a low pathologic size compared to 36% in 2016 and 44% in 2015, and 29% presented with low histologic grade compared to 14% in 2016 and 12% in 2015, and 0% of patients presented with lymph node metastases compared to 18% in 2016 and 20% in 2015. Overall 100% of patients with HER-2 NEU positive tumors presented at a low stage compared to 73% in 2016 and 52% in 2015. Conclusions: Our data shows a decrease in HER-2 NEU positive cancers from 2015 to 2017. It is important to note that these HER-2 NEU lesions were associated with, smaller pathologic size, lower histologic grade, lower incidence of lymph node involvement and lower clinical stage. The identification of this subset of low grade, low stage HER-2 NEU positive tumors may be attributed to newer imaging modalities such as digital tomosynthesis and more aggressive preventive screening measures. These sensitive screening techniques may ensure a good clinical outcome.

Abstract P6-17-04: 3-year relapse-free survival of stage II-III HER2-neu positive breast cancer treated with pertuzumab and trastuzumab-containing neoadjuvant therapy compared to trastuzumab-containing therapy

Abstract Background: Pertuzumab (P) in combination with trastuzumab (H) based chemotherapy is FDA-approved as a standard neoadjuvant treatment for patients with clinical stage II-III HER2-positive (HER2+) breast cancer (BC). The goal of this study was to evaluate the pathologic complete response (pCR) rate for neoadjuvant HP-containing regimens compared to H-containing regimens and report the 3-year relapse-free survival (RFS) for patients who had a pCR compared to those with residual disease (RD). Methods: All patients with stage II-III non-inflammatory HER2+ BC who received neoadjuvant H-containing or HP-containing therapy and underwent definitive breast and axillary surgery were identified from 2005 to 2016 through an institutional database. Medical records were examined for patient demographics, breast cancer stage, pathology results, surgical outcomes, and treatment details. pCR was defined as ypT0/is, ypN0. RFS was defined as the interval from surgery to date of last followup or death from any cause. Descriptive statistics, Cox proportional hazards, and Kaplan-Meier estimates were used for statistical analysis. Results: Patient characteristics and results by pCR or RD status are shown in the table below. The median age was 51 (22-84) years for the HP group and 50 (21-87) years for the H group. The median follow-up time was 1.9 (0-4.2) years for the HP group and 5.3 (0.1-12) years for the H group. For the HP group, the 3-year RFS was 98% (95% CI: 95, 100) for the pCR group and 90% (95% CI: 83, 97) for the RD group; HR 0.17 (0.04, 0.82), p=0.012. For the H group, the 3-year RFS was 91% (95% CI: 88,94) for the pCR group and 75% (95% CI: 71-79) for the RD group; HR 0.31 (0.22, 0.44), p&amp;lt;0.0001. Among the 520 patients who achieved pCR and the 502 patients who had RD, the effect of HP vs. H was statistically significant (pCR: HR 0.24 (0.06, 1.00); p=0.015) (no pCR: HR 0.46 (0.22, 0.94); p=0.017). Conclusion: Patients who achieve pCR have an improved 3-year RFS compared to patients who have RD. Treatment with HP-containing neoadjuvant regimens is associated with a high 3-year RFS. VariableHP (n=215)H (n=807) pCR n=121RD n=94pCR n=399RD n= 408Age at Diagnosis&amp;lt;5043%46%46%51% ≥5057%54%54%49%Menopausal StatusPremenopausal46%50%53%57% Postmenopausal54%50%47%43%Clinical Stage at DiagnosisIIA40%29%34%29% IIB29%31%23%28% IIIA14%15%17%16% IIIB0%5%5%9% IIIC17%20%21%18%Clinical Nodal StatusNode (+)63%76%69%73% Node (-)37%24%31%27%Nuclear Grade1II25%32%22%28% III75%65%78%72%HR statusHR(+)52%74%52%67% HR(-)48%26%48%33%Adjuvant therapyTrastuzumab88%80%100%100% Trastuzumab and Pertuzumab3%5%0%0% Unknown9%15%20%0%11 patient in the HP pCR group had nuclear grade 1; 2 patients in the HP RD group had nuclear grade 1 tumors 2 2 patients received adjuvant TDM-1 on the NSABP B50 protocol Citation Format: Murthy RK, Raghavendra AS, Hess KR, Barcenas CH, Lim B, Moulder SL, Giordano SH, Mittendorf EA, Thompson A, Ueno NT, Valero V, Litton JK, Tripathy D, Chavez-Macgregor M. 3-year relapse-free survival of stage II-III HER2-neu positive breast cancer treated with pertuzumab and trastuzumab-containing neoadjuvant therapy compared to trastuzumab-containing therapy [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P6-17-04.

Practical consensus recommendations regarding the management of HER2 neu positive early breast cancer.

Over-expression of HER2 is generally considered to be a negative prognostic feature because it accompanies an increase in breast cancer mortality. However, the development of agents that specifically target HER2 has improved the management of patients with these tumours. This expert group used data from published literature, practical experience and opinion of a large group of academic oncologists to arrive at these practical consensus recommendations with regards to the use of these agents and the management of HER2 neu early breast cancer for the benefit of community oncologists.

Practical consensus recommendations regarding the management of HER2 neu positive metastatic breast cancer.

Metastatic breast cancer (MBC) is cancer that has spread from the breast to another part of the body or has come back in another distant location. Treatment options for MBC depend on several factors, including where the cancer has spread, the patient's overall health, and the levels of hormone receptors and HER2 in the tumour. Over-expression of HER2 is generally considered to be a negative prognostic feature because it accompanies an increase in breast cancer mortality. However, the development of agents that specifically target HER2 has improved the management of patients with these tumours.[7],[8],[9],[10] This expert group used data from published literature, practical experience and opinion of a large group of academic oncologists to arrive at these practical consensus recommendations in regards with the use of these agents and the management of HER2 positive MBC for the benefit of community oncologists.

Abstract P5-20-10: Patterns of use and effectiveness of neoadjuvant pertuzumab-containing regimens in stage II-III HER2-neu positive breast cancer: A retrospective, single institutional experience

Abstract Background: Pertuzumab (P) in combination with trastuzumab (H) based chemotherapy is currently FDA- approved as a standard neoadjuvant treatment for patients with clinical stage II-III HER2-positive (HER2+) breast cancer (BC). The chemotherapy backbone of HER2-targeted therapy varies and includes a taxane (T) and/or an anthracycline coupled with cyclophosphamide (A), or carboplatin (C). The goal of this study was to retrospectively evaluate patterns of use and the pathologic complete response (pCR) rate for HP-containing regimens comparing the 3 treatment groups: A-containing, C-containing, and taxane only for stage II-III HER2+ BC. Methods: We identified all patients (n=226) with stage II-III non-inflammatory HER2+ BC who received neoadjuvant HER2-targeted therapy in combination with P and H from 2013 to 2016 through an institutional database. 48 received THP, 85 received TCHP, 5 received TCHP-A, and 88 received THP-A. All patients underwent definitive breast and lymph node surgery. Medical records were examined for patient demographics, breast cancer stage, pathology results, surgical outcomes, and treatment details. pCR was defined as ypT0/is, ypN0. Descriptive statistics and logistic regression analysis was used for statistical analysis. Results: Patient characteristics are shown in Table1. The median age was 51 (22-84) years. The pCR rates by regimen were as follows: THP (65%), TCHP (50%), THP-A (58%). After controlling for age, stage, HR status, grade, and menopausal status, THP was associated with a modestly higher pCR rate compared to TCHP or THP-A: OR = 1.82 (0.88, 3.74)(p = 0.11). Efficacy and toxicity differences will continue to be evaluated as more analytic cases become available at our institution. Conclusion: Although it is challenging to demonstrate non-inferiority without a prospective randomized trial, THP, a regimen not containing carboplatin or anthracycline, appears to have similar efficacy in selected patients with stage II-III HER2+ BC. Further research is needed to identify biomarkers to select patients appropriate for de-escalation of therapy. Table 1: Patient CharacteristicsVariable Anthracycline Containing (THP-A) N=88Carboplatin Containing (TCHP; TCHP-A*) N=90Taxane alone (THP) N=48Age at Diagnosis&amp;lt; 5058%52%60% &amp;gt; 5042%48%40%Menopausal StatusPremenopausal44%53%40% Postmenopausal56%47%60%Clinical State at DiagnosisIIA34%34%35% IIB33%32%23% IIIA12%13%23% IIIB3%3%0% IIIC18%18%19%Clinical Nodal StatusNode (+)70%70%71% Node (-)30%30%29%Nuclear Grade**II27%34%25% III73%66%75%HR statusHR(+)58%67%60% HR(-)42%33%40%*5/90 received TCHP-A; **3 patients did not have nuclear grade available; 3 patients had nuclear grade 1 cancer Citation Format: Rashmi MK, Akshara RS, Kenneth HR, Amy HZ, Bora L, Carlos BH, Mariana C-M, Elizabeth MA, Jennifer LK, Sharon GH, Alastair T, Vicente V, Debu T, Naoto UT. Patterns of use and effectiveness of neoadjuvant pertuzumab-containing regimens in stage II-III HER2-neu positive breast cancer: A retrospective, single institutional experience [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P5-20-10.

Abstract 2761: Adjuvant chemotherapy outcomes of node negative, T1a,T1b,T1c hormone receptor-negative HER2-positive breast cancer patients

Abstract Background: Patients (pts) with early stage HER2neu-positive breast cancers have a higher risk of recurrence and death compared to hormone receptor positive patients. NCCN guidelines recommends adjuvant chemotherapy for Stage II and above HER2-positive breast cancer patients. It is unclear what benefit patients with Stage I HER2-positive breast cancer receive from adjuvant chemotherapy. The current study evaluates the effects of adjuvant chemotherapy on the survival of early stage ER/PR negative, HER2-positive breast cancer patients registered to the National Cancer Data base (NCDB) from 2010-2012. Patients and Methods: 3416 women from the NCDB were identified with Stage I ER, PR negative, HER2-positive breast cancer diagnosed between 2010-2012. The primary measured outcome was overall survival. Pts were grouped by tumor size (T1a,T1b,T1c) and adjuvant chemotherapy or no adjuvant chemotherapy. Additionally, patients were also grouped into lumpectomy with radiation and mastectomy with or without radiation. Adjusted variables included age, race, Charlson Comorbidity Index (CCI), payer status, income, education, distance travelled, diagnosing/treating facility and treatment delay. Multivariate Cox regression was used to investigate the effect of adjuvant chemotherapy on overall survival while adjusting for other factors. Results: There were a total of 3416 patients, mean age at diagnosis of 57.9 (range 22-90). The mean age was 56.2 years for the chemotherapy group and 61.8 for the no chemotherapy group. Pathological stage distribution was T1a (24.9%), T1b (24.7%) and T1c (50.2%). Adjuvant chemotherapy was received by 49.5% of T1a, 83.5% of T1b and 95% of T1c pts. Mean patient follow up was 2.7 years (range 0.05-5 years) In univariate analysis, the hazard ratio (HR) of death for chemotherapy vs no chemotherapy in each T stage was: T1a; 1.22 (0.46-3.28), T1b; 0.221 (0.095-0.512), T1c; 0.217 (0.094-0.498). In multivariate analysis, adjusting for other factors in the model, HR of death was 0.51 (95%CI: 0.26-1.03) for chemotherapy vs no chemotherapy. The HR of death was 1.92 (95%CI: 1.11-3.32) for pts who received mastectomy without radiation compared to lumpectomy with radiation. In addition, we observed a HR of 5.16 for CCI score of 2 or above as compared to score of 0. There was no difference in outcome based on payer status or race. Conclusion: Patients with early stage T1 a-c HER2-positive breast cancer had a marginal improvement in overall survival with the addition of chemotherapy. Patients who underwent lumpectomy with radiation were also found to have better overall survival compared to mastectomy without radiation. However, the relatively short follow up and the lack of cancer recurrence information preclude making definitive conclusions relative to adjuvant therapy for pts with these tumors. Longer follow-up and prospective controlled trials will be needed to quantify these potential benefits. Citation Format: Anu Paul, Runhua Shi, Prakash Peddi, Gary Burton. Adjuvant chemotherapy outcomes of node negative, T1a,T1b,T1c hormone receptor-negative HER2-positive breast cancer patients [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 2761. doi:10.1158/1538-7445.AM2017-2761

Effect of neoadjuvant pertuzumab-containing regimens on pathologic complete response rates in stage II-III HER2-neu positive breast cancer: A retrospective, single institutional experience.

580 Background: Pertuzumab (P) in combination with trastuzumab (H) based chemotherapy is currently FDA- approved as a standard neoadjuvant treatment for patients with clinical stage II-III HER2-positive (HER2+) breast cancer (BC). The chemotherapy backbone of HER2-targeted therapy varies and may include taxane (T) and/or anthracycline (A), or carboplatin (C). The goal of this study was to retrospectively evaluate the pathologic complete response (pCR) rate for HP-containing regimens compared to H containing regimens for stage II-III HER2+ BC. Methods: We identified all patients (n = 1150) with stage II-III HER2+ BC who received neoadjuvant HER2-targeted therapy from 2005 to 2016 through an institutional database. All patients underwent primary breast and lymph node surgery. pCR was defined as ypT0/is, ypN0. Univariate/multivariate logistic regression and chi-squared test for comparing proportions was used for the statistical analysis. Results: pCR was significantly higher for the HP group (n = 200) compared to the H group (n = 950): 44% vs. 41%, odds ratio = 1.8 (95% CI = 1.3, 2.5; P = 0.0002). Even with adjustment for all clinically significant factors (age, stage, tumor grade, hormone receptor (HR) status, A or C exposure), the improvement was statistically significant (adjusted OR = 2.1 (95% CI = 1.5, 2.9; P &lt; 0.0001). The pCR rate by stage and HR status for the HP group is 62% vs. 55% (stage II vs. III) and 71% vs. 51% (HR- vs. HR+). The effect of P was not modified by HR status (HR-, OR = 2.3; HR+, OR = 1.7, P = 0.39) or by A (A-yes, OR = 1.8; A-no, OR = 2.6) (P = 0.28 for interaction) or C (C-yes, OR 2.6; C-no, OR = 1.8) (P = 0.30 for interaction). P was significantly more likely to be given to patients without A (36% vs. 10%, P &lt; 0.0001) and more likely to be given to patients with C (30% vs. 14%, P &lt; 0.001). In both groups, significant predictors of pCR were found to be stage, HR status, and C exposure. Conclusions: Pertuzumab containing regimens yield higher pCR rates compared to non-Pertuzumab containing regimens in stage II- III HER-2 positive breast cancer. The effect of Pertuzumab is not modified by anthracycline or carboplatin use.

Utility of folate receptor alpha immunohistochemistry in cytology specimens of metastatic breast carcinoma, metastatic serous carcinoma of Müllerian origin, and primary lung adenocarcinoma

Folate receptor alpha (FRA) overexpression by immunohistochemistry (IHC) has been shown to various degrees in histologic specimens from breast ductal carcinoma (DC), serous carcinoma of Müllerian origin (SCM), and primary lung adenocarcinoma (ADC) among others. Antifolate therapies have recently shown usefulness in FRA overexpressing malignancies. We assessed the feasibility for detecting FRA overexpression by IHC in cytologic cell blocks (CB) from the aforementioned carcinomas. Cases of breast DC, SCM and lung ADC were included. The CB were immunostained with FRA employing mAb 26B.3.F2 (Biocare Medical, Concord, CA). FRA staining was scored qualitatively, by intensity, and staining area. 4/20 (20%) triple negative breast cancer (TNBC), 27/29 (93%) SCM, and 20/22 (91%) lung ADC showed positive FRA immunoreactivity. All ER/PR positive (n = 5) and Her2-neu positive (n = 5) DC were negative with FRA IHC. FRA expression can be detected with a higher degree of confidence in SCM (93%) and lung ADC (91%) in CB, and to a lesser degree in TNBC. Our data also shows that FRA expression by IHC was more frequently associated with TNBC (20%) when compared with ER/PR positive or Her2neu positive breast cancers. FRA overexpression detected by IHC in CB is highly concordant with the published results of surgical specimens from SCM and lung ADC and less so from TNBC. Hence, IHC FRA analysis can be performed in the CB preparation with a high degree of confidence in SCM and lung ADC.

Abstract P3-07-37: Quantitative analysis of T cell and macrophage immune markers in Her2-positive breast cancer

Abstract Purpose/Objectives: Her2-neu positive breast cancers have a good overall prognosis with the advent of Her2-directed therapies such as trastuzumab. However, despite the increased efficacy with Her-2-directed therapies 20-30% of patients still have local and/or distant failure despite being Her-2 amplified on pathology. The etiology of this local failure remains unknown. Recent evidence has suggested that there may be immune factors that contribute to the progression of breast cancer and the response to therapy so we undertook a study to examine the relationship between immune-based markers and traditional pathologic and clinical markers of outcome. Materials/Methods: Paraffin-embedded sections were generation and clinical records were reviewed for 88 patients, age ≥ 18 years, with pathologically-proven Her2-neu+ breast cancer who were treated at a single institution from 01/2001 to 12/2013. Single-color immunohistochemical staining was performed for CK5/6, CK14 and EGFR and scored by a breast pathologist. Adjacent sections were also then stained for CD45, CD4, CD8 and CD68 using a multi-color immunohistochemical approach. Slides were scanned using the Vectra Automated Quantitative Pathology Imaging System and analyzed using an in-house algorithm to quantitate the number of immune cells within the tumor, tumor margin and within 2 mm outside the tumor. We then compared the level of CK5/6, CK14, EGFR with the number of immune cells. The number of different immune cells were also analyzed with respect to other clinical parameters including age, tumor size, nodal status, hormone receptor status, time to progression, progression-free survival and overall survival. Results: At a median follow-up of 66.5 months, 20 (22.7%) patients had progressed. We found that the number of CD45+ leukocytes at the margin correlates with the expression of CK5/6 (p = 0.015) which predicted for local failure. Further, we found that the ratio of CD8 to CD4 cells within the tumor and margin highly correlates with the expression of the hormone receptors (p = 0.01). Conclusions: Our preliminary results suggest that immune markers may be important predictors of a basal-like phenotype as defined by CK5/6 expression in Her2+ breast cancers which itself correlated with significantly higher local failure. Further higher CD8 to CD4 ratios were highly correlated with hormone receptor expression, particularly PR expression suggesting that in the Her2+ population the more favorable prognosis for the "triple-positive" subtype of Her2+ cancers may be in part due to a more favorable immune microenvironment. Citation Format: Shiao SL, Gertych A, Ma Z, Zhang X, Burnison CM, Mirhadi AJ, Giuliano A, Knudsen BS, Chung A. Quantitative analysis of T cell and macrophage immune markers in Her2-positive breast cancer. [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 P3-07-37.

CYP2D6 Genotype and Risk of Recurrence in Tamoxifen Treated Breast Cancer Patients

Despite consistent pharmacogenetic effects of CYP2D6 on tamoxifen exposure, there is considerable controversy regarding the validity of CYP2D6 as a predictor of tamoxifen outcome. Understanding the current state of evidence in this area and its limitations is important for the care of patients who require endocrine therapy for breast cancer. A total of 101 patients with breast cancer who received tamoxifen therapy for at least 3 years, were genotyped for common alleles of the CYP2D6 gene by nested-PCR and restriction fragment length polymorphism PCR. Patients were classified as extensive or poor metabolizers (PM) based on CYP2D6*4 alleles in 3 different groups according to the menopause, Her2-neu status, and stage 3. The mean age of the patients with the disease recurrence was 50.8±6.4 and in non recurrent patients was 48.2±6.8. In this study 63.3% (n=64) patients were extensive metabolizers and 36.6% (n=37) were poor metabolizers. Sixty four of the 101 patients (63.3%) were Her2-neu positive. For tamoxifen- treated patients, no statistically significant difference in rate of recurrence observed between CYP2D6 metabolic variants in stage 3 and post-menopausal patients. However, there was a significant association between CYP2D6 genotype and recurrence in tamoxifen-treated Her2-neu positive patients. Compared with other women with breast cancer, those with Her2-neu positive breast cancer and extensive metabolizer alleles had a decreased likelihood of recurrence. This study for the first time demonstrated significant effects of CYP2D6 extensive metabolizer alleles on risk of recurrence in Her2-neu positive breast cancer patients receiving adjuvant tamoxifen therapy. Therefore, CYP2D6 metabolism, as measured by genetic variation, can be a predictor of breast cancer outcome in Her2-neu positive women receiving tamoxifen.

Molecular Treatment of Different Breast Cancers.

Breast cancer is subdivided into three types: hormone (estrogen and progesterone) receptor (ER and PR) positive, Her2-neu positive and triple negative breast cancers. In general, surgical and radiation treatments are similar, but drug treatment for different subtypes of breast cancers is different. Endocrine therapy (ET) is specifically used for the treatment of ER and PR positive breast cancers. This review discusses every aspect of endocrine therapy: ovarian suppression agents, selective estrogen receptor modulators (SERMs) and downregulators, and aromatase inhibitors (AIs). The most famous agents for the treatment of HER2 positive breast cancers are trastuzumab and its derivative Kadcyla (ado-trastuzumabemtansine). Other agents for the treatment of this subtype of breast cancers are also discussed. For the treatment of triple-negative breast cancers (TNBC) and other breast cancers, the following agents are discussed: anthracyclines and related regimens, taxanes, combination therapy of platinum with taxanes, combination therapy to counter drug resistance, ixabepilone and other epothilones, angiogenesis inhibitors. The lack of known specific molecular targets has promoted abundant research in order to find possible "vulnerabilities" in TNBC. For the first time, we propose thetranslocator protein (TSPO) 18 kDa as a potential target for TNBC. Furthermore, currently Photodynamic Therapy (PDT) is way under-explored for the treatment of breast cancers. In this review, PDT for the treatment of breast cancers is discussed. We also discuss imaging-guided therapy for breast cancers. Finally, from a perspective point of view, we call on the development of more potent agents for differentiation therapy.

Pro1170 Ala polymorphism in HER2-neu is associated with risk of trastuzumab cardiotoxicity.

BackgroundVariations in single nucleotide polymorphisms (SNPs) have been associated with enhanced drug efficacy and toxicity in cancer therapy. SNP variations in the ErbB2 gene have been identified that alter the protein sequence of the HER2-neu protein, but how these polymorphisms affect prognosis and response to HER2 targeted therapy is unknown. We examined eleven ErbB2 SNPs that alter the HER2-neu amino acid sequence to determine whether any of these particular polymorphisms were associated with increased trastuzumab cardiotoxicity in a case–control study.Methods140 subjects were enrolled from a single institution under Weill Cornell Medical College IRB protocol #0804009734. Patients were eligible if they had histologically or cytologically proven HER2-neu positive breast cancer and more than 3 months of trastuzumab therapy. Cases had either symptomatic CHF or a decline in LVEF of 15% (or if the LVEF <55%, a decline in LVEF of 10%) that resulted in at least temporary discontinuation of trastuzumab, whereas controls had no decline in their LVEF. Eleven ErbB2 single gene SNPs that resulted in an alteration in the HER2-neu protein amino acid sequence were studied. Single gene SNP analysis was carried out using SNP genotyping assays from genomic DNA obtained from peripheral blood or buccal swab.ResultsOnly two of the ErbB2 SNPs (Ile 655 Val and Pro 1170 Ala) were found to have variation. There was no association between codon 665 and cardiotoxicity; however the proline variant of amino acid 1170 was more likely than the alanine variant to be found in cases with trastuzumab cardiotoxicity (35% of case patients as compared to 17% of controls, p = 0.04). This association remained significant in multivariable analysis taking into account age, race, and history of hypertension (adjusted OR = 2.60, 95% CI = 1.02, 6.62, p = 0.046).ConclusionsThe Her2/neu Pro 1170 Ala polymorphism can be used to identify a subset of patients who are at increased risk of cardiotoxicity from trastuzumab therapy. Her2/neu single nucleotide polymorphisms may be useful in conjunction with other biomarkers to risk stratify patients in order to optimize clinical management.

Peculiarities of diagnostics and clinical course of different immunohistochemical subtypes of breast cancer.

Modern global guidelines in oncology consider treatment of various forms of breast cancer according to molecular tumor subtype. Steroid receptors, epidermal growth factor receptors, p53, Ki67 proliferative activity index and others are the key indicators of aggressiveness of malignant breast tumors. The material for this study was the retrospective study of the standard set of breast cancer immuno­histochemical markers (estrogen receptors, progesterone, epidermal growth factor type 2) in 8171 patients. 4 groups of patients - luminal A, luminal B, triple negative and HER2-neu positive subtypes of tumors were identified according to immunohistochemical status. We analyzed overall survival without relapse in 491 patients with breast cancer, clinical data and data of immunohistochemical studies were matched. Based on the investigation it was determined that in the early stages of the disease (1-2) luminal A subtype of cancer is often diagnosed. In the late stages the most common subtype is HER2-neu positive breast cancer. Herewith, patients with luminal A subtype of cancer have the best performance of the overall survival (OS ) (32,91±2,33 months), and the worst results were found in patients with HER2 - neu positive breast cancer (22,58±1,28 months). The data obtained determine HER2 - neu positive subtype as the most aggressive type of breast cancer, and the luminal A subtype – as the least aggressive one.

A phase I trial of the histone deacetylase inhibitor panobinostat (LBH589) and epirubicin in patients with solid tumor malignancies.

3058 Background: Preclinical and clinical data suggest pre-exposure of cancer cells to a histone deacetylase inhibitor (HDACi) potentiates topoisomerase inhibitors. HDACi-induced histone acetylation and chromatin modulation facilitates DNA access and target recruitment for topo II inhibitors. In vitro data further suggest effective inhibition of HDAC2 is necessary for enhanced epirubicin-induced apoptosis. Methods: This phase I trial explores the safety, tolerability, and maximum tolerated dose (MTD) of escalating doses of panobinostat given orally on days 1, 3, and 5 followed by epirubicin administered intravenously at 75 mg/m2 on day 5 in 21-day cycles. Histone acetylation and HDAC2 expression are evaluated in pre- and post-treatment peripheral blood mononuclear cells (PBMCs) in all patients and in tumor cells of 16 patients treated at the MTD. Results: 36 patients have enrolled [10M/26F, median age 47 years (22-80)] in 5 panobinostat cohorts: 20, 30, 40, 50, 60 mg. Tumor types include melanoma (n=6), breast (n=6), sarcoma (n=16), ovarian (n=2), lung (n=2), and one each of neuroblastoma, pancreatic, testicular, and colon cancer. Prior to enrollment, patients received a median of 3 (0-8) prior chemotherapy regimens and 40% had anthracyclines. Dose-limiting toxicities (DLTs) included 1/3 grade 3 fatigue and 1/3 grade 4 thrombocytopenia at 60 mg of panobinostat, 1/6 patient experienced grade 3 atrial fibrillation at 50 mg, defining 50 mg panobinostat as the MTD. Non-dose–limiting grade 3/4 hematological toxicities include neutropenia (n=19, 53%), febrile neutropenia (n=6, 17%), thrombocytopenia (n=6, 17%), and anemia (n=4, 11%). Of 34 evaluable patients, 5 had partial responses and 14 had stable disease in anthracycline-refractory sarcomas (4) and Her2neu positive breast cancer (2), and small cell lung cancer. Correlative studies demonstrate increased H4 acetylation in PBMCs on day 3 and 5 suggesting sufficient histone deacetylase inhibition. Conclusions: Sequence-specific combination of panobinostat and epirubicin shows early activity without potentiating epirubicin toxicity. Dose expansion in anthracycline-pretreated sarcoma patients is ongoing.

Risk factors of brain metastasis in a series of Egyptian breast cancer patients: A single-institution experience.

50 Background: Incidence of cerebral metastasis is increasing among breast cancer patients. Many factors have been reported associated with increased risk of brain metastasis. The aim of this retrospective analysis is to investigate the predictive factors for the development of brain metastasis in breast cancer patients. Methods: We retrospectively analyzed histologically proven breast cancer patients who presented to Cairo Oncology Center (COC) in the period from 1999 till 2008, with follow up period of 6 months at least for those in adjuvant setting. The following factors were analyzed: age, tumor size and grade, nodal status, ER, PgR and HER2 over-expression status. Results: Our study included 2,338 patients. 96 patients (4.1%) experienced brain metastasis during the course of their disease. 3 patients had brain metastasis among other sites of distant spread at first presentation to COC. 30 out of 96 patients (31.25%) with localized breast cancer had brain metastasis at first relapse with 13 (13.5%) of them had isolated brain metastasis. In a median follow-up of 37.1 months (6-277) the median time to develop brain metastasis was 26.5 months (0-144). Based on univariate analysis, the following variables were associated with shorter time to develop brain metastasis: tumor size more than 5 cm (HR = 2.1, 95% CI 1.14-3.87), lymph node involvement at diagnosis (HR = 1.57, 95%CI 1.17-2.10), ER negativity (HR = 1.58, 95%CI 1.33-1.73), PgR negativity (HR = 1.55, 95%CI 1.29-1.72) and HER2-neu over-expression (HR = 2.68, 95%CI 1.51-4.75). On multivariate analysis, only patients with lymph node involvement at diagnosis and those with HER2-neu positive breast cancer were associated with shorter time to develop brain metastasis. Conclusions: We concluded that HER2 over-expression as well as lymph node involvement are the 2 main factors associated with shorter time to develop brain metastasis. These patients could be good candidates for trials investigating the role of any prophylactic intervention to decrease their risk to develop brain metastases.