Issam Makhoul

Mechanisms of bone metastases of breast cancer

Cancer development is a multi-step process driven by genetic alterations that elicit the progressive transformation of normal human cells into highly malignant derivatives. The altered cell proliferation phenotype of cancer involves a poorly characterized sequence of molecular events, which often result in the development of distant metastasis. In the case of breast cancer, the skeleton is among the most common of metastatic sites. In spite of its clinical importance, the underlying cellular and molecular mechanisms driving bone metastasis remain elusive. Despite advances in our understanding of the phenotype of cancer cells, the increased focus on the contribution of the tumor microenvironment and the recent revival of interest in the role of tumor-propagating cells (so called cancer stem cells) that may originate or be related to normal stem cells produced in the bone marrow, many important questions remain unanswered. As such, a more complete understanding of the influences of both the microenvironment and the tumor phenotype, which impact the entire multi-step metastatic cascade, is required. In this review, the importance of tumor heterogeneity, tumor-propagating cells, the microenvironment of breast cancer metastasis to bone as well as many current endocrine therapies for the prevention and treatment of metastatic breast cancer is discussed.

Neoadjuvant systemic treatment of breast cancer

Neoadjuvant systemic breast cancer therapy is the administration of systemic therapy to eligible breast cancer patients prior to surgery. This treatment modality was developed out of necessity to downstage inoperable tumors, but it has evolved into a tool for breast conservation surgery. The neoadjuvant approach is also commonly used now to explore the efficacy of new therapeutics by assessing their impact on pathologic complete response or other endpoints. This article will review the foundations of this treatment modality and the latest progress in the field. Considering the heterogeneity of breast cancer, it is clear that no single treatment will fit all types of breast cancer. Thus, there is a need to understand the biological underpinnings of the different types of breast cancer in order to design better treatments that will ultimately improve the eradication rate of this disease. J. Surg. Oncol. 2011; 103:348–357.

Bevacizumab and erlotinib in previously untreated inoperable and metastatic hepatocellular carcinoma.

Purpose:To evaluate the combination of erlotinib and bevacizumab in subjects with hepatocellular carcinoma (HCC) who are not candidates for local therapy. Patients and Methods:Twenty-one subjects with metastatic or inoperable HCC who had not received local or systemic therapy were treated with 15 mg/kg bevacizumab every 3 weeks and a daily dose of 150 mg oral erlotinib. The primary endpoint was progression-free survival (PFS) at 27 weeks. The secondary endpoints were median time to progression and median overall survival. Results:Twenty-one subjects were enrolled. Eighteen were evaluable for the primary endpoint; all subjects were evaluable for toxicity. The median age was 60 years (range, 33 to 81 y). Five subjects (28%) were progression free at 27 weeks (90% confidence interval (CI), 12%-50%). Median time to progression was 2.57 months (95% CI, 2.13-4.20 mo). Median overall survival was 8.33 months (95% CI, 5.73-13.97 mo). Two subjects withdrew consent, and 1 subject did not have adequate baseline scans. Conclusions:The 28% progression-free survival rate at 27 weeks was not significantly higher than the recent historical control rate of 20% observed on the placebo arm of the Sorafenib Hepatocellular Carcinoma Assessment Randomized Protocol trial (P=0.28). The combination of bevacizumab and erlotinib does not appear to have sufficient efficacy in patients with unresectable and metastatic HCC not amenable to local therapy, and may not warrant further investigation. However, this could be evaluated as an alternative to those intolerant to sorafenib therapy.

Transcriptome Profiling of Peripheral Blood Cells Identifies Potential Biomarkers for Doxorubicin Cardiotoxicity in a Rat Model

Aims Doxorubicin (DOX), a widely used anticancer agent, can cause an unpredictable cardiac toxicity which remains a major limitation in cancer chemotherapy. There is a need for noninvasive, sensitive and specific biomarkers which will allow identifying patients at risk for DOX-induced cardiotoxicity to prevent permanent cardiac damage. The aim of this study was to investigate whether the expression of specific genes in the peripheral blood can be used as surrogate marker(s) for DOX-induced cardiotoxicity. Methods/Results Rats were treated with a single dose of DOX similar to one single dose that is often administered in humans. The cardiac and peripheral blood mononuclear cells (PBMCs) genome-wide expression profiling were examined using Illumina microarrays. The results showed 4,409 differentially regulated genes (DRG) in the hearts and 4,120 DRG in PBMC. Of these 2411 genes were similarly DRG (SDRG) in both the heart and PBMC. Pathway analysis of the three datasets of DRG using Gene Ontology (GO) enrichment analysis and Ingenuity Pathways Analysis (IPA) showed that most of the genes in these datasets fell into pathways related to oxidative stress response and protein ubiquination. IPA search for potential eligible biomarkers for cardiovascular disease within the SDRG list revealed 188 molecules. Conclusions We report the first in-depth comparison of DOX-induced global gene expression profiles of hearts and PBMCs. The high similarity between the gene expression profiles of the heart and PBMC induced by DOX indicates that the PBMC transcriptome may serve as a surrogate marker of DOX-induced cardiotoxicity. Future directions of this research will include analysis of PBMC expression profiles of cancer patients treated with DOX-based chemotherapy to identify the cardiotoxicity risk, predict DOX-treatment response and ultimately to allow individualized anti-cancer therapy.

Relevance of Pathological Complete Response after Neoadjuvant Therapy for Breast Cancer.

Breast cancer is a heterogeneous disease, and the different biological subtypes have different prognostic impacts. Neoadjuvant trials have recently become popular as they offer several advantages compared to traditional adjuvant trials. Studies have shown that patients who achieve pathological complete response (pCR) after neoadjuvant treatment have a better long-term outcome. Consequently, increasing the rate of pCR became the end point of neoadjuvant trials with the expectation of translation into improved survival. However, the definition of pCR has lacked uniformity, and the prognostic impact of achievement of pCR on survival in different breast cancer subtypes is uncertain. In this review, we present the controversies associated with the use of pCR as an end point in neoadjuvant trials.

Combined neoadjuvant chemotherapy with bevacizumab improves pathologic complete response in patients with hormone receptor negative operable or locally advanced breast cancer.

Objectives:To evaluate the pathologic complete response (pCR) and safety of bevacizumab (B) with chemotherapy in the neoadjuvant setting of breast cancer (BC). Methods:A prospective single-arm, single-institution phase II trial for women with stage IIA-B/IIIA-B-C BC. Patients received neoadjuvant docetaxel, cyclophosphamide, B every 3 weeks for 4 cycles followed by doxorubicin every 3 weeks for 4 cycles followed by surgery. After healing, B was given every 3 weeks for 9 cycles. Radiation therapy, trastuzumab and endocrine therapy were given as indicated. Results:Thirty-nine of 40 patients were evaluable. Median age of participants was 45 years (range, 26 to 72 y). The most serious grade ≥3 adverse events were infection (4), congestive heart failure (2), and pulmonary embolism (1). Thirty-eight of 39 patients underwent surgery. The pCR rate was 41% (16/39), significantly higher than the null-hypothesis rate of 25% (P=0.0204). Rates of pCR were 52% (15/29) in ductal carcinoma compared with 10% (1/10) in nonductal disease (P=0.021), and 59% (10/17) in estrogen receptor−/progesteron receptor− patients compared with 27% (6/22) among patient with at least one positive hormone receptor (P=0.047). African Americans (AA) had 75% pCR (9/12), whereas Whites had only 28% pCR (7/25; P=0.0069), possibly in part because 100% of AA (12/12) had ductal carcinoma compared with only 64% (16/25) of Whites (P=0.017). Conclusions:Chemotherapy with B improved pCR in BC patients, but was associated with significant toxicity and rare but very serious complications. The improvement was more pronounced in AA patients, those with ductal carcinoma, and those with estrogen receptor−/progesteron receptor − BC.ClinicalTrials.gov Identifier: NCT00203502.

Response of metastatic mucosal melanoma to immunotherapy: It can get worse before it gets better

Immune therapy with checkpoint inhibitors has revolutionized the management of metastatic melanoma. Ipilimumab, nivolumab, and pembrolizumab are all FDA-approved immune checkpoint inhibitors to treat metastatic melanoma. Responses to immune checkpoint inhibitors are usually delayed. An interim progression on restaging computed tomography scans “pseudo-progression” may be observed before response to treatment occur. In this case, we report a significant interim progression of metastatic mucosal melanoma before meaningful responses to immunotherapy occurred. The patient developed significant immune therapy-related colitis and new onset vitiligo. Further restaging computed tomography scans showed sustained tumor response despite stopping the immune therapy.

Bevacizumab combined with chemotherapy significantly improves pathologic complete response in patients with operable or locally advanced breast cancer.

CTRC-AACR San Antonio Breast Cancer Symposium: 2008 Abstracts Abstract #5114 Bevacizumab (B) improved progression free survival in metastatic breast cancer (BC) when added to chemotherapy (CT) and was relatively safe in the adjuvant setting. This study evaluated pathologic complete response (pCR) and safety of B with CT in the neoadjuvant setting. Methods: This is a single arm, single institution phase II trial. Patients (Pts) eligible for the study were women with proven BC (T1-4 and/or positive axillary LN -excluding inflammatory BC). Pts received CT with docetaxel (T, 75 mg/m2), cyclophosphamide (C, 500 mg/m2) and B (15 mg/kg), TCB every 3 wks x 4 cycles followed by doxorubicin (A, 60 mg/m2) every 3 wks for 4 cycles. After CT, Pts were evaluated clinically (clinical complete or partial response cCR or cPR), by mammogram and for their heart function by MUGA. Breast conserving surgery was considered if the response was deemed satisfactory, otherwise mastectomy was performed and pCR was evaluated. 28 to 84 days after surgery and after documented healing of the operative incision, B was restarted at 15 mg/kg x 9 cycles. XRT, herceptin and endocrine therapy were given as indicated concurrently with B. Results: As planned, 40 Pts were enrolled. Average age 46 (range 27-73). One patient withdrew consent after 2 cycles of TCB. Average tumor size was 5.26 cm (range 1.8 - 15 cm). Lobular 7/ductal 32. Grade I/II/III: 3/12/24. ER +/PR +: 11; ER+/PR-8; ER-/ PR +: 3, ER-/PR-:17. HER2 +: 8. Triple negative: 14. Lymph nodes were + in 25 patients. 32 Pts completed all pre-op CT cycles. One Pt died after 2 cycles of TCB of bilateral PE, 4 Pts received a truncated doxorubicin course due to side effects, 2 Pt received TCB x 2 followed by A x 4. The most common grade 3/4 AEs (#): diarrhea (4), febrile neutropenia (4), musculoskeletal pain (10), fatigue (8), mucositis (3), nausea (2), hypertension (5), syncope (2) infection (3). No clinically significant change in LVEF was noticed (Pre-CT EF 63.3% (55-76%); post-CT EF 61.2% (49-72%)). 4 Pts had a decrease of EF > 10. 21 cCR and 16 cPR were seen.1 Pt had progression and 1 Pt had no change. 38 Pts underwent surgery. 10 had lumpectomy (average pre-CT size 4.8 cm) and 28 had mastectomy (average pre-CT size 6.1 cm). One Pt had infusaport infection and another had breast implant infection, both required device removal and had delayed wound healing. 16 pCR/39 in the breast and 13 pCR/39 in the breast and axilla were seen (pCR breast 41%, pCR breast and axilla 33%). Several Pts had near pCR. Post-operative B safety data will be presented. Conclusions: When added to CT, B improved pCR in a poor prognostic BC Pts and was associated with manageable toxicity. Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 5114.

Long-Term Results of Phase II Ablation after Breast Lumpectomy Added to Extend Intraoperative Margins (ABLATE l) Trial

BACKGROUND Excision followed by radiofrequency ablation (eRFA) is an intraoperative method that uses intracavitary hyperthermia to create an additional tumor-free zone around the lumpectomy cavity in breast cancer patients. We hypothesized that eRFA after lumpectomy for invasive breast cancer could reduce the need for re-excision for close margins as well as potentially maintain local control without the need for radiation. STUDY DESIGN This prospective phase II institutional review board-approved study was conducted from March 2004 to April 2010. A standard lumpectomy was performed, then the RFA probe was deployed 1 cm circumferentially into the walls of the lumpectomy cavity and maintained at 100 °C for 15 minutes. Validated Doppler sonography was used to intraoperatively determine adequacy of ablation. RESULTS One hundred patients were accrued to the trial, with an average age of 65.02 years ± 10.0 years. The stages were Tis (n = 30); T1mic (n = 1); T1a (n = 9); T1b (n = 27); T1c (n = 22); T2 (n = 10) ; and T3 (n = 1). Grades were I (n = 48); II (n = 29); and III (n = 23). Seventy-eight subjects had margins >2 mm (negative), 22 patients had margins ≤ 2 mm, of which 12 were close and 3 focally positive, which, at our institution, would have required re-excision (only 1 patient in this group had re-excision). There were 6% postoperative complications, and 24 patients received radiation therapy (XRT). During the study mean follow-up period of 62 months ± 24 months (68-month median follow-up) in patients not treated with XRT, there were 2 in-site tumor recurrences treated with aromitase inhibitor, 3 biopsy entrance site recurrences treated with excision and XRT to conserve the breast, and 2 recurrences elsewhere and 1 contralateral recurrence; all 3 treated with mastectomy. CONCLUSIONS Long-term follow-up suggests that eRFA may reduce the need for re-excision for close or focally positive margins in breast cancer patients, and eRFA may be a valuable tool for treating favorable patients who desire lumpectomy and either cannot or do not want radiation. A multicenter trial has been initiated based on these results.

Cancer: Update on bone-modifying agents in metastatic breast cancer

Advances in the development of bone-modifying agents have led to the approval of new drugs for the prevention and treatment of skeletal-related events in patients with bone metastases from breast cancer. In light of these advances, the American Society of Clinical Oncology has published a guideline update.