Karel A. Dicke M.D., Ph.D.

Transcription

1 Karel A. Dicke M.D., Ph.D. 1

2 Genomic Medicine Chemotherapy is selected on the basis of biomarkers in tumor cells. Chemotherapy kills tumor cells. Precision medicine: drugs targeting mutations in single genes to silence proliferation, cell division, metabolism and angiogenesis. Targeting drugs do not necessarily kill tumor cells but silence specific functions of the cell. Chemotherapy based on biomarker selection + drugs targeting single gene mutations, (i.e. precision medicine) = Genomic Medicine 2

3 Evaluation of Efficacy of Genomic Medicine 1. Randomized studies 2. Comparison with carefully matched historical controls 3. Comparison outcomes with similar cohorts of patients published in the literature, including tumor registry 4. Observational studies, single or multiple patients. 3

4 Comparison of overall survival (OS) between breast cancer (BRCA) patients treated with biomarker-selected chemotherapy (Caris) versus physician-selected treatment (non-caris) OS BRCA from 2 nd Met: Caris versus non-caris 4

5 Focus In this lecture I will present 6 cases treated with genomic medicine of which the last 2 are updates from the 2013 conference. 5

6 Case Report 1 DOB: 1968 Diagnosis: History: Female with triple-negative breast cancer 2007 left breast lumpectomy Treatment (adjuvant, 2007): Adriamycin, cyclophosphamide x4 courses Paclitaxel (Taxol) x4 courses Recurrence in right breast December, 2013 Bilateral mastectomy January, 2014 Transferred to ACC. 6

7 Genomic Profile Biomarkers SPARC (++) Caris Life Sciences - Chemotherapy Drugs nab-paclitaxel (Abraxane) TS ( - ) 5FU Foundation Medicine Targeted Therapy Single Gene Mutations MCL-1 amplification PIK3R1 T369fs*6 BAP1 K626fs*11 Drugs sorafenib (Nexavar), vorinostat Everolimus (Afinitor) Vorinostat (Zolinza) *3 non drugable mutations: MLL-2 amplification, TP53 Q144 and LYN1 amplification identified 7

8 Rationale of the Treatment Program (1) Chemotherapy disrupts DNA synthesis and kills the cells and therefore reduces the tumor load. Drugs targeting single gene mutations usually silence the pivotal genetic pathway and make cells dormant. 8

9 Rationale of the Treatment Program (2) MCL-1 amplification Gene: MCL-1 encodes a member of the BCL-2 family regulating apoptosis. Amplification of MCL-1 has been reported to be associated with high grade and poor prognosis in breast cancer and is inhibitory for apoptosis. Studies have shown that the multikinase inhibitor sorafenib (Nexavar) down- regulates MCL-1 and synergizes with vorinostat (Zolinza), a HDAC inhibitor, inducing cell death. 9

10 Rationale of the Treatment Program (3) PIK3R1 (T3bgfs*6) Gene: PIK3R1 encodes the protein stabilizing and inhibiting PI3K. Mutation of PIK3R1 (T3bgfs*6) activates PI3K pathway signaling and subsequently the downstream AKT/mTOR pathway. This will stimulate cell proliferation. Everolimus is an mtor inhibitor and negatively affects proliferation. 10

11 Rationale of the Treatment Program (4) BAP-1 K626fs*11 Gene: BAP-1 encodes a pivotal protein in the degradation pathway. The BAP-1 is a tumor suppressor and interacts with BRACA-1. BAP-1 mutation K626fs*11 truncates BAP-1. This results in loss of BAP-1 function and deregulates BRACA-1, a tumor suppressor gene important in cell cycle regulation. HDAC inhibitors, such as vorinostat, are being used for treatment. 11

12 Treatment Schedule Drug and Dose Duration* Sorafenib (Nexavar) 200mg bid Days 1 15 Vorinostat (Zolinza) 200mg qd Everolimus (Afinitor) 5mg qd Nab-paclitaxel (Abraxane) 75mg/m 2 Days FU, 1000 mg/m 2 c.i. over 24 hours *Duration of treatments 15 days with time intervals of 15 days. 12

13 Evaluation of Treatment Results Survival after recurrence: 36+ months Clinical status: NED PET scan: neg., tumor marker: BR 27-29: <25 cfdna (Foundation act): MCL1-, BAP1-, PIK3R1- MLL2-, TP53 equivocal CTC (circulating tumor cells, Biocept): 0 Number of treatment courses: 33 Toxicity: Minimal GI toxicity Grade 1 hematotoxicity Minimal weakness QOL: Excellent, patient takes care of a family and works a full-time job. 13

14 CASE REPORT 2 DOB: 1964 Diagnosis: Female, adenocarcinoma of the pancreas diagnosed in 9/2013, pt N1 M0 stage II. Treatment: Treated with Gemzar, became stage IV in 12/2014 with disease in the liver. Cyberknife liver lesion in 2/2015. No further treatment until 10/2015 when disease progressed in the liver. Treatment with 2 courses of FOLFIRI with significant side effects and transferred to ACC on 12/1/

15 Genetic Analysis (1) TS- ERCC1- Chemotherapy genotyping: (Caris) Potential benefit 5FU, Xeloda Cisplatin, Carboplatin TUBB3+, TLE3++ Equivocal benefit Taxanes RRM1- Potential lack of benefit Gemzar 15

16 Next Generation Sequencing (Foundation Medicine) GENE KRAS TP53 CDKN2A/B INPP4B Mutation G12R L111fs*9 Loss Splice site G>A 16

17 KRAS Mutation G12R Gene: KRAS encodes a member of the RAS family. Activating mutations in RAS genes can cause uncontrolled proliferation and tumor formation. KRAS mutation G12R has been characterized to be activating and oncogenic. KRAS mutations have been observed in 91-95% of pancreatic adenocarcinoma cases. Potential treatment strategies: KRAS activation predicts sensitivity to MEK inhibitors alone, such as tramatinib (Mekinist), or in combination with other targeted therapies such as CDK4/6 inhibitors such as palbociclib (Ibrance). 17

18 CDKN2A/B : LOSS Gene: CDKN2A encodes two different, unrelated tumor suppressor proteins, p16ink4a and p14arf. Gene CDKN2B encodes the tumor suppressor p15ink4b. Both p16ink4a and p15ink4b bind to and inhibit CDK4 and CDK6, thereby maintaining the activity of the Rb tumor suppressor. Loss or inactivation of either p16ink4a or p15ink4b contributes to dysregulation of the CDK4/6-cyclin-Rb pathway and loss of cell cycle control. Potential treatment strategies: preclinical studies suggest that tumors with loss of p16ink4a or p15ink4b function may be sensitive to CDK4/6 inhibitors such as palbociclib. 18

19 INPP4B mutation: splice site >A Gene: INPP4B encodes an enzyme that negatively regulates the P13K-AKT pathway and behaves as a tumor suppressor. Loss of activation of INPP4B by mutation 2276 leads to activation of the P13K-AKT pathway and, therefore, the downstream mtor pathway, activating cell proliferation. Potential Treatment: Inhibitors of the P13K-AKT pathway have not been tested clinically but it would make sense to inhibit the mtor pathway with everolimus to inhibit cell proliferation. 19

20 Treatment and Results Treatment started at ACC in Jan. 2016, 2+ years after diagnosis. Tumor was kept under control for 8 months with Abraxane, 5FU and Cisplatinum. Patient received one course of palbociclib. In Sept. 2016, a new liver lesion was detected, which was removed. At that time, right-sided sinus cavernous thrombosis in the brain developed, treated with Lovenox (blood thinner). Cancer treatment had to be interrupted for 1 month and liver lesions returned. In Nov. 2016, trametinib (Mekinist) became available; immediately after start with 1mg (=50%), patient developed anasarca (fluid retention) so that palbociclib (Ibrance) was postponed. Patient had an excellent response to Mekinist and weekly Abraxane + 5FU and liver lesions responded and were not visible on MRI 12/7/2016 and CT abdomen 2/7/2017. CA 19-9 decreased from 6000 to 120. QOL is compromised by fluid retention. Palbociclib will be held until anasarca has resolved. Plan is to combine Mekinist with palbociclib with intermittent everolimus. 30+ months survival after metastatic disease is exceptional. 20

21 Case Report 3 DOB: 1957 Diagnosis: 9/2013, female with ductal cell adenocarcinoma in the left breast, ER+, PR-, Her-2/neu-, 1/8 nodes+, pt2n1m0. Oncotype score: 58%. Treatment: Anastrozole, double mastectomies. No radiation and chemotherapy. Recurrence in 5/2015 in lymph nodes of the axilla and neck. Treated with naturopathic medicine. In addition, in October 2015, disease progressed in lungs and nodes in the neck. Treatment with proton radiation to neck and chest from January to March, After which, she transferred to Arlington Cancer Center. 21

22 Genomic Profile Caris Life Sciences - Chemotherapy Biomarkers TLE3 (+) ERCC1 (-) AR (+) ER (+) Drugs Docetaxel (Taxotere), paclitaxel (Taxol), nab-paclitaxel (Abraxane Platinol Casodex (bicalutamide) Fulvestrant Foundation Medicine Targeted Therapy CCND1 (+) MEN1 G42V FGF19 amplification FGF3 amplification FGF4 amplification GATA3 L417fs*30+ palbociclib palbociclib None None None None 22

23 Rationale of the Treatment Program (1) Chemotherapy: Hormonal therapy: Targeted therapy: docetaxel fulvestrant bicalutamide palbociclib 23

24 Rationale of the Treatment Program (2) CCND1 amplification Gene: CCND1 encodes cyclin D1, a binding partner of the kinases CDK4 and CDK6 that regulate Rb activity and cell cycle progression. Amplification of CCND1 has been positively correlated with overexpression of cyclin D1 and leads to excessive proliferation. Prognosis: Both CCND1 amplification and Cyclin D1 overexpression predict poor prognosis in patients with ER-positive breast cancer. Treatment Strategies: Amplification of CCND1 may predict sensitivity to CDK4/6 inhibitors such as palbociclib. 24

25 Rationale of Treatment Program (3) MEN1 (G42V) Gene: MEN1 encodes menin and activates directly p18ink4c, which is associated with regulating CDK4. Loss of MEN1 or inactivation such as mutation of G42V, deactivates p18ink4c and increases expression and activation of CDK4. Treatment Strategy: Tumors with MEN1 loss or inactivation may be sensitive to CDK4/6 inhibitors such as palbociclib. 25

26 Rationale of Treatment Program (4) FGF4 Amplification Gene: FGF4 encodes fibroblast growth factor 4 and lies in the region of chromosome 11q13 that also contains FGF19, FGF3 and CCND1, the latter gene encoding cyclin D1, a key regulator of cell cycle progression. Amplification of FGF4 has not yielded strong evidence of an independent role of FGF4 over and above the influence exerted by CCND1. Treatment Strategies: Treatment will be limited to palbociclib, which affects the CCND1 pathway. 26

27 Treatment Program Chemotherapy: Taxol 60mg/m 2 weekly Hormonal Therapy: fulvestrant 500mg i.m. monthly bicalutamide 50mg p.o. daily Targeted Therapy: palbociclib 75mg p.o. daily 3 wks on, 1 wk off 27

28 Treatment, Results, Clinical Course (1) The last proton treatment to thorax and neck finished at the end of March On 3/17/2016, fulvestrant and palbociclib were started but had to be stopped on 4/7/2016 due to severe thrombocytopenia. On 5/1/2016, everolimus and estemestane were started due to brain mets per MRI. Everolimus crosses the blood-brain barrier. Treatment had to be stopped due to mucositis. 28

29 Treatment, Results, Clinical Course (2) On 5/25/2016, after finishing brain radiation, we decided to return to treatment program based on outcome of genomic testing: Taxol, fulvestrant, casodex, palbociclib. Tumor markers normalized and PET scan activity became negative in August From the end of May, patient s general condition improved dramatically due to tumor response and aggressive supportive care. Performance status dropped from 2 to 0 (Zubrod classification). From wheelchair to normal activity! 29

30 Treatment, Results, Clinical Course (3) Response lasted until 1/30/2017, when CNS lesions markedly increased. Tumor markers started to rise. PET scan revealed return of active lung and bone lesions. On 2/23/2017, PET scan showed multiple new liver lesions. Patient expired. 30

31 Case 3 Concluding Remarks From Hospice to Hospice: one year delay. 8 of the 12 months, a good quality of life. Goals set by patient achieved. Response to treatment: 8 months No hospitalization Side effects: G.I. and bone marrow toxicity, weakness treated on outpatient basis. Supportive care: i.v. fluids, antibiotics, food supplements and blood products, highly essential. A hands-on approach, physically and spiritually! 31

32 Case Report 4 DOB: 1953 Disease History: Female diagnosed in 2010 with endometrial cancer, FIGO grade 2, 13/15 lymph nodes positive. Treatment: Oopherectomy, hysterectomy, lymph node dissection. Patient stayed disease-free until 6/2014 when she relapsed in the spleen. Despite extensive treatment with Taxol, Carboplatinum, Adriamycin, Yttrium 90 in the liver, disease progressed in liver, lung, pelvis, peritoneum and abdominal lymph nodes. Only everolimus stabilized disease for 3 months but it had to be stopped because of oral mucositis. Patient stopped treatment in June 2016 and considered hospice. 32

33 Reason for Consultation at ACC 9/14/2016 Patient wanted to look for options to limitedly extend life to reach 2 goals: a. Time to organize her end-of-life and level with her family, especially her daughters. b. Realize her desire to become a grandmother. 33

34 Genomic Profile No time for Caris Life Science analysis Foundation Medicine analysis, already available PIK3CA mutation E545G PTEN inactivating mutation Estrogen receptor-positive 34

35 Rationale of Treatment Program (1) Everolimus (Afinitor) Olaparib (Lynparza) Letrozole (Femara) 35

36 Rationale of Treatment Program (2) PIK3CA (C545G) Gene: PIK3CA encodes the protein p110 alpha. The PIK3K pathway is involved in cell signaling that regulates cell growth proliferation and survival. The C545G mutation is an activating mutation and stimulates the AKT mtor pathway and therefore cell growth and proliferation. This mutation predicts sensitivity to mtor inhibitors such as everolimus. 36

37 Rationale of Treatment Program (3) PTEN mutation K267fs*9 Gene: PTEN functions as a tumor-suppressor by negatively regulating the P13K/AKT/mTOR pathway. Mutations inactivating PTEN such as K267fs*9, or loss of PTEN, leads to activation of P13K/AKT/mTOR pathway and diseaseprogression and predicts sensitivity to mtor inhibitors such as everolimus. Also, preclinical studies suggest that loss of PTEN predicts sensitivity of PARP inhibitors such as olaparib in BRCA1 mutation-negative pts. and restores cell cycle regulation. Treatment Strategies: Everolimus and olaparib. 37

38 Treatment Plan Everolimus (Afinitor), 5 mg p.o. daily Olaparib (Lynparza), 300 mg p.o. b.i.d. Letrozole (Femara), 2.5 mg p.o. daily 38

39 Results of Treatment: Response Treatment start date: 9/14/2016 PET SCAN 9/14/ /6/ /20/2016 One picture is worth a thousand words! 39

40 Clinical Course In the first month, patient improved clinically. On 10/25 she was diagnosed with peritonitis and bowel perforation. Exploratory surgery confirmed diagnosis. Perforations most likely caused by weakening of tumor/regression due to treatment. Expired 11/

41 Goals Achieved 1. Patient had gained enough time and quality of life to communicate effectively with family and died in peace. 2. In the 2 months of life extension, one of her daughters became pregnant and the sonogram hung at her bedside to connect with her grandchild. Hang in there! 41

42 Case Report (5) Update 2015 DOB: 1972 Diagnosis: Status: Treatment: Male, nonseminoma, yolk sac tumor After 4 th recurrence ACC treatment involvement since 2010 High-dose chemo with autologous stem cells, achieved CR, followed with involved-field radiation and maintenance with irinotecan (CPT-11), Doxorubicin (Adriamycin) followed by Gemcitabine (Gemzar) + Carboplatin with the addition of Sunitinib (Sutent) according to Caris. Result: NED 60+ months; AFP <10 Data in literature: OS <10% 12 mo. after high-dose. 42

43 Case Report (5) Update 2017 In 7/2015, recurrence of disease in lungs, lymph nodes, skeletal system and skin. From 7/2015 9/2016: genomic immunotherapy: nivolumab (anti PD-1) and ipilimumab (Yervoy, anti-ctla-4). Response in lungs, lymph nodes and skeletal system, but not in skin. 7/2015 9/2016: orthovolt radiotherapy to skin lesions: response. 9/2016 2/2017: oxaliplatin/gemcitabine x 5 courses. Result: AFP decreased from 1760 to 120. QOL last 6 months from 0 2 (Zubrod) due to immune pneumonitis. Treatment plan: high dose Sutent as single agent. Survival since 2010: 84+ months. 43

44 2002 HERO: Jop Rappange 21 months old, inoperable anaplastic astrocytoma; c- Kit+++Treated with radiation, Temodar, Thalidomide, Gleevec. 44

45 2013 In action - CR 11+ years. 45

46 2017 CR 15 + years, A Dream Come True! On Gleevec for 15+ years! 46

47 CONCLUSIONS The observational approach allows us to tailor treatment to focus on benefit and expectations of each individual: One patient at a time This approach still enables publication of interesting scientific findings for potential benefit to others. 47

48 A Special Thank You to: Our Patients and Their Families Arlington Cancer Center Staff 48