Lisa K Jacobs

Johns Hopkins University, Baltimore, MD, United States

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Publications (34)151 Total impact

  • [Show abstract] [Hide abstract]
    ABSTRACT: Epigenetic modifiers, including the histone deacetylase inhibitor vorinostat, may sensitize tumors to chemotherapy and enhance outcomes. We conducted a multicenter randomized phase II neoadjuvant trial of carboplatin and nanoparticle albumin-bound paclitaxel (CP) with vorinostat or placebo in women with stage II/III, HER2-negative breast cancer, in which we also examined whether change in maximum standardized uptake values corrected for lean body mass (SULmax) on FDG-PET predicted pathologic complete response (pCR) in breast and axillary lymph nodes. Participants were randomly assigned to 12 weeks of preoperative carboplatin (AUC 2 weekly) and nab-paclitaxel (100 mg/m(2) weekly) with vorinostat (400 mg oral daily, days 1-3 of every 7-day period) or placebo. All patients underwent FDG-PET and research biopsy pretreatment and on C1D15. The primary endpoint was the pCR rate. Secondary objectives included correlation of change in tumor SULmax on FDG-PET by C1D15 with pCR, and to correlate baseline and change in Ki67 with pCR. In an intent-to-treat analysis (n = 62), overall pCR was 27.4% (vorinostat 25.8%, placebo 29.0%). In a pooled analysis (n = 59), we observed a significant difference in median change in SULmax 15 days after initiating preoperative therapy between those achieving pCR versus not (percent reduction 63.0% vs. 32.9%; P = 0.003). Patients with ≥50% reduction in SULmax were more likely to achieve pCR, which remained statistically significant in multivariable analysis including estrogen receptor status (OR=5.1; 95% CI=1.3-22.7; P = 0.023). Differences in baseline and change in Ki67 were not significantly different between those achieving pCR versus not. Preoperative CP with vorinostat or placebo is associated with similar pCR rates. Early change in SULmax on FDG-PET 15 days after initiating preoperative therapy has potential in predicting pCR in patients with HER2-negative breast cancer. Future studies will further test FDG-PET as a potential treatment-selection biomarker. Copyright © 2014 by the Society of Nuclear Medicine and Molecular Imaging, Inc.
    Journal of nuclear medicine : official publication, Society of Nuclear Medicine. 12/2014;
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    ABSTRACT: Detecting circulating plasma tumor DNA (ptDNA) in early stage cancer patients has the potential to change how oncologists recommend systemic therapies for solid tumors after surgery. Droplet digital polymerase chain reaction (ddPCR) is a novel sensitive and specific platform for mutation detection. In this prospective study, primary breast tumors and matched pre- and post-surgery blood samples were collected from early stage breast cancer patients (n=29). Tumors (n=30) were analyzed by Sanger sequencing for common PIK3CA mutations, and DNA from these tumors and matched plasma were then analyzed for PIK3CA mutations using ddPCR. Sequencing of tumors identified seven PIK3CA exon 20 mutations (H1047R) and three exon 9 mutations (E545K). Analysis of tumors by ddPCR confirmed these mutations and identified five additional mutations. Pre-surgery plasma samples (n=29) were then analyzed for PIK3CA mutations using ddPCR. Of the fifteen PIK3CA mutations detected in tumors by ddPCR, fourteen of the corresponding mutations were detected in pre-surgical ptDNA, while no mutations were found in plasma from patients with PIK3CA wild type tumors (sensitivity 93.3%, specificity 100%). Ten patients with mutation positive ptDNA pre-surgery had ddPCR analysis of post-surgery plasma, with five patients having detectable ptDNA post-surgery. This prospective study demonstrates accurate mutation detection in tumor tissues using ddPCR, and that ptDNA can be detected in blood before and after surgery in early stage breast cancer patients. Future studies can now address whether ptDNA detected after surgery identifies patients at risk for recurrence, which could guide chemotherapy decisions for individual patients.
    Clinical Cancer Research 02/2014; · 7.84 Impact Factor
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    ABSTRACT: PURPOSE Preoperative sentinel node localization (SNL) is now a standard of care for patients undergoing surgical treatment for breast cancer. It requires a subareolar injection of radiotracer Tc99-sulfur colloid which often causes severe pain for a few minutes (if lidocaine is not used), but has been characterized by numerous patients as the “worst pain of my life.” Subareolar administration of lidocaine in conjunction with the radiotracer injection has been demonstrated to be effective in alleviating pain during SNL. However, the use of lidocaine during SNL is not a widely adopted practice. One concern is that lidocaine use can obscure the subsequent identification of sentinel node during surgery and thereby reduce the diagnostic accuracy of SNL. This project aims to compare the diagnostic accuracy of SNL with and without lidocaine injection prior to the injection of Tc99-sulfur colloid utilizing ultrasound guidance. We hypothesize that lidocaine administration will not impact accurate identification of the axillary sentinel lymph node. METHODS This study is IRB approved and HIPAA compliant. For the pre-intervention phase, we performed a retrospective analysis of surgical rates of sentinel lymph node identification from 205 women from 2005-2009 who did not receive lidocaine during preoperative SNL. For the post-intervention phase, women were enrolled from January 2011 to July 2012 and surgical identification rates were analyzed. Both groups were identified from the Johns Hopkins Breast Center and the same eligibility criteria were used. Exclusion criteria include painful cancer, lidocaine allergy, age younger than 18, lesion or microcalcifications >4cm in the upper outer breast, prior surgical interventions in upper outer breast, and history of chemotherapy and tamoxifen treatment. All of the exclusions were for the possibility of impeding lymphatic drainage to the axilla for reasons other than the additional injection of lidocaine. Patients who consented to the prospective portion were interviewed and given the McGill pain questionnaire to complete prior to and after the SNL. The diagnostic accuracy of SNL was determined by successful identification of the sentinel node during surgery based on medical record review, for both pre- and post-intervention groups. We evaluated the proportion of women with successful SNL by technetium alone and those requiring additional periareolar intraoperative injection of methylene blue dye or saline to assist in the sentinel node identification. To assess the similarity between the pre- and post intervention groups, demographic and tumor characteristics of both groups were collected and compared, including age, ethnicity, tumor type, size, grade, estrogen receptor/progesterone receptor/HER2 positivity, and status of nodal metastasis. P values for differences between cohorts are from Wilcoxon rank sum tests comparing continuous measures and Fisher's exact test for categorical measures. RESULTS The pre- and post-intervention groups have similar demographic and tumor characteristics. In the pre- intervention group, 204 patients were included; the diagnostic accuracy of SNL is 94% and 100% with the use of intraoperative methylene blue dye/saline (table). In the post-intervention group, 107 patients (80% participation rate) consented to and received the lidocaine administration prior to the radiotracer injection. The post-lidocaine diagnostic accuracy of SNL is 95% and 100% with the use of intraoperative methylene blue dye/saline (table). There is no significant difference in diagnostic accuracy of SNL pre- and post- lidocaine intervention. The reported level of pain following lidocaine injection is very low (mean = 0.481) on the McGill pain scale of 0 to 10. CONCLUSION The administration of lidocaine during preoperative SNL not only reduces patient pain but also maintains diagnostic accuracy of the procedure itself. Our project validates a patient-centered approach for performing a standard-of-care procedure in breast cancer treatment. At our institution, because of the encouraging result of this project, we have changed our practice behavior to incorporate the use of lidocaine during all preoperative sentinel lymph node injections (unless there is a lidocaine allergy).
    Radiological Society of North America 2013 Scientific Assembly and Annual Meeting; 12/2013
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    ABSTRACT: Digital polymerase chain reaction is a new technology that enables detection and quantification of cancer DNA molecules from peripheral blood. Using this technique, we identified mutant PIK3CA DNA in circulating ptDNA (plasma tumor DNA) from a patient with concurrent early stage breast cancer and non-small cell lung cancer. The patient underwent successful resection of both her breast and lung cancers, and using standard Sanger sequencing the breast cancer was shown to harbor the identical PIK3CA mutation identified in peripheral blood. This case report highlights potential applications and concerns that can arise with the use of ptDNA in clinical oncology practice.
    Human pathology 10/2013; · 3.03 Impact Factor
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    ABSTRACT: Postoperative nausea and vomiting (PONV) are commonly feared after general anesthesia and can impact results. The primary aim of our study was to examine incidence and severity of PONV by investigating complete response, or absence of PONV, to prophylaxis used in patients undergoing DIEP flaps. Our secondary aims were definition of the magnitude of risk, state of the art of interventions, clinical sequelae of PONV, and interaction between these variables, specifically for DIEP patients. A retrospective chart review occurred for 29 patients undergoing DIEP flap breast reconstruction from September 2007 to February 2008. We assessed known patient and procedure-specific risks for PONV after DIEPs, prophylactic antiemetic regimens, incidence, and severity of PONV, postoperative antiemetic rescues, and effects of risks and treatments on symptoms. Three or more established risks existed in all patients, with up to seven risks per patient. Although 90% of patients received diverse prophylaxis, 76% of patients experienced PONV, and 66% experienced its severe form, emesis. Early PONV (73%) was frequent; symptoms were long lasting (average 20 hours for nausea and emesis); and multiple rescue medications were frequently required (55% for nausea, 58% for emesis). Length of surgery and nonsmoking statistically significantly impacted PONV. We identify previously undocumented high risks for PONV in DIEP patients. High frequency, severity, and refractoriness of PONV occur despite standard prophylaxis. Plastic surgeons and anesthesiologists should further investigate methods to optimize PONV prophylaxis and treatment in DIEP flap patients. © 2013 Wiley Periodicals, Inc. Microsurgery, 2013.
    Microsurgery 08/2013; · 1.62 Impact Factor
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    ABSTRACT: PURPOSE: Agents that target the epigenome demonstrate activity in breast cancer models. In preclinical studies, the histone deacetylase inhibitor vorinostat induces cell cycle arrest, apoptosis and differentiation. We evaluated biomarker modulation in breast cancer tissues obtained from women with newly-diagnosed invasive disease who received vorinostat and those who did not. EXPERIMENTAL DESIGN: Tumor specimens were collected from 25 women who received up to 6 doses of oral vorinostat 300 mg twice daily and from 25 untreated controls in a non-randomized study. Candidate gene expression was analyzed by RT-PCR using the Oncotype DX® 21-gene assay, and by immunohistochemistry for Ki-67 and cleaved caspase-3. Matched samples from treated women were analyzed for gene methylation by QM-MSP. Wilcoxon non-parametric tests were used to compare changes in quantitative gene expression levels pre- and post-vorinostat with changes in expression in untreated controls, and changes in gene methylation between pre- and post-vorinostat samples. RESULTS: Vorinostat was well-tolerated and there were no study-related delays in treatment. Compared to untreated controls, there were statistically significant decreases in the expression of proliferation-associated genes Ki-67 (p=0.003), STK15 (p=0.005), and Cyclin B1 (p=0.03) following vorinostat, but not in other genes by the Oncotype DX® assay, or in expression of Ki-67 or cleaved caspase-3 by immunohistochemistry. Changes in methylation were not observed. CONCLUSIONS: Short term vorinostat administration is associated with a significant decrease in expression of proliferation-associated genes in untreated breast cancers. This demonstration of biological activity supports investigation of vorinostat in combination with other agents for the management of breast cancer.
    Clinical Cancer Research 05/2013; · 7.84 Impact Factor
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    ABSTRACT: Collagen I (Col1) fibers are a major structural component in the extracellular matrix of human breast cancers. In a preliminary pilot study, we explored the link between Col1 fiber density in primary human breast cancers and the occurrence of lymph node metastasis. Col1 fibers were detected by second harmonic generation (SHG) microscopy in primary human breast cancers from patients presenting with lymph node metastasis (LN+) versus those without lymph node metastasis (LN-). Col1 fiber density, which was quantified using our in-house SHG image analysis software, was significantly higher in the primary human breast cancers of LN+ (fiber volume=29.22%±4.72%, inter-fiber distance=2.25±0.45  μm) versus LN- (fiber volume=20.33%±5.56%, inter-fiber distance=2.88±1.07  μm) patients. Texture analysis by evaluating the co-occurrence matrix and the Fourier transform of the Col1 fibers proved to be significantly different for the parameters of co-relation and energy, as well as aspect ratio and eccentricity, for LN+ versus LN- cases. We also demonstrated that tissue fixation and paraffin embedding had negligible effect on SHG Col1 fiber detection and quantification. High Col1 fiber density in primary breast tumors is associated with breast cancer metastasis and may serve as an imaging biomarker of metastasis.
    Journal of Biomedical Optics 11/2012; 17(11):116017. · 2.75 Impact Factor
  • Rosemarie Hardin, Lisa K Jacobs
    Oncology (Williston Park, N.Y.) 03/2012; 26(3):256-7. · 3.19 Impact Factor
  • Lisa K Jacobs, Rosemarie E Hardin
    Archives of surgery (Chicago, Ill.: 1960) 11/2011; 146(11):1271. · 4.32 Impact Factor
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    ABSTRACT: Most breast cancers originate in the epithelial cells lining the breast ducts. Intraductal administration of cancer therapeutics would lead to high drug exposure to ductal cells and eliminate preinvasive neoplasms while limiting systemic exposure. We performed preclinical studies in N-methyl-N'-nitrosourea-treated rats to compare the effects of 5-fluorouracil, carboplatin, nanoparticle albumin-bound paclitaxel, and methotrexate to the previously reported efficacy of pegylated liposomal doxorubicin (PLD) on treatment of early and established mammary tumors. Protection from tumor growth was observed with all five agents, with extensive epithelial destruction present only in PLD-treated rats. Concurrently, we initiated a clinical trial to establish the feasibility, safety, and maximum tolerated dose of intraductal PLD. In each eligible woman awaiting mastectomy, we visualized one ductal system and administered dextrose or PLD using a dose-escalation schema (2 to 10 mg). Intraductal administration was successful in 15 of 17 women with no serious adverse events. Our preclinical studies suggest that several agents are candidates for intraductal therapy. Our clinical trial supports the feasibility of intraductal administration of agents in the outpatient setting. If successful, administration of agents directly into the ductal system may allow for "breast-sparing mastectomy" in select women.
    Science translational medicine 10/2011; 3(106):106ra108. · 10.76 Impact Factor
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    ABSTRACT: Merkel cell carcinoma (MCC) is a rare, aggressive, and often fatal cutaneous malignancy that is not usually suspected at the time of biopsy. Because of its increasing incidence and the discovery of a possible viral association, interest in MCC has escalated. Recent effort has broadened our breadth of knowledge regarding MCC and developed instruments to improve data collection and future study. This article provides an update on current thinking about the Merkel cell and MCC.
    Seminars in cutaneous medicine and surgery 03/2011; 30(1):48-56. · 1.81 Impact Factor
  • Eman Sbaity, Lisa K. Jacobs
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    ABSTRACT: The role of sentinel lymph node biopsy for staging of primary breast cancer is well established. However, in cases of previous surgery to the breast or axilla, the reliability of sentinel lymph node biopsy has not been well established. Reoperative sentinel lymph node biopsy potentially has the same benefits as sentinel lymph node biopsy done at the time of the primary diagnosis, including staging, identifying at-risk lymph nodes, and providing critical information for use in treatment decision making. This article reviews the literature regarding reoperative sentinel lymph node biopsy and makes recommendations for implementation of the technology in this setting.
    Current Breast Cancer Reports 01/2011; 3(2):117-123.
  • Radiotherapy and Oncology - RADIOTHER ONCOL. 01/2011; 99.
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    ABSTRACT: Patients at high risk for developing breast cancer and those with early stage breast cancer may have treatment options in addition to systemic therapy for the prevention and treatment of this disease in the near future. Methods of intraductal diagnosis and treatment of breast cancer, including nipple aspiration, ductal lavage and ductoscopy, are discussed in this review. Advances in this field include improvements in equipment and techniques, more reliable biomarker assessment and improved targeted therapies. As a result of these advances, intraductal treatment in high-risk populations is being investigated in clinical trials.
    Current opinion in investigational drugs (London, England: 2000) 06/2010; 11(6):646-52. · 3.55 Impact Factor
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    ABSTRACT: The oncologic management of breast cancer has evolved over the past several decades from radical mastectomy to modern-day preservation of chest and breast structures. The increased rate of mastectomies over recent years made breast reconstruction an integral part of the breast cancer management. Plastic surgery now offers patients a wide variety of reconstruction options from primary closure of the skin flaps to performance of microvascular and autologous tissue transplantation. Well-coordinated partnerships between surgical oncologists, plastic surgeons, and patients address concerns of tumor control, cosmesis, and patients' wishes. The gamut of breast reconstruction options is reviewed, particularly noting state-of-the-art techniques, as well as the advantages and disadvantages of various timing modalities.
    Annals of Surgical Oncology 03/2010; 17(7):1890-900. · 4.12 Impact Factor
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    ABSTRACT: Four major clinical trials have established that trastuzumab added to adjuvant systemic chemotherapy for women with HER2+ breast cancer significantly improves disease-free and overall survival compared with chemotherapy alone. We evaluated pathologic complete response (pCR) rate and cardiac safety of preoperative doxorubicin and cyclophosphamide followed by a taxane with or without trastuzumab. We reviewed pCR rate and change in left ventricular ejection fraction in women with operable HER2+ breast cancer (defined as immunohistochemical 3+ or fluorescence in situ hybridization ratio > or = 2.2) who were treated between 2002 and 2008 with doxorubicin and cyclophosphamide followed by a taxane with or without trastuzumab before definitive breast surgery. We identified 33 patients, of whom 42.4% received preoperative chemotherapy without trastuzumab and 57.6% of whom received trastuzumab with chemotherapy. The pCR rates were 28.6% and 52.6% in the group that received chemotherapy alone or with trastuzumab, respectively (odds ratio, 2.78; 95% CI, 0.64-12.1; P = .173). Severe cardiac events or treatment delays as a result of cardiac toxicity were not observed. With a median follow-up time of 14 months, 21.4% of patients in the non-trastuzumab group and 10.5% in the trastuzumab group had disease recurrence. Sequential administration of preoperative doxorubicin and cyclophosphamide followed by a taxane and trastuzumab combination is safe in women with primary operable HER2+ breast cancer and is associated with a high pCR rate. Large randomized phase III clinical trials are evaluating the role of preoperative trastuzumab when added to anthracycline- and/or taxane-based regimens.
    Clinical Breast Cancer 02/2010; 10(1):40-5. · 2.42 Impact Factor
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    ABSTRACT: To review cutting-edge, novel, implemented and potential translational research and to provide a glimpse into rich, innovative, and brilliant approaches to everyday surgical problems. Scientific literature and unpublished results. Articles reviewed were chosen based on innovation and application to surgical diseases. Each section was written by a surgeon familiar with cutting-edge and novel research in their field of expertise and interest. Articles that met criteria were summarized in the manuscript. Multiple avenues have been used for the discovery of improved means of diagnosis, treatment, and overall management of patients with surgical diseases. These avenues have incorporated the use of genomics, electrical impedence, statistical and mathematical modeling, and immunology.
    Archives of surgery (Chicago, Ill.: 1960) 02/2010; 145(2):187-96. · 4.32 Impact Factor
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    ABSTRACT: Sentinel lymph node biopsy has allowed improved staging of the axilla with reduced morbidity in breast cancer patients. However, as with any new technology there are questions as to how to best implement the technique into clinical practice. Changes in the staging system for breast cancer have incorporated sentinel lymph node biopsy findings, resulting in questions as to how to manage the remainder of the axilla when there is low volume disease in the sentinel lymph nodes. The use of the sentinel lymph node to predict additional positive nodes and to direct surgical management of the axilla and adjuvant systemic and radiation therapy is reviewed.
    Breast disease 01/2010; 31(2):99-106.
  • Plastic and Reconstructive Surgery - PLAST RECONSTR SURG. 01/2010; 125.
  • Journal of Clinical Oncology 10/2009; 27(34):5673-5. · 18.04 Impact Factor

Publication Stats

260 Citations
151.00 Total Impact Points

Institutions

  • 2007–2012
    • Johns Hopkins University
      • Department of Surgery
      Baltimore, MD, United States
  • 2010
    • University of Maryland, Baltimore
      Baltimore, Maryland, United States
  • 2008–2010
    • Johns Hopkins Medicine
      • Department of Surgery
      Baltimore, Maryland, United States