Daniel F. Argolo

Cardiac Surveillance Guidelines for Trastuzumab-Containing Therapy in Early-Stage Breast Cancer: Getting to the Heart of the Matter

Trastuzumab-containing regimens for breast cancer have significantly improved survival both in the early-stage and metastatic settings.1-8 Nevertheless, given the early signals of cardiotoxicity, a prevailing concern exists regarding the risk of cardiotoxicity, defined as a decline in left ventricular ejection fraction (LVEF) both asymptomatic and symptomatic. This concern that LVEF decline would be an early and actionable surrogate for subsequent development of congestive heart failure (CHF) led to the design and implementation of specific eligibility criteria and LVEF surveillance guidelines for the pivotal randomized adjuvant trials. These guidelines were subsequently adopted as the standard of care. However, it is increasingly unclear whether these specific recommendations are justified for all patients. Resolution of this matter is critical for our community because adherence to these guidelines was recently proposed as a quality metric.9 This issue raises the general question of the level of evidence needed to accept a toxicity screening schedule as a quality indicator. If following these guidelines is not associated with improved outcomes, then adherence to them as a quality metric should be challenged. Cardiotoxicity screening can serve to illuminate this issue. Here, we review the historical events that led to the development of the current guidelines and highlight critical knowledge gaps with regard to the benefits of screening and intervention.

Pathologic Complete Response with Neoadjuvant Doxorubicin and Cyclophosphamide Followed by Paclitaxel with Trastuzumab and Pertuzumab in Patients with HER2‐Positive Early Stage Breast Cancer: A Single Center Experience

OBJECTIVES Trastuzumab (H) and pertuzumab (P) with standard chemotherapy is approved for use in the neoadjuvant setting for human epidermal growth receptor 2 -positive patients. A retrospective analysis was performed of patients treated with dose-dense (dd) doxorubicin and cyclophosphamide (AC) followed by paclitaxel (T), trastuzumab, and pertuzumab (THP) in the neoadjuvant setting. Here, the pathologic complete response (pCR) rates are reported. METHODS An electronic medical record review was conducted of patients treated with HP-based therapy in the neoadjuvant setting from September 1, 2013, to March 1, 2015. Data on patient demographics, stage of breast cancer, pathology reports, surgical data, and information on systemic therapy were collected. The pCR was defined as total (tpCR, ypT0/is ypN0), German Breast Group (GBG) pCR (ypT0 ypN0), breast pCR (bpCR) with in situ disease (ypT0/is) and without in situ disease (ypT0), and explored axillary pCR (ypN0). RESULTS Charts from 66 patients were reviewed, and 57 patients were evaluable for pCR. Median age was 46 years (range 26-68 years). Median tumor size was 4 cm. Of 57 patients, 53 (93%) had operable breast cancer (T1-3, N0-1, M0). Three patients (5.3%) had locally advanced disease (T2-3, N2-3, M0 or T4a-c, any N, M0), and 1 (1.7%) had inflammatory breast cancer (T4d, any N, M0). Overall, 44 (77%) and 13 (23%) had hormone receptor (HR)-positive and negative diseases, respectively. Median numbers of cycles of neoadjuvant treatment were as follows: AC (4, range 1-4), T (4, range 1-4), trastuzumab (6, range 3-8), and pertuzumab (6, range 2-8). In these 57 patients, the rates of tpCR and bpCR with in situ disease were demonstrated in 41/57 (72%) patients, and the rates of GBG pCR and bpCR without in situ disease were found in 30/57 (53%) patients. Of 26 patients with biopsy-proven lymph nodal involvement, axillary pCR occurred in 22 (85%) patients. CONCLUSION At a single center, the tpCR and GBG pCR rates of dd AC followed by THP are high at 72% and 53%, respectively. The Oncologist 2017;22:139-143Implications for Practice: This is the first study describing the role of doxorubicin and cyclophosphamide followed by paclitaxel and dual anti-HER2 therapy with trastuzumab and pertuzumab (ACTHP) in patients with early stage HER2-positive breast cancer. Total (breast + lymph node) pathological complete remission (pCR) remission (ypT0/is ypN0) and German Breast Group pCR rates (ypT0/ ypN0) were high at 72% and 53%, respectively, with the ACTHP regimen. Rate of axillary clearance in patients with known axillary involvement was high at 85%, which may translate into less extensive axillary surgeries in this subset in the future.

Obesity and Cancer: Concepts and Challenges

The rates of overweight and obesity are increasing worldwide in both developed and developing countries. Obesity is a major public health problem as it is associated with many diseases, including diabetes, hypertension, dyslipidemia, atherosclerosis, and some types of cancer. Breast cancer is a malignancy in which both the risk of development and the prognosis are negatively impacted by the obese state. The precise mechanisms pathophysiologically linking obesity and cancer are still under investigation. The biological basis for these associations includes both systemic and local tissue effects and white adipose tissue inflammation appears to be a critical component. A comprehensive understanding of the mechanisms linking obesity, inflammation and cancer may provide an opportunity for the development of strategies to attenuate the negative impact of obesity.

The Impact of Obesity on Breast Cancer

The rates of obesity are increasing worldwide and this condition is now recognized as a leading preventable cause of cancer. Several diseases are directly related to obesity, including diabetes, hypertension, atherosclerosis, stroke, musculoskeletal disorders, and a diverse range of malignances—such as breast cancer. Obesity is associated with an increased risk of postmenopausal estrogen receptor-positive breast cancer and worse cancer-related outcomes for all breast tumor subtypes. Several mechanisms have been proposed to contribute to the obesity-cancer link, including high levels of circulating and local estrogens, altered amounts of adipokines (leptin and adiponectin), disrupted insulin/IGF signaling, modifications within the microbiome, and local and systemic effects of inflammation. Here we will review recent advances in our understanding of the complex signaling pathways underlying the obesity-cancer link. An improved understanding of these processes is anticipated to propel novel and effective intervention strategies to reduce the global obesity-cancer burden.

Obesity and Cancer—Opportunities to Break the Link

Obesity is a major global health problem with a rising worldwide burden. In addition to its association with several diseases, obesity is associated with increased incidence and worse prognosis for many malignances. Many possible mechanisms that contribute to the obesity-cancer link have been proposed, but key pathways likely include steroid hormone signaling, altered gut microbiota, insulin and insulin growth factor interactions, levels of circulating adipokines, and local and systemic inflammation. By understanding these mechanisms and their interactions, we may be able to intervene to improve the public health burden imposed by obesity. Equally critical to the development of targeted intervention strategies is the identification of accurate biomarkers to better detect populations that are more or less likely to benefit from specific interventions.

Abstract P1-14-17: Pathologic complete response rate with doxorubicin and cyclophosphamide followed by weekly paclitaxel with trastuzumab and pertuzumab in patients with HER2-positive early stage breast cancer: A single institution experience

Background: Trastuzumab and pertuzumab (HP) with standard chemotherapy is approved for use in the neoadjuvant setting. We performed a retrospective analysis of patients (pts) treated with dose-dense doxorubicin and cyclophosphamide (AC) → paclitaxel, trastuzumab, pertuzumab (THP) in the neoadjuvant setting. Here we report the pathologic complete response (pCR) rate. Methods: We abstracted medical records of patients who were treated with pertuzumab-based therapy in the neoadjuvant setting from September 1, 2013 to March 1, 2015. Charts were analyzed for pt demographics, stage of breast cancer, pathology reports, surgical data, and information on systemic therapy. Results: Charts from 66 pts were reviewed; 60 pts were evaluable for pCR defined as absence of invasive disease in the breast, and 6 were not (3-no anthracycline, 1-incomplete chart, 1-no surgery yet, 1-metastatic). Median age was 47 years (range 28-68 years). Of 60 pts, 52 (86%) had operable breast cancer (T1-3, N0-1, M0) of which 7 had clinical stage I disease (T1N0)]; 7 (12%) had locally advanced disease (T2-3, N2-3, M0 or T4a-c, any N, M0), and 1 (2%) had inflammatory breast cancer (T4d, any N, M0). 49 (82%) and 11 (18%) had hormone receptor (HR)-positive and negative diseases, respectively. All patients had HER2-positive breast cancer defined as immunohistochemistry (IHC) 3+ and/or fluorescent in-situ hybridization (FISH) of > 2.0. 30 pts (50%) underwent mastectomy and lumpectomy, respectively. Out of 60 evaluable pts, 41 (68%) had pCR; 32/49 (65%) with HR-positive and 9/11 (82%) with HR-negative diseases had pCR, respectively. Overall 58/60 (97%) pts completed neoadjuvant therapy; 2 did not (1 developed Steven Johnson Syndrome after one cycle of AC and 1 developed pneumonitis after third weekly dose of T with HP). Conclusions: At our single center experience the pCR rate of dose dense AC→THP is high at 68 %. These data are similar to results seen in the TRYPHAENA study, and we await the results from the BERENICE trial evaluating pCR as a secondary endpoint. Citation Format: Singh JC, Sugarman S, Jones L, Boafo C, Patil S, Schweber S, Yu A, Argolo D, Modi S, Iyengar N, Smyth L, Norton L, Baselga J, Hudis C, Dang C. Pathologic complete response rate with doxorubicin and cyclophosphamide followed by weekly paclitaxel with trastuzumab and pertuzumab in patients with HER2-positive early stage breast cancer: A single institution experience. [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 P1-14-17.

Abstract P4-13-20: Activity of HP-based therapies as third and later lines for the treatment of HER2-positive metastatic breast cancer: A retrospective study from a single institution

Background: Dual anti-HER2 blockade with trastuzumab and pertuzumab (HP) plus chemotherapy is an effective therapy (Rx) in the 1st-line setting for HER2-positive metastatic breast cancer (MBC). Our single arm phase II study included patients (pts) treated with HP plus paclitaxel in the 2nd-line setting with progression-free survival (PFS) benefit. Recently, we reported results from a retrospective study of pts treated at our institution, suggesting a longer PFS for those who received HP-based Rxs when compared to any other anti-HER2 based Rxs in the 2nd-line setting. To further assess the activity of this combination in later Rx lines, we conducted a retrospective analysis of pts with HER2-positive MBC who had progressive disease after 2nd-line and were treated with HP-based Rxs in the 3rd and later lines at MSKCC. Historically, the median (med) PFS in this setting with trastuzumab-based Rx is about 3-4 months. Methods: Pts diagnosed with HER2-positive MBC and treated with HP-based Rxs at MSKCC between 1-1-2011 and 03-30-2015 and who progressed on 2nd-line Rx were identified through an institutional database. Primary endpoint was PFS in 3rd and later treatment lines. Results: 70 pts who received any HP-based Rx in the 3rd or later lines of treatment were eligible. The med number of prior anti-HER2 Rx was 3. The baseline characteristics and Rxs are summarized in Table 1. The med PFS for the entire cohort was 5.7 months (95% CI, 4.8-6.5). Conclusions: In this retrospective analysis involving heavly pretreated patients, HP-based Rx appears to be an active regimen and compares favorably to historical data. This supports the NCCN endorsement of HP-based Rx in later lines if HP has not been delivered previously. Citation Format: Argolo D, Friedman M, Smyth L, Iyengar N, Singh J, Patil S, Norton L, Baselga J, Hudis C, Dang C. Activity of HP-based therapies as third and later lines for the treatment of HER2-positive metastatic breast cancer: A retrospective study from a single institution. [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 P4-13-20.

Abstract OT3-01-09: Phase II study of gemcitabine, trastuzumab, and pertuzumab in the treatment of metastatic HER2-positive breast cancer after prior trastuzumab/pertuzumab- or pertuzumab-based therapy

Background: Despite significant therapeutic advances in the treatment of breast cancers that overexpress human epidermal growth factor receptor-2 (HER2), the large majority of patients (pts) with metastatic disease will experience progression. The development of new HER2 directed therapies has led to improvements in progression free and overall survival; however optimal therapeutic sequencing remains under study. The combination of taxanes with trastuzumab (H) and pertuzumab (P) is active in the first line setting; however the efficacy of continuing dual anti-HER2 therapy with HP after initial progression is unknown. Trial design: This is a single arm phase II trial of gemcitabine (G) with HP for pts with metastatic HER2-positive breast cancer who have had prior HP-based treatment. G is administered at 1200 mg/m2 on days 1 and 8 of an every 3 week cycle. H is given 8 mg/kg load → 6 mg/kg every 3 weeks or 4 mg/kg load → 2 mg/kg every week. P is given 840 mg load → 420 mg every 3 weeks. All agents will be given intravenously. This trial is currently enrolling pts. Eligibility criteria: Eligible pts are adults with stage IV HER2-positive (3+ IHC or FISH ≥ 2.0 of primary or metastatic site) breast cancer. Pts may have received prior treatment with HP- or P-based therapy in the (neo)adjuvant, unresectable, locally advanced, or metastatic setting. In the metastatic setting, ≤ 3 prior chemotherapies are permitted. Prior G is allowed only if it was not combined with P. Bone-only non-measurable disease is permitted. Adequate organ and bone marrow function, left ventricular ejection fraction > 50%, and ECOG status ≤ 1 are required. Pts with previously treated brain metastases stable for ≥ 2 months may be enrolled. Specific aims: The primary objective is to determine the progression free survival (PFS) at 3 months. Secondary objectives include overall survival, safety and tolerability. An exploratory endpoint is to compare PFS determined by RECIST criteria versus 18-F FDG-PET response criteria. Statistical methods: Based on historical data, the anticipated median PFS in this setting is 3 months. The study will be considered positive if the 3-month PFS is ≥ 70%. A Simon optimal 2-stage design will be used. If 12/21 pts in stage 1 are alive and progression free at 3 months, stage 2 will accrue for a total of 45 pts. If at least 27/45 pts are alive and progression free, the trial will be deemed a success. This design assumes a 10% type I and type II error. Present accrual and target accrual: 3 out of a planned 45 pts have been enrolled. Contact information: For more information, please visit clinicaltrials.gov (NCT02252887). Citation Format: Iyengar NM, Argolo D, Smyth L, Chen MF, Hudis CA, Dang CT. Phase II study of gemcitabine, trastuzumab, and pertuzumab in the treatment of metastatic HER2-positive breast cancer after prior trastuzumab/pertuzumab- or pertuzumab-based therapy. [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 OT3-01-09.

Erratum to: Obesity and Cancer: Concepts and Challenges

[This corrects the article DOI: 10.1007/s13193-015-0483-z.].