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Published: February 2016

Open Access Gateway

A Combination of Targeted Therapy with Chemotherapy Backbone Induces Response in a Treatment-Resistant Triple-Negative MCL1-Amplified Metastatic Breast Cancer Patient

Ali S.M.a · Watson J.b · Wang K.a · Chung J.H.a · McMahon C.a · Ross J.S.a, c · Dicke K.A.b

Author affiliations

aFoundation Medicine Inc., Cambridge, Mass., bArlington Cancer Center, Arlington, Tex., and cAlbany Medical College, Albany, N.Y., USA

Corresponding Author

Karel A. Dicke, MD, PhD

Arlington Cancer Center

906 West Randol Mill Rd

Arlington, TX 76012 (USA)

E-Mail precisionmedicinekd@gmail.com

Related Articles for ""

Case Rep Oncol 2016;9:112-118

Abstract

After failure of anthracycline- and platinum-based therapy, no effective therapies exist for management of metastatic triple-negative breast cancer (TNBC). We report a case of metastatic TNBC harboring MCL1 amplification, as identified by comprehensive genomic profiling in the course of clinical care. MCL1 is an antiapoptotic gene in the BCL2 family, and MCL1 amplification is common in TNBC (at least 20%). A personalized dose-reduced regimen centered on a combination of sorafenib and vorinostat was implemented, based on preclinical evidence demonstrating treatment synergy in the setting of MCL1 amplification. Although hospice care was being considered before treatment initiation, the personalized regimen yielded 6 additional months of life for this patient. Further rigorous studies are needed to confirm that this regimen or derivatives thereof can benefit the MCL1-amplified subset of TNBC patients.

© 2016 The Author(s). Published by S. Karger AG, Basel


Case Presentation

A 51-year-old female was diagnosed in November 2008 with stage IIA, N0, M0, ER-/PR-, HER2-negative breast cancer with two lumpectomies. She received six rounds of cyclophosphamide and docetaxel from December 2008 to March 2009, followed by irradiation to the left breast in April/May 2009. She remained disease free for 2 years and then had a recurrence in the left breast in September 2011. The patient received two rounds of doxorubicin and paclitaxel, but she did not respond. In November 2011, she received carboplatin/nab-paclitaxel without response. In December 2011, a left total mastectomy was performed demonstrating a poorly differentiated breast adenocarcinoma measuring 7.1 cm in the greatest dimension located centrally in the specimen and with clear margins. The tumor was Nottingham grade 3, with lymphovascular invasion but no evidence of nipple and skin involvement. The left central node was identified and assessed as free of tumor, demarcating this as T3, N0, (clinical) M0 disease and as stage IIB, node-negative and triple-negative breast cancer (TNBC).

Over the next 2 months, the patient received two rounds of gemcitabine and carboplatin with additional irradiation to the skin on the left side. Six months later, PET scan imaging revealed suspicious lesions in the right (contralateral) breast with suspicious foci also in the operative site on the left. A right mastectomy was performed in March 2012, and the patient received four cycles of eribulin. Two months later, biopsy of the left neck was performed revealing metastatic carcinoma. Subsequent PET scan then revealed lesions in the axial skeleton consistent with metastatic disease.

Having exhausted standard-of-care treatment, the patient was entered into three clinical trials serially utilizing NOTCH inhibitors, MEK inhibitors, and a trial utilizing a CDK4/6 dual inhibitor. After rapid failure of each investigational agent in the course of 1 year, a CT performed on April 17, 2013, showed greater than 50% liver involvement of tumor; other sites also involved were the lymph nodes, lung, and skeletal systems. On May 9, 2013, the patient came to the Arlington Cancer Center for a fourth clinical opinion. At that time, tumor involvement in the liver had increased to greater than 85% per CT scan, and because of rapid progression in the liver, life expectancy was estimated to be 1 month. Earlier that year a breast tissue specimen was submitted for comprehensive genomic profiling which was used by us to identify options for treatment as all standard-of-care and clinical trials had been exhausted (see Methods). On May 14, 2013, personalized treatment based on the genomic profile of the tumor was initiated.

Methods

With patient permission, the left primary mastectomy specimen was submitted for comprehensive genomic profiling (FoundationOne), performed in a CLIA-certified, CAP-accredited, NYS-regulated laboratory (Foundation Medicine). DNA extracted from formalin-fixed paraffin-embedded tumor was analyzed by hybridization capture of 3,320 exons from 186 cancer-related genes and 37 introns of 14 genes commonly rearranged in cancer. At least 50 ng of DNA was isolated and sequenced to high, uniform coverage, as previously described [1]. All classes of genomic alterations (GA) consisting of base substitutions, short insertions, and deletions, focal gene amplifications, homozygous deletions, and select rearrangements were determined and reported for this case. Clinically relevant GA (CRGA) were defined as those which suggest benefit from targeted therapies, or mechanism-based clinical trials. Tumor response was measured by PET/CT and CT scans throughout the treatment.

Results

Hybrid capture-based CGP demonstrated that the tumor harbored MCL1 amplification and base substitutions in BAP1 C649fs*6 (a truncating alteration) and a TP53 (a splice site mutation). On the basis of the genomic profiling results, the patient was treated with an intensive personalized multidrug regimen with targeted therapy including sorafenib (Nexavar) and vorinostat (Zolinza) to target MCL1 [2,3,4,5,6], everolimus (Afinitor), cetuximab (Erbitux) to specifically target the mTOR and EGFR pathways [7,8], as well as the chemotherapeutic agent nab-paclitaxel (Abraxane), which was selected by biomarker testing (SPARC poly- and monoclonal antibodies [9]), and denosumab (Xjeva), a RANKL binder, was added for bone metastases [10,11] (table 1). Eight courses (C) were administered with variable dosing of vorinostat, sorafenib, and nab-paclitaxel. Dosing for each agent was altered on the basis of toxicity during treatment as observed by the treating physician.

Table 1

Treatment program

http://www.karger.com/WebMaterial/ShowPic/494257

C1 showed a major response in the liver, lung, and lymph nodes, but not in the skeletal system (fig. 1). Toxicity was noted, mainly weakness, GI toxicity consisting of nausea, vomiting, and diarrhea, and bone marrow toxicity consisting of anemia, thrombocytopenia and neutropenia (grade 3). Platelets were kept artificially above 70,000/m3 to avoid severe nose bleeding by sorafenib, and hemoglobin was kept above 8 g/100 ml to avoid fatigue due to anemia. Still there was significant total overall weakness, and the patient needed treatment respite of 4 weeks. After 4 weeks of rest, significant progression of disease was noted in the skeletal system, so denosumab was added to the previous regimen and then maintained throughout future courses. C2 was started and in order to decrease toxicity, we shortened the length of treatment from 6 weeks to 3 weeks. Response was shown in C2, but not as profound as after C1. The doses of vorinostat and sorafenib were increased in C3,4. A significant overall response was observed. However, side effects significantly increased including weakness, diarrhea, nausea, vomiting and bone marrow toxicities. In C5 vorinostat was held, and the other drugs including sorafenib were decreased by 25%. Disease progression was observed in this cycle. In C6 vorinostat was restarted at lower dose, and sorafenib and the other drugs were continued at the same level as C5, resulting in stabilization of disease, including osseous metastases. In C7 vorinostat and sorafenib were further increased, which resulted in overall decrease of disease. However, toxicity was significant and the treatment was interrupted for 1 month and the patient's disease further progressed. C8 was started with lower doses of sorafenib, vorinostat, and nab-paclitaxel. Due to weakness and GI toxicity, treatment was discontinued at patient's request, and the patient expired thereafter.

Fig. 1

Left: PET scan 5/14/2013 before treatment shows hepatomegaly with intense hypermetabolic FDG accumulation (SUV up to 20) throughout the entire liver with very low areas of normal hepatic parenchyma. Right: PET scan 6/27/13 after C1 shows subsided hepatomegaly and decrease of liver metastases with a decrease in FDG activity (SUV between 4 and 6).

http://www.karger.com/WebMaterial/ShowPic/494256

Discussion

TNBC is an aggressive disease defined as breast carcinoma with negative slide-based assays for estrogen, progesterone receptor and HER2. Consistent with being a diagnosis of exclusion, TNBC is widely understood to encompass significant genomic heterogeneity [12]. Alterations in BRCA1/2 that create defects in homologous recombination define an important subset of TNBC with sensitivity to first-line platinum treatment and PARP inhibitors, but for the remaining majority of TNBC not harboring BRCA alterations, no particular benefit can be ascribed to such therapies [13].

The metastatic TNBC case reported here harbored amplification of MCL1, and a truncating mutation in BAP1, as well as a mutated TP53. MCL1, a member of the BCL2 antiapoptotic gene family is amplified in 20-54% of TNBC cases [14]. Amplification of MCL1 is thought to interfere with the physiologic induction of apoptosis, which is broadly consistent with a role in oncogenesis [15]. MCL1 amplification is one of three alterations observed in this tumor, potentially empirically consistent with this alteration being an oncogenic driver. Given the assumption of MCL1 amplification serving as an oncogenic driver, no molecularly targeted therapies specific to this alteration are known to exist at present, highlighting a large unmet medical need in this subset of MCL1-amplified TNBC patients with a poor prognosis.

Sorafenib is a promiscuous multikinase inhibitor that has defied ready characterization of its antineoplastic in vivo effect. Preclinical studies have demonstrated that sorafenib can induce cell death/apoptosis mediated by the downregulation of MCL1, but it remains to be definitively demonstrated whether this is the relevant effect of sorafenib [2,3]. Interestingly, a synergy of co-administration of sorafenib and vorinostat, a histone deacetylase inhibitor has been observed, and this proapoptotic effect is also thought to be routed through MCL1 [4,5,6].

For this patient, the clinical benefit of the regimen was quite remarkable, and the ‘dropout' of individual therapies does hint at the relevant importance of each component. However, it is impossible to define the most important components, and relevance of each therapy vis-à-vis the GA. Sorafenib has previously been investigated as a combination therapy in breast cancer, typically with a chemotherapy backbone, but differing conclusions as to clinical benefit have been reached, and definitive studies are ongoing [15,16]. In such studies, even if biomarker stratification was performed, no genomic stratification was used as criteria for entry, so responders to sorafenib cannot be segregated on the basis of MCL1 amplifications or other alterations [17].

No anecdotal clinical reports or completed clinical trials are currently available to guide treatment for MCL1-amplified breast cancers. The personalized treatment regimen utilized here resulted in the patient experiencing 6 months of extended survival. The administration of sorafenib and vorinostat in the presence of the MCL1 amplification is essential to the success of this program. Given the high frequency of MCL1 amplification in TNBC, the current case study potentially suggests that other such patients might benefit from a similar treatment regimen.

The importance of vorinostat and sorafenib is supported by results of C5 when a decreased dose of sorafenib and deletion of vorinostat led to progression of disease, furthermore by results of C6 which stabilized disease when vorinostat was reintroduced. In C7 there was additional disease response when raising the dosage of the 2 drugs. In contrast to other cycles in which dropout of other agents, e.g., everolimus, were still effective in inducing disease response.

In conclusion, the efficacy of sorafenib and vorinostat in combination with a backbone of other nontargeted therapies in this MCL1-amplified TNBC is a provocative observation that warrants additional investigation, as at present, MCL1-amplified TNBC patients are unable to benefit from molecular targeted therapy in current practice paradigms.

Statement of Ethics

The patient and her husband gave informed consent to Dr. Karel Dicke at the time of treatment protocol, after full disclosure of risks, side effects and potential benefit.

Disclosure Statement

S.M.A., C.M., J.H.C., and J.S.R. are employees of and have equity interest in Foundation Medicine, Inc. K.W. is a former employee of, current consultant to, and has equity interest in Foundation Medicine, Inc. J.W. and K.D. have nothing to declare.


References

  1. Frampton GM, Fichtenholtz A, Otto GA, Wang K, Downing SR, He J, et al: Development and validation of a clinical cancer genomic profiling test based on massively parallel DNA sequencing. Nat Biotechnol 2013;31:1023-1031.
  2. Fecteau J-F, Bharati IS, O'Hayre M, Handel TM, Kipps TJ, Messmer D: Sorafenib-induced apoptosis of chronic lymphocytic leukemia cells is associated with downregulation of RAF and myeloid cell leukemia sequence 1 (Mcl-1). Mol Med Camb Mass 2012;18:19-28.
  3. Abdulghani J, Allen JE, Dicker DT, Liu YY, Goldenberg D, Smith CD, et al: Sorafenib sensitizes solid tumors to Apo2L/TRAIL and Apo2L/TRAIL receptor agonist antibodies by the Jak2-Stat3-Mcl1 axis. PloS One 2013;8:e75414.
  4. Dasmahapatra G, Yerram N, Dai Y, Dent P, Grant S: Synergistic interactions between vorinostat and sorafenib in chronic myelogenous leukemia cells involve Mcl-1 and p21CIP1 down-regulation. Clin Cancer Res Off J Am Assoc Cancer Res 2007;13:4280-4290.
  5. Park MA, Zhang G, Martin AP, Hamed H, Mitchell C, Hylemon PB, et al: Vorinostat and sorafenib increase ER stress, autophagy and apoptosis via ceramide-dependent CD95 and PERK activation. Cancer Biol Ther 2008;7:1648-1662.
  6. Park MA, Mitchell C, Zhang G, Yacoub A, Allegood J, Häussinger D, et al: Vorinostat and sorafenib increase CD95 activation in gastrointestinal tumor cells through a Ca(2+)-de novo ceramide-PP2A-reactive oxygen species-dependent signaling pathway. Cancer Res 2010;70:6313-6324.
  7. Pirker R, Pereira JR, von Pawel J, et al: EGFR expression as a predictor of survival for first-line chemotherapy plus cetuximab in patients with advanced non-small-cell lung cancer: analysis of data from the phase 3 FLEX study. Lancet Oncol 2012;13:33-42.
  8. Baselga J, Campone M, et al: Everolimus in postmenopausal hormone-receptor-positive advance breast cancer. N Eng J Med 2012;366:520-529.
  9. Desai N, Trieu V, et al: SPARC expression correlates with tumor response to albumin-bound paclitaxel in head and neck cancer patients. Transl Oncol 2009;2:59-64.
  10. Roodman GD: Mechanisms of bone metastasis. N Engl J Med 2004;350:1655-1664.
  11. Mundy GR: Metastasis to bone: causes, consequences and therapeutic opportunities. Nat Rev Cancer 2002;2:584-593.
  12. Cancer Genome Atlas Network: Comprehensive molecular portraits of human breast tumours. Nature 2012;490:61-70.
  13. Lord CJ, Ashworth A: Mechanisms of resistance to therapies targeting BRCA-mutant cancers. Nat Med 2013;19:1381-1388.
  14. Balko JM, Giltnane JM, Wang K, Schwarz LJ, Young CD, Cook RS, et al: Molecular profiling of the residual disease of triple-negative breast cancers after neoadjuvant chemotherapy identifies actionable therapeutic targets. Cancer Discov 2014;4:232-245.
  15. Haschka MD, Soratroi C, Kirschnek S, Häcker G, Hilbe R, Geley S, et al: The NOXA-MCL1-BIM axis defines lifespan on extended mitotic arrest. Nat Commun 2015;6:6891.
  16. Gradishar WJ, Kaklamani V, Sahoo TP, Lokanatha D, Raina V, Bondarde S, et al: A double-blind, randomised, placebo-controlled, phase 2b study evaluating sorafenib in combination with paclitaxel as a first-line therapy in patients with HER2-negative advanced breast cancer. Eur J Cancer 2013;49:312-322.
  17. Baselga J, Segalla JGM, Roché H, Del Giglio A, Pinczowski H, Ciruelos EM, et al: Sorafenib in combination with capecitabine: an oral regimen for patients with HER2-negative locally advanced or metastatic breast cancer. J Clin Oncol Off J Am Soc Clin Oncol 2012;30:1484-1491.

Author Contacts

Karel A. Dicke, MD, PhD

Arlington Cancer Center

906 West Randol Mill Rd

Arlington, TX 76012 (USA)

E-Mail precisionmedicinekd@gmail.com


Article / Publication Details

First-Page Preview
Abstract of Published: February 2016

Published online: February 18, 2016
Issue release date: January – April

Number of Print Pages: 7
Number of Figures: 1
Number of Tables: 1


eISSN: 1662-6575 (Online)

For additional information: http://www.karger.com/CRO


Open Access License / Drug Dosage / Disclaimer

This article is licensed under the Creative Commons Attribution-NonCommercial 4.0 International License (CC BY-NC). Usage and distribution for commercial purposes requires written permission. Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug. Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.

References

  1. Frampton GM, Fichtenholtz A, Otto GA, Wang K, Downing SR, He J, et al: Development and validation of a clinical cancer genomic profiling test based on massively parallel DNA sequencing. Nat Biotechnol 2013;31:1023-1031.
  2. Fecteau J-F, Bharati IS, O'Hayre M, Handel TM, Kipps TJ, Messmer D: Sorafenib-induced apoptosis of chronic lymphocytic leukemia cells is associated with downregulation of RAF and myeloid cell leukemia sequence 1 (Mcl-1). Mol Med Camb Mass 2012;18:19-28.
  3. Abdulghani J, Allen JE, Dicker DT, Liu YY, Goldenberg D, Smith CD, et al: Sorafenib sensitizes solid tumors to Apo2L/TRAIL and Apo2L/TRAIL receptor agonist antibodies by the Jak2-Stat3-Mcl1 axis. PloS One 2013;8:e75414.
  4. Dasmahapatra G, Yerram N, Dai Y, Dent P, Grant S: Synergistic interactions between vorinostat and sorafenib in chronic myelogenous leukemia cells involve Mcl-1 and p21CIP1 down-regulation. Clin Cancer Res Off J Am Assoc Cancer Res 2007;13:4280-4290.
  5. Park MA, Zhang G, Martin AP, Hamed H, Mitchell C, Hylemon PB, et al: Vorinostat and sorafenib increase ER stress, autophagy and apoptosis via ceramide-dependent CD95 and PERK activation. Cancer Biol Ther 2008;7:1648-1662.
  6. Park MA, Mitchell C, Zhang G, Yacoub A, Allegood J, Häussinger D, et al: Vorinostat and sorafenib increase CD95 activation in gastrointestinal tumor cells through a Ca(2+)-de novo ceramide-PP2A-reactive oxygen species-dependent signaling pathway. Cancer Res 2010;70:6313-6324.
  7. Pirker R, Pereira JR, von Pawel J, et al: EGFR expression as a predictor of survival for first-line chemotherapy plus cetuximab in patients with advanced non-small-cell lung cancer: analysis of data from the phase 3 FLEX study. Lancet Oncol 2012;13:33-42.
  8. Baselga J, Campone M, et al: Everolimus in postmenopausal hormone-receptor-positive advance breast cancer. N Eng J Med 2012;366:520-529.
  9. Desai N, Trieu V, et al: SPARC expression correlates with tumor response to albumin-bound paclitaxel in head and neck cancer patients. Transl Oncol 2009;2:59-64.
  10. Roodman GD: Mechanisms of bone metastasis. N Engl J Med 2004;350:1655-1664.
  11. Mundy GR: Metastasis to bone: causes, consequences and therapeutic opportunities. Nat Rev Cancer 2002;2:584-593.
  12. Cancer Genome Atlas Network: Comprehensive molecular portraits of human breast tumours. Nature 2012;490:61-70.
  13. Lord CJ, Ashworth A: Mechanisms of resistance to therapies targeting BRCA-mutant cancers. Nat Med 2013;19:1381-1388.
  14. Balko JM, Giltnane JM, Wang K, Schwarz LJ, Young CD, Cook RS, et al: Molecular profiling of the residual disease of triple-negative breast cancers after neoadjuvant chemotherapy identifies actionable therapeutic targets. Cancer Discov 2014;4:232-245.
  15. Haschka MD, Soratroi C, Kirschnek S, Häcker G, Hilbe R, Geley S, et al: The NOXA-MCL1-BIM axis defines lifespan on extended mitotic arrest. Nat Commun 2015;6:6891.
  16. Gradishar WJ, Kaklamani V, Sahoo TP, Lokanatha D, Raina V, Bondarde S, et al: A double-blind, randomised, placebo-controlled, phase 2b study evaluating sorafenib in combination with paclitaxel as a first-line therapy in patients with HER2-negative advanced breast cancer. Eur J Cancer 2013;49:312-322.
  17. Baselga J, Segalla JGM, Roché H, Del Giglio A, Pinczowski H, Ciruelos EM, et al: Sorafenib in combination with capecitabine: an oral regimen for patients with HER2-negative locally advanced or metastatic breast cancer. J Clin Oncol Off J Am Soc Clin Oncol 2012;30:1484-1491.
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