Heather L. McArthur

Adjuvant trastuzumab with chemotherapy is effective in women with small, node‐negative, HER2‐positive breast cancer

Several large, randomized trials established the benefits of adjuvant trastuzumab with chemotherapy. However, the benefit for women with small, node‐negative HER2‐positive (HER2+) disease is unknown, as these patients were largely excluded from these trials. Therefore, a retrospective, single‐institution, sequential cohort study of women with small, node‐negative, HER2+ breast cancer who did or did not receive adjuvant trastuzumab was conducted.

Adjuvant trastuzumab reduces locoregional recurrence in women who receive breast-conservation therapy for lymph node-negative, human epidermal growth factor receptor 2-positive breast cancer

Patients with human epidermal growth factor receptor 2 (HER2)‐positive breast cancer have a higher risk of locoregional recurrence (LRR), even in the setting of early stage, lymph node‐negative disease. In this sequential, retrospective study, the authors evaluated whether adjuvant trastuzumab was associated with reduced LRR in women with lymph node‐negative, HER2‐positive disease who received breast‐conservation therapy (BCT).

Phase IB Randomized, Double-Blinded, Placebo-Controlled, Dose Escalation Study of Polyphenon E in Women with Hormone Receptor–Negative Breast Cancer

Epidemiologic data support an inverse association between green tea intake and breast cancer risk, and numerous experimental studies have shown the antitumor effects of its main component, epigallocatechin gallate (EGCG). We conducted a phase IB dose escalation trial in women with a history of stage I to III hormone receptor–negative breast cancer of an oral green tea extract, polyphenon E (Poly E) 400, 600, 800 twice daily or matching placebo for 6 months. The primary endpoint was to determine the maximum tolerated dose (MTD), defined as the dose that causes 25% dose-limiting toxicity (DLT, grade ≥II). Assignment to dose level was based upon an adaptive design, the continual reassessment method. A mammogram and random core biopsy of the contralateral breast were obtained at baseline and 6 months and serial blood/urine collections every 2 months for biomarker analyses. Forty women were randomized: 10 to placebo, 30 to Poly E (16 at 400 mg, 11 at 600 mg, 3 at 800 mg). There was one DLT at 400 mg (grade III rectal bleeding), three DLTs at 600 mg (grade II weight gain, grade III indigestion and insomnia), and one DLT at 800 mg (grade III liver function abnormality). The DLT rate at 600 mg was 27% (3 of 11). Pharmacologic levels of total urinary tea polyphenols were achieved with all three dose levels of Poly E. Using a novel phase I trial design, we determined the MTD for Poly E to be 600 mg twice daily. This study highlights the importance of assessing toxicity for any chemopreventive agent being developed for chronic use in healthy individuals. Cancer Prev Res; 5(9); 1144–54. ©2012 AACR.

Standardized uptake value by positron emission tomography/computed tomography as a prognostic variable in metastatic breast cancer†

In this retrospective, single‐institution study, the authors examine the maximum standardized uptake value (SUVmax) on positron emission tomography/computed tomography (PET/CT) images as a prognostic variable in patients with newly diagnosed metastatic breast cancer (MBC).

Detection of HER2-Positive Metastases in Patients with HER2-Negative Primary Breast Cancer Using 89Zr-Trastuzumab PET/CT

Our objective was to determine whether imaging with a human epidermal growth factor receptor 2 (HER2)–targeted PET tracer can detect HER2-positive metastases in patients with HER2-negative primary breast cancer. Methods: Patients with HER2-negative primary breast cancer and evidence of distant metastases were enrolled in an Institutional Review Board–approved prospective clinical trial. Archived pathologic samples from the patient’s primary breast cancer were retested to confirm HER2-negative disease. Patients with confirmed HER2-negative primary breast cancer underwent 89Zr-trastuzumab PET/CT to screen for 89Zr-trastuzumab metastases. Metastases avid for 89Zr-trastuzumab by PET/CT were biopsied and pathologically examined to define HER2 status. Patients with pathologically proven HER2-positive metastases subsequently received off-protocol HER2-targeted therapy to evaluate treatment response. Results: Nine patients were enrolled, all of whom had pathologic retesting that confirmed HER2-negative primary breast cancer. Five demonstrated suggestive foci on 89Zr-trastuzumab PET/CT. Of these 5 patients, 2 had biopsy-proven HER2-positive metastases and went on to benefit from HER2-targeted therapy. In the other 3 patients, biopsy showed no evidence of HER2-positive disease, and their foci on 89Zr-trastuzumab PET were considered false-positive. Conclusion: In this proof-of-concept study, we demonstrated that 89Zr-trastuzmab PET/CT detects unsuspected HER2-positive metastases in patients with HER2-negative primary breast cancer. Although these are only initial results in a small sample, they are a proof of the concept that HER2-targeted imaging can identify additional candidates for HER2-targeted therapy. More specific HER2-targeted agents will be needed for clinical use.

A Pilot Study of Preoperative Single-Dose Ipilimumab and/or Cryoablation in Women with Early-Stage Breast Cancer with Comprehensive Immune Profiling

Purpose: To assess the safety and tolerability of preoperative cryoablation-mediated tumor antigen presentation and/or ipilimumab-mediated immune modulation in women with operable breast cancer. Experimental Design: In this pilot study, 19 women with breast cancer for whom mastectomy was planned were treated with preoperative tumor cryoablation (n = 7), single-dose ipilimumab at 10 mg/kg (n = 6), or both (n = 6). The primary outcome for this pilot study was safety/tolerability as defined as freedom from delays in pre-planned, curative-intent mastectomy. Exploratory studies of immune activation were performed on peripheral blood and tumor. Results: Preoperative cryoablation and/or ipilimumab were safe and tolerable, with no delays in pre-planned surgery. Grade III toxicity was seen in 1 of 19 (unrelated rash after ipilimumab). Combination therapy was associated with sustained peripheral elevations in: Th1-type cytokines, activated (ICOS+) and proliferating (Ki67+) CD4+ and CD8+ T cells, and posttreatment proliferative T-effector cells relative to T-regulatory cells within tumor. Conclusions: Preoperative cryoablation and single-dose ipilimumab are safe alone or in combination with no surgical delays incurred. Potentially favorable intratumoral and systemic immunologic effects were observed with the combination, suggesting the possibility for induced and synergistic antitumor immunity with this strategy. Clin Cancer Res; 22(23); 5729–37. ©2016 AACR.

Deep Sequencing of T-Cell Receptor DNA as a biomarker of clonally expanded TILs in breast cancer after immunotherapy

Tumor cryoablation plus immune checkpoint blockade facilitates antitumor T-cell responses (TCRs) and improves survival in mice. Deep sequencing of TCRs in human early-stage breast cancer tumors revealed T-cell clonality and density and served as a biomarker after cryo-immunotherapy. In early-stage breast cancer, the degree of tumor-infiltrating lymphocytes (TIL) predicts response to chemotherapy and overall survival. Combination immunotherapy with immune checkpoint antibody plus tumor cryoablation can induce lymphocytic infiltrates and improve survival in mice. We used T-cell receptor (TCR) DNA sequencing to evaluate both the effect of cryoimmunotherapy in humans and the feasibility of TCR sequencing in early-stage breast cancer. In a pilot clinical trial, 18 women with early-stage breast cancer were treated preoperatively with cryoablation, single-dose anti–CTLA-4 (ipilimumab), or cryoablation + ipilimumab. TCRs within serially collected peripheral blood and tumor tissue were sequenced. In baseline tumor tissues, T-cell density as measured by TCR sequencing correlated with TIL scores obtained by hematoxylin and eosin (H&E) staining. However, tumors with little or no lymphocytes by H&E contained up to 3.6 × 106 TCR DNA sequences, highlighting the sensitivity of the ImmunoSEQ platform. In this dataset, ipilimumab increased intratumoral T-cell density over time, whereas cryoablation ± ipilimumab diversified and remodeled the intratumoral T-cell clonal repertoire. Compared with monotherapy, cryoablation plus ipilimumab was associated with numerically greater numbers of peripheral blood and intratumoral T-cell clones expanding robustly following therapy. In conclusion, TCR sequencing correlates with H&E lymphocyte scoring and provides additional information on clonal diversity. These findings support further study of the use of TCR sequencing as a biomarker for T-cell responses to therapy and for the study of cryoimmunotherapy in early-stage breast cancer. Cancer Immunol Res; 4(10); 835–44. ©2016 AACR.

Emerging immunotherapy strategies in breast cancer

Although immunogenicity is typically associated with renal cell carcinomas and melanoma, there are several compelling reasons why immune-based therapies should be explored in breast cancer. First, breast cancers express multiple putative tumor-associated antigens, such as HER-2 and MUC-1, which have been the successful focus of vaccine development over the past decade, translating into tumor-specific immune responses and, in some cases, clinical benefit. Second, passive immune strategies with anti-HER-2 antibodies, such as trastuzumab and pertuzumab, have led to survival benefits in breast cancer. Finally, the successes observed with novel immunotherapeutic strategies, such as immune checkpoint blockade and adoptive T-cell therapies in other malignancies, combined with a growing body of literature that supports an interplay between solid tumors and the immune system, indicate that these strategies have the potential to revolutionize the treatment of breast cancer.

An overview of HER-targeted therapy with lapatinib in breast cancer

Breast cancer is a global public health burden with more than one million new diagnoses worldwide each year. As a significant proportion of women with early-stage breast cancer experience a relapse and metastatic breast cancer is generally incurable, therapeutic innovations are ongoing. One notable innovation in recent decades has been the identification of a subset of breast cancers that overexpress the transmembrane glycoprotein human epidermal growth factor receptor 2 (HER2) and the consequent development of HER2-targeted therapy. Given the significant benefits demonstrated with the HER2-targeted monoclonal antibody, trastuzumab, in the adjuvant and metastatic settings, investigators have endeavored to develop novel mechanisms for disrupting HER2-mediated signaling. Lapatinib, an orally available HER1- and HER2-targeted tyrosine kinase inhibitor, represents one such notable innovation. Lapatinib is currently being evaluated in both the adjuvant and metastatic settings and was recently approved by the United States Food and Drug Administration in combination with capecitabine, for the treatment of women with HER2-positive, pretreated, metastatic breast cancer. However, the ideal strategy for incorporating novel HER2-targeted agents, including lapatinib, into existing management paradigms is uncertain.

High resolution representational oligonucleotide microarray analysis (ROMA) suggests that TOPO2 and HER2 co-amplification is uncommon in human breast cancer.

CTRC-AACR San Antonio Breast Cancer Symposium: 2008 Abstracts Abstract #2023 Background Clinical studies relating TOPO2A expression or amplification by FISH have yielded inconsistent results regarding prediction of benefit from various drug therapies, particularly in the setting of HER2 amplification by FISH. Because HER2 and TOPO2A are relatively small genes that are close to each other, and because the relevant commercially-available FISH probes hybridize to DNA sequences beyond the genes of interest, there is significant potential for false positive results. We therefore conducted an exploratory study comparing HER2 and TOPO2A amplification by ROMA and FISH. Methods: Forty-two archived formalin-fixed paraffin-embedded primary breast cancer specimens were pre-selected to contain 36 HER2 amplified and 6 HER2 non-amplified cases by FISH. These specimens were evaluated for HER2 and TOPO2A amplification by FISH at Memorial Sloan-Kettering Cancer Center and by ROMA at Cold Spring Harbor Laboratory in a double-blinded experiment. Two HER2 amplified by FISH specimens proved inevaluable for technical reasons. The results for the remaining 40 evaluable specimens were then compared. Results: Of the 40 evaluable specimens, the 6 cases selected as HER2 non-amplified by FISH were HER2 non-amplified by ROMA and TOPO2A non-amplified by both FISH and ROMA. Thirty-two specimens were HER2 amplified by both FISH and ROMA. Two specimens with HER2 FISH results of 2.2 and 2.4 did not demonstrate focal amplification by ROMA. Twenty-five (74%) of the 34 specimens with HER2 amplification by FISH were TOPO2A non-amplified by both FISH and ROMA (Table 1). However, only 2 (22%) of the 9 specimens with HER2 and TOPO2A co-amplification by FISH demonstrated TOPO2A amplification by ROMA. ![][1] Conclusions: Our results suggest that by ROMA, the determination of HER2 status (amplified and non-amplified) and TOPO2A non-amplification by FISH is accurate. The absence of TOPO2A amplification in HER2 non-amplified breast cancer is consistent with published reports. We also confirmed the published frequency of HER2 and TOPO2A co-amplification by FISH. However, we found that co-amplification of HER2 and TOPO2A by ROMA is uncommon, which suggests that commercially-available FISH probes over-estimate the frequency of TOPO2A amplification in HER2 amplified cases. Studies evaluating the clinical implications of these findings are underway. Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 2023. [1]: /embed/graphic-1.gif