Breast Cancer (April 2017): Molecular Oncology Tumor Board

ASCO University
Apr 12, 2017 9:01 AM

Participant Instructions: Welcome to the Molecular Oncology Tumor Board Series! This educational initiative is a collaboration between the American Society of Clinical Oncology (ASCO), College of American Pathologists (CAP), and Association for Molecular Pathology (AMP).

A new case will be presented each month with discussions led by an expert pathologist and medical oncologist. Drs. Carmen Calfa, MD (Medical Oncologist, Sylvester Comprehensive Cancer Center) and Anupma Nayak, MD (Pathologist, Hospital of the University of Pennsylvania) lead the discussion for the topic this month.

   

This discussion is based on a TAPUR, breast cancer patient case.

Do you have an interesting case in mind? Submit your hypothetical patient cases for consideration in an upcoming Molecular Oncology Tumor Board discussion forum.

Participants are encouraged to leave comments and post questions about the case in order to generate a wide discussion among the cancer care community. You can also receive email notifications when new comments are posted by clicking the “Follow this Conversation” option located at the bottom of this page.

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Comments

14386

ASCO University
Re: Breast Cancer (April 2017): Molecular Oncology Tumor Board
Apr 12, 2017 9:12 AM

Patient Case

Clinical history: A 55-year-old postmenopausal white Caucasian female presented with a palpable right breast mass 3/2011, at age 50.  She had a benign mammogram 9/2010. A diagnostic mammogram and ultrasound revealed a 4 cm mass and suspicious axillary lymphadenopathy. Ultrasound guided biopsy of the mass and the suspicious LN with clip placement revealed invasive ductal carcinoma (IDC), high nuclear grade (HNG) ER 0, PR 0, Her 2 1+ and FISH negative, Ki 67 50%. Staging work up revealed no distant metastasis, cT2N1M0. 
May 2011-Sept 2011: She received neoadjuvant chemotherapy with DD AC x4 followed by Paclitaxel weekly x 12 with clinical partial response. 
Oct 2011: She underwent breast conservation surgery with Right Lumpectomy and Right Axillary Lymph Node Dissection. Pathological findings ypT1N1miM0, negative surgical margins.
Nov 2011-Dec 2011: She received Radiation Right Breast, Supraclavicular, Infraclavicular Lesions 60GY 

Jan 2015: She presents to her 6-month follow-up visit complaining of a 2 month dry cough. Physical examination reveals no concerning findings. She undergoes CT chest with multiple lung nodules found, suspicious for metastasis. A PET CT identifies hypermetabolic uptake in the lung nodules and no additional findings. A CT guided biopsy confirms the diagnosis of breast cancer recurrence, ERPRHer2 negative. She receives palliative chemotherapy with Doxorubin and cyclophosphamide 2/15-2/15. Doxetaxel 3/15-7/15. Gemcitabine 7/15-10/15. Carboplatin 10/15-6/16 with maximum response being stable disease.

July 2016: She complains of headache and MRI brain identifies 3 lesions consistent with metastatic disease in the right frontal, right cerebellar and left frontal lesion. Full staging workup reveals progression of disease with new liver lesions.

Past medical history: denies
Family history: denies any cancer in her mother side, father unknown

Co-morbidities: None

14391

ASCO University
Re: Breast Cancer (April 2017): Molecular Oncology Tumor Board
Apr 12, 2017 9:13 AM

Discussion Questions

  1. Would you recommend clinical genetics consultation for BRCA testing? Would an expanded panel be beneficial?
  2. What would be the next step in this patient’s management?
  3. Is there a value in performing biopsy of liver lesion before starting any treatment?
  4. Would molecular testing for potential actionable targets be helpful?

 

14396

Anis Toumeh, MD
Re: Breast Cancer (April 2017): Molecular Oncology Tumor Board
Apr 12, 2017 1:24 PM

1- In a patient with TNBC phenotype, younger than 60 y/o, I would refer for genetic counseling/testing

2/3/4: would refer to radiation oncology for consideration of SRS to the brain lesions +/- WBRT. A repeat biopsy/molecular profiling might help finding targets that could allow the patient to either enrol in a study protocol or to receive a targeted therapy down the road. Options for systemic therapy after adressing her brain metastasis would include Capecitabine alone or in combination with Ixabepilone as well as single agent Eribulin. Those will be my next choices outside a clinical trial.  

14401

Roseann Wu
Re: Breast Cancer (April 2017): Molecular Oncology Tumor Board
Apr 13, 2017 5:02 PM

I'd be interested to know whether most oncologists would recommend the liver biopsy in a patient with known metastatic disease.  It doesn't seem cost effective to perform molecular testing for every metastatic breast cancer, but testing for potential enrollment in a clinical trial or for research purposes seems worthwhile, in select cases.

14406

Peter H. Slee, MD, PhD
Re: Breast Cancer (April 2017): Molecular Oncology Tumor Board
Apr 13, 2017 5:32 PM

I would not refer this patient of 55 years with a negative family history and no children (I assume) for genetic counseling. The findings will not change the therapy. I would only consider this when the patient is under 50 years of age.

 

14421

Carmen Julia Calfa, MD
Re: Breast Cancer (April 2017): Molecular Oncology Tumor Board
Apr 17, 2017 9:00 AM

Course Faculty Response

1. Would you recommend clinical genetics consultation for BRCA testing? Would an expanded panel be beneficial?

      The NCCN Guidelines for Genetic/Familial High-Risk Assessment has recommended genetic risk evaluation for patients 60 years of age or less with a diagnosis of triple negative breast cancer. The reported incidence of BRCA1/2 mutations in triple negative breast cancer is 10 - 20%.Next-generation sequencing technology has allowed for ease of multi-gene testing for hereditary forms of cancer. However, panel testing differs in specific genes analyzed, inclusion of moderate risk genes or those of intermediate penetrance, and increased likelihood of finding variants of unknown or uncertain significance. For these reasons, multigene testing is ideally offered in the context of professional genetic expertise and counseling.

ASCO statement published in JCO 2015 (Robson et al. 2015) calls for careful utilization of NGS and proper counseling:

    ASCO recognizes that concurrent multigene testing (ie, panel testing) may be efficient in circumstances that require evaluation of multiple high-penetrance genes of established clinical utility as possible explanations for a patient's personal or family history of cancer. Depending on the specific genes included on the panel employed, panel testing may also identify mutations in genes associated with moderate or low cancer risks and mutations in high-penetrance genes that would not have been evaluated on the basis of the presenting personal or family history. Multigene panel testing will also identify variants of uncertain significance (VUSs) in a substantial proportion of patient cases, simply as a result of the multiplicity of genes tested. ASCO affirms that it is sufficient for cancer risk assessment to evaluate genes of established clinical utility that are suggested by the patient's personal and/or family history. Because of the current uncertainties and knowledge gaps, providers with particular expertise in cancer risk assessment should be involved in the ordering and interpretation of multigene panels that include genes of uncertain clinical utility and genes not suggested by the patient's personal and/or family history.

See references here.

14426

Anupma Nayak
Re: Breast Cancer (April 2017): Molecular Oncology Tumor Board
Apr 17, 2017 9:03 AM

Course Faculty Response

1. Would you recommend clinical genetics consultation for BRCA testing? Would an expanded panel be beneficial?

    As Dr. Calfa cited, per current NCCN guidelines this patient certainly is eligible for further genetic risk evaluation which should include detailed family history by pedigree analysis, genetic testing for BRCA1/2 mutations, and pre-test and post-test genetic counselling. Germline testing for BRCA1/2 mutations can be done on blood or saliva sample using single or multi-gene panel testing.

   Coming to second part of question, multi-gene panel testing versus a single gene test. Traditionally, the genetic test for BRCA1/2 in high risk patients use to be offered as a single gene test by Sanger sequencing. Lately, many academic centers and commercial genetic testing labs have switched to multiple gene sequencing platforms because it is economical, efficient, more informative and less time consuming as compared to single gene tests. Multi-gene panels can detect other genes besides BRCA1/2 which increase the risk of hereditary predisposition of breast cancer for example, TP53, STK11, PTEN, CHEK2, PALB2, ATM, BARD1, BRIP1, RAD51, MLH1, MLH2, MSH6, PMS2 etc. Not only it provides patients with a broader picture of their cancer risks, it also directs more precise treatment options. For example, if tested positive for BRCA1/2 or non-BRCA mutations involved in DNA repair pathway, patient can be enrolled in ongoing clinical trials studying the use of platinum based therapy and poly adenosine diphosphate-ribose polymerase (PARP) inhibitors in the metastatic settings for breast cancer. These panels are especially useful in a patient like ours when there are imperfect family histories or incorrectly communicated medical history because the results may impact cancer prevention and surveillance strategies for unaffected family members of this patient.

   However, one needs to be aware that multigene testing has some drawbacks. As Dr. Calfa mentioned, few comprehensive panels include genes associated with low to moderate cancer risk and/or variants of undetermined significance for which we currently lack established surveillance guideline or clinical management strategies. So, explaining these results to patient and her family can be challenging. To avoid this complication, before ordering the test patient should be referred for pre-test counselling with genetic counselors. Also, it is important to understand that even with negative results, or test results that don’t identify any genetic mutations associated with hereditary cancer, many individuals and their families remain at increased risk for cancer due to family history, environmental and other genetic risk factors.

See references here.

14431

Carmen Julia Calfa, MD
Re: Breast Cancer (April 2017): Molecular Oncology Tumor Board
Apr 17, 2017 9:07 AM

Course Faculty Response

2. What would be the next step in this patient’s management?

   At present, treatment options for local disease control from brain metastasis include surgical resection (if solitary lesion), stereotactic radiosurgery (for limited number of lesions i. e. <3) and whole-brain radiation therapy (WBRT). Stereotactic radiosurgery is preferred over WBRT because WBRT is associated with severe neurocognitive decline and it delays the administration of systemic therapy.

   This patient has unfavorable prognostic factors such as age >50 yrs, triple negative status and presence of extracranial (liver and lung) disease. Stereotactic radioactive surgery can be offered to this patient given her good performance status and limited number of brain lesions. For systemic control, cytotoxic chemotherapy should be offered in the absence of a clinical trial.

   Role of systemic therapy (chemotherapy/targeted therapy) has not been studied well in the treatment of brain metastases assuming majority of chemotherapeutic agents cannot cross the blood-brain barrier (BBB) either due to their large molecular size, or hydrophilic nature or due to certain drug efflux transporters present on BBB for example, P-glycoproteins. Patients with brain metastases were excluded from most of the clinical trials in the past because of this reason and partly because of their poor performance status. Recently, there has been renewed interest in systemic therapy because evidence is emerging that some breast cancer drugs do cross the blood-brain barrier. Furthermore, studies have shown that growing brain metastases can itself disrupt the blood-brain barrier, making it possible for chemotherapeutic agents to get into the brain.

   At present, we do not have any FDA–approved drug for brain metastases; however, many drugs/compounds are being investigated in the clinical trial setting. Some of these compounds are molecules that are small enough to cross the blood-brain barrier, and others are carrier-mediated systemic therapies, such as nanoparticles. For example, a phase 2 study (NCT02048059) is investigating the use of ANG1005, which crosses the blood-brain barrier via receptor mediated endocytosis and releases paclitaxel intracellularly that further blocks mitosis and promotes apoptosis of metastatic tumor cell. Other agents that are being explored in the clinical trial setting include 1) EGFR inhibitors such as Cetuximab for TNBCs expressing EGFR (approx. 40% of BCBM) 2) PARP inhibitors (Iniparib) for TNBCs with defect in homologous recombination dependent-DNA repair pathway, including BRCA-promotor methylation and aberrations in MRE11–RAD50–NBS1, ATM, p53, and PALB2 3) VEGF inhibitor (Bevacizumab) to inhibit angiogenesis 4) PIK3/AKT/mTOR pathway inhibitor (Buparlisib) 5) Cyclin-dependent kinase (CDK4/6) inhibitor Palbociclib (NCT02774681) Emerging data suggest that immunotherapy with monoclonal antibodies that target the PD-1 or CTLA-4 pathways may lead to substantial and durable intracranial responses concordant with their systemic activity. This may be because immune checkpoint inhibitors do not require direct access to brain parenchyma, as their effects are mediated by proxy on peripheral T cells, which in turn penetrate into the CNS. The hallmark of successful immunotherapy is the potential for durable responses and long- term survival in responding patients, which appears to be preserved in patients with BM. Immunotherapy often has a delayed onset of response and may lead to inflammatory treatment effects, which are highly relevant to the patients with BM at risk of neurologic complications due to increased mass effects.the role  of immune checkpoint inhibitors in inducing host antitumor activity in CNS, is evidenced in preclinical studies and a phase II clinical trial of melanoma with brain metastases. Notably, the high expression of PD-L1 in TNBC suggests that this pathway is a potential therapeutic target. In preliminary results of a phase 1 study (KEYNOTE 012) of pembrolizumab, patients with TNBC (13% with BM) had an overall response rate of 19%. Partial response with disease stabilization for >24 weeks was noted in 25.9% of patients. Furthermore, several ongoing clinical trials are investigating pembrolizumab in TNBC (NCT02447003, NCT02555657, NCT02622074, NCT02513472, and NCT02648477).

   In patients naïve to cyclophosphamide and anthracyclines, FEC (5-FU, Epirubicin, Cyclophosphamide) and CMF (Cyclophosphamide, Methotrexate, 5-FU) have purported activity in patients with BM. Of the few cytotoxic chemotherapeutic agents that can penetrate the BBB when disrupted by BM or radiation, cisplatin demonstrated clinical activity in patients with BM from breast cancer, particularly TNBC, as a single agent and in combination with other chemotherapies or with Vinorelbine plus WBRT. Phase 2 trials have also been completed evaluating Capecitabine monotherapy in patients with CNS progression after WBRT alone or with SRS and no prior systemic therapy for BM (NCT01077726, NCT00977379, and NCT00570908).

   The novel cytotoxic agent Sagopilone, a microtubule stabilizer that penetrates the BBB and is not a substrate for CNS efflux transporters, has been evaluated in a single- arm, phase 2 study of 15 breast cancer patients with BM. A CNS partial response was seen in 13% of patients, with a median PFS and OS of 1.4 and 5.3 months, respectively. Additionally, a peptide-facilitated, brain-penetrating formulation of paclitaxel (GRN1005) was well tolerated and decreased tumor size in heavily pretreated patients with advanced solid tumors, including those who had BM and/ or failed prior taxane therapy.

   Given the lack of prospective data showing an improvement in OS among patients with MBC who are treated with combination rather than single-agent chemotherapy and the lack of a well-validated, consensus-derived surrogate endpoint, the choice between chemotherapy strategies is typically dependent upon many factors, including the degree of tumor burden, rate of disease progression, site of metastasis, organ involvement and function, cancer-related symptoms, and residual toxicities from prior therapies. Taking these variables into account, clinicians often use combination chemotherapy in MBC only when it has been determined that the patient is in need of significant treatment response or stabilization in a relatively short amount of time.

See references here.

14436

Anupma Nayak
Re: Breast Cancer (April 2017): Molecular Oncology Tumor Board
Apr 17, 2017 9:10 AM

Course Faculty Response

3. Is there a value in performing biopsy of liver lesion before starting any treatment?

   Performing biopsy of liver lesion before starting any treatment would be valuable in this case for three reasons. First, histopathology evaluation of liver biopsy would confirm the metastases from breast cancer and rule out the possibility of an unexpected second primary or metastases from an unknown primary.

   Second, it would be used for biomarker (ER/PR/HER2) assessment before starting treatment. Many studies have highlighted the discordance in biomarker expression pattern in primary and metastatic tumors and the reported incidence varies from 3 to 35%. In a retrospective study by Liedtke et al of 789 patients with recurrent breast cancer, discordance of ER, PR, and HER2 expression between primary and metastatic tumors was 18%, 40%, and 14%, respectively. In 10% cases triple-negative tumors changed to a receptor-positive subtype. Nishimura et al studied the expression of ER, PR, HER2, Ki-67, and p53 between primary tumor and recurrent metastatic disease in 97 patients with breast cancer including breast relapses, lung, liver, brain, and bone metastases. The ER-positive rate from primary tumor to recurrence decreased from 64% to 58%; PR decreased from 57% to 43%. HER2 overexpression changed in 14% of patients. In 24 patients (25%), the subtype in recurrent disease was dissimilar to primary breast cancer with the lowest frequency of change in triple-negative cases. Of note, in 11 of 97 patients (11%), HER2 was overexpressed in recurrent disease unlike primary tumors. In 2 of 18 TNBCs, HER2 was positive in recurrent/metastatic tumor and 1 of 18 became positive for ER.  This discordance can be fundamentally explained by inherent inter or intra-tumoral heterogeneity of breast cancer. Cancer cells within one tumor of a patient at any given time frequently exhibit heterogeneity for metastatic potential. The clone of tumor cells may be very minute in the primary tumor and may skip detection due to sampling issues. With disease progression and accumulation of genetic and epigenetic aberrations, this clone can evolve and expand to form metastatic tumors that are genetically different from majority of tumor cells in the primary tumor. Prior treatment such as hormonal therapy and chemotherapy may also contribute to changes in biomarker status due to clonal selection. Also, it is possible that in a small percentage of cases, the discordance is merely the result of suboptimal standardization and reproducibility of the assay methods. Hence, current NCCN guidelines do recommend that metastatic disease should be biopsied as a part of a workup for patients with recurrent or stage IV disease; ER, PR, and HER2 status should be reevaluated if it is unknown, negative, or not overexpressed. Hypothetically, if the metastatic liver tumor in this patient turns out to be positive for HER2 overexpression, she can be offered anti-HER2 targeted therapy and can be enrolled in ongoing clinical trials investigating newer anti-HER2 therapies in metastatic setting.

   Third, liver tumor tissue can be used for testing other potential actionable targets as discussed later.

See references here.

14441

Anupma Nayak
Re: Breast Cancer (April 2017): Molecular Oncology Tumor Board
Apr 17, 2017 9:13 AM

Course Faculty Response

4. Would molecular testing for potential actionable targets be helpful?

   While acquiring liver tumor biopsy for confirming diagnosis and reassessing biomarker (ER/PR/HER2) status, one can acquire few more cores for molecular profiling of tumor with appropriate consent from patient. This will allow matching patient’s tumor with novel therapies in the clinical trial setting.

   There are many molecular profiling platforms available, including multiplexed hotspot mutation panels, CGH arrays, next generation sequencing (NGS), whole exome sequencing (WES), Sanger sequencing and FISH. Molecular profiling is helpful in identifying potentially actionable a) driver mutations/amplifications for example, PIK3CA and AKT1 mutation, FGFR, EGFR, and CCND1 amplifications b) alterations that might be involved in resistance to targeted therapies, such as PTEN mutations and deletions c) DNA repair defects for example BRCA1/2 mutations or non-BRCA somatic mutations d) tumor mutation load or “neoantigens”.

   Studies have shown TNBC’s are heterogeneous tumors and can be further subtyped by molecular profiling studies into: 1) basal-like TNBC (BL-TNBC), characterized by DNA-repair deficiency and growth factor pathway expression; 2) mesenchymal-like TNBC (ML-TNBC), with epithelial to mesenchymal transition (EMT) and cancer stem cell (CSC) features; 3) immune-associated TNBC (I-TNBC); 4) luminal/apocrine TNBC (LAR-TNBC), with androgen receptor (AR) overexpression. This molecular classification has therapeutic implications and would be relevant in tailoring therapy for this patient.

   Once categorized into one of the subtypes, this patient could be appropriately triaged to ongoing clinical trials. For example, targeting DNA-repair deficiency with PARP inhibitors or platinum based therapy appears to be a promising treatment for BL-TNBC with BRCAness characteristics or BRCA-mutations. EGFR, and other tyrosine-kinase receptor inhibitors (c-MET, fibroblast growth factor, insulin growth factor [IGF], platelet-derived growth factor, transforming growth factor β (TGFβ), Notch, and Wnt/β-catenin) have potential in mesenchymal-like TNBC. In immune-associated TNBC, inhibiting the immune checkpoint pathways and enhancing T-cell activity against tumor cells could be used therapeutically. LAR-TNBC, can be targeted with AR inhibitors.

   The PI3K/AKT/mTOR pathway is activated in 10% of triple negative breast cancers and is one of the common routes for conferring treatment resistance to TNBCs. The mutations in the PI3KCA gene involve two hotspot areas within exon 9 (amino acids E542 and E545 in the helical domain) and exon 20 (H1047R in the kinase domain). In addition, mutation in AKT1 gene, amplification of AKT2, and loss of PTEN due to deletion or mutation can result in hyperactivity of PI3K pathway. Agents targeting this pathway are also being investigated in clinical trial setting.

   It is important to understand that tumor profiling can be done on frozen or formalin fixed paraffin embedded tumor tissue alone, or can be combined with paired non-tumor sample to assess germline mutations particularly in patients with a history suspicious for inherited cancer.

   Dr. Calfa will now discuss the available clinical trials for advanced TNBC patients.

See references here.

14446

Carmen Julia Calfa, MD
Re: Breast Cancer (April 2017): Molecular Oncology Tumor Board
Apr 17, 2017 9:25 AM

Course Faculty Response

4. Would molecular testing for potential actionable targets be helpful?

As eloquently stated above by Dr. Nayak, biopsy of the liver lesion provides an opportunity to look for additional targets in the metastatic setting.

The schema found here summarizes different pathway of activation and targets for new therapies:

Abbreviations: PI3K, phosphatidylinositol 3-kinase; MEK, mitogen-activated protein kinase kinase; Akt, v-Akt murine thymoma viral oncogene; mTOR, mammalian target of rapamycin; HSP-90, heat shock protein 90; CXCR, chemokine receptor; HDAC, histone deacetylase; PARP, poly adenosine diphosphate-ribose polymerase; Trop-2, tumor-associated calcium signal transducer 2; GPNMB, glycoprotein nonmetastatic b; EGFR, epidermal growth factor receptor; VEGFR, vascular endothelial growth; PD1, programmed death 1; PDL1, programmed death ligand 1; CTLA4, cytotoxic T-lymphocyte-associated protein 4; AR, androgen receptor; CYP17A1, cytochrome P450 17A1; CSF1R, colony-stimulating factor 1 receptor; JAK1/2, janus kinase 1 and 2; Sine XPO1, selective inhibitor of nuclear export exportin 1; VDR, vitamin D pathway receptor genes; HMGCR, HMG-CoA reductase; RAS, rat sarcoma; RAF, B-raf and v-Raf murine sarcoma viral oncogene homolog B; ERK, extracellular signal-regulated kinases; STAT, signal transducer and activator of transcription; GRB2, growth factor receptor-bound protein 2; TNBC, triple-negative breast cancer.

Here is a table with the links to clinical trials looking at targeted agents and chemotherapeutic, hormonal, immune strategies in metastatic triple-negative breast cancer (mTNBC):

NCT NUMBER

PHASE

INTERVENTION

TARGET OF NEW AGENT

(n)

ESTIMATED DATE OF COMPLETION

NCT02120469

I

Eribulin mesylate and everolimus

MTOR

45

 

NCT01939418

I/II

Gemcitabine, cisplatin and everolimus

MTOR

116

July 2017

NCT02506556

II

BYl719

PI3K

34

December 2018

NCT02485119

I

BAY94-9343

Mesothelin

15

November 2017

NCT01997333

II

Glembatumumab vedotin plus capecitabine

gpNMB

300

November 2018

NCT02370238

II

Paclitaxel in combination with reparixin

CXCR1/2

190

February 2018

NCT01837095

I

POL6326 in combination with eribulin

CXCR4

24

December 2016

NCT02227082

I

Olaparib and radiotherapy

PARP

36

August 2018

NCT02567396

I

Talazoparib

PARP

105

 

NCT02158507

Pilot

Veliparib and lapatinib

PARP

25

June 2018

NCT01145430

I

Veliparib and pegylated liposomal doxorubicin

PARP

58

NCT02358200

I

BMN-673 with carboplatin and paclitaxel

PARP

20

May 2017

NCT02498613

II

Cediranib maleate and olaparib

VEGF and PARP

121

 

NCT01631552

I/II

Sacituzumab govitecan

TROP-2

250

June 2016

NCT02574455

III

Sacituzumab govitecan with eribulin, capecitabine, or gemcitabine

anti-TROP-2-SN-38

328

June 2019

NCT02071862

I

CB-839

Glutaminase

165

March 2016

NCT02048059

II

ANG1005

Taxane

56

October 2016

NCT01910870

II

Cisplatin and metronomic cyclophosphamide

35

NCT02263495

II

Eribulin plus gemcitabine

112

December 2018

NCT02207335

III

Gemcitabine and capecitabine versus gemcitabine and carboplatin

120

December 2015

NCT01898117

II

Carboplatin-cyclophosphamide versus paclitaxel with or without bevacizumab

VEGFR

304

December 2029

NCT02202746

II

Lucitanib

VEGFR-FGFR

201

November 2016

NCT00733408

II

Nab-paclitaxel and bevacizumab followed by bevacizumab and erlotinib

VEGFR and EGFR

63

NCT02362230

II

Icotinib

EGFR

67

December 2017

NCT01939054

II

Nimotuzumab plus docetaxel and capecitabine versus docetaxel and capecitabine

EGFR

90

September 2016

NCT01990209

II

Orteronel

CYP17A1

86

June 2018

NCT02580448

I/II

VT-464

CYP17A1

81

December 2017

NCT02353988

II

Bicalutamide

AR

60

May 2017

NCT02348281

II

Bicalutamide

AR

44

June 2018

NCT02014337

I

Mifepristone and eribulin

Anti-progestogen and anti-glucocorticoid

40

February 2016

NCT02457910

I/II

Taselisib and enzalutamide

PIK3CA and AR

74

NCT02322814

II

Cobimetinib in combination with paclitaxel

MEK

112

April 2018

NCT01964924

II

Trametinib and Akt inhibitor GSK2141795

MEK and AKT

41

NCT02423603

II

AZD5363 in combination with paclitaxel

AKT

140

January 2017

NCT02162719

II

Ipatasertib in combination with paclitaxel

AKT

120

February 2017

NCT02476955

Ib

ARQ 092 in combination with carboplatin plus paclitaxel

AKT

49

June 2017

NCT02543645

I/II

Varlilumab and atezolizumab

Anti-CD27 and Anti-PDL1

55

June 2019

NCT02478099

II

MPDL3280A

Anti-PDL1

40

August 2017

NCT01928394

I

Nivolumab monotherapy or nivolumab combined with ipilimumab

Anti-PD1, Anti-CTLA4

1100

December 2017

NCT02309177

I

Nivolumab with nab-paclitaxel

Anti-PD1

138

July 2018

NCT02447003

II

Pembrolizumab

Anti-PD1

245

November 2019

NCT02513472

I/II

Eribulin mesylate plus pembrolizumab

Anti-PD1

95

January 2018

NCT02555657

III

Pembrolizumab vs. chemotherapy

Anti-PD1

600

September 2017

NCT02187991

II

Alisertib with paclitaxel

Aurora A kinase

252

September 2017

NCT01837602

I

cMet CAR RNA T cells

 

15

April 2017

NCT02402764

II

Selinexor

SINE XPO1

34

NCT02041429

I/II

Ruxolitinib lus chemo

JAK1/2

24

January 2021

NCT01596751

Ib/II

PLX 3397 and eribulin

colony-stimulating factor 1 receptor

80

December 2016

NCT02203513

II

LY2606368

Chk1/2

108

June 2019

NCT02474173

I

AT13387 and paclitaxel

HSP-90

24

NCT02393794

I/II

Romidepsin plus cisplatin

HDAC

54

December 2018

NCT02425891

III

Atezolizumab in combination with nab-paclitaxel

Anti-CD52

350

May 2019

NCT02027376

II

LDE225 in combination with docetaxel

Hedgehog

18

May 2017

14451

ASCO University
Re: Breast Cancer (April 2017): Molecular Oncology Tumor Board
Apr 17, 2017 9:34 AM

Patient Case Update

Patient received stereotactic radiation to brain lesions. Patient was started on Capecitabine (Xeloda).

ECOG performance status: 0 - Fully active, able to carry on all pre-disease performance without restriction.

A new biopsy of liver lesion was performed and confirmed TNBC. Tumor was sent for molecular profiling.

How tissue was acquired/preserved: Liver Biopsy/Frozen

Testing Platform/Molecular Profiling: MI-ONCOSEQ

Relevant Markers: The tumor/germline genomic profiling on the University of Michigan’s Mi-Oncoseq test reported a germline MLH1 pathogenic mutation and a somatic tumor profile containing hundreds of mutations (including a BRCA1 loss) clearly consistent with MSI-H phenotype and a high mutational load. PIK3CA (E545kvaf12%) hotspot activating mutation was also found.

14456

ASCO University
Re: Breast Cancer (April 2017): Molecular Oncology Tumor Board
Apr 17, 2017 9:38 AM

Discussion Questions

5. What targeted therapeutic options would you recommend and what are the potential biomarkers of response based on patient’s test results?

6. Based on the germline mutation found, what additional testing/counseling would you offer?

 

14466

Carmen Julia Calfa, MD
Re: Breast Cancer (April 2017): Molecular Oncology Tumor Board
Apr 21, 2017 8:12 AM

Course Faculty Response

5. What targeted therapeutic options would you recommend and what are the potential biomarkers of response based on patient’s test results?

   I will address the potential targeted therapies in this patient and Dr. Nayak will discuss the potential biomarkers associated with response to therapy.

   Molecular profiling of this patient’s paired tumor and non-tumor sample revealed high   somatic mutation load with MSI signature, germline mutation in MLH1 gene (p.R226Q), and somatic hotspot activating mutation in PI3KCA gene (E545K; vaf 12%).

   Based on these results, we currently don’t have any FDA approved standard therapy to offer to this patient. However, given the hypermutated status of tumor she is eligible for Pembrolizumab (PD-1 inhibitor) under the ASCO Targeted Agent Profiling and Utilization Registry (TAPUR) study protocol.

   The Programmed Death 1 (PD-1) pathway is a negative feedback system that blocks Th1 cytotoxic immune responses. Studies have shown that this pathway is up-regulated in many tumors and in their surrounding microenvironment secondary to constitutive and adaptive mechanisms. Blockade of this pathway with antibodies to PD-1 or its ligands has led to remarkable clinical responses in patients with many different types of cancer, including melanomas, non–small-cell lung cancer, and renal-cell carcinoma. Pembrolizumab, an anti-PD1 antibody, is currently FDA approved to treat patients with advanced melanoma that has not responded to other standard therapies. Preliminary results from the immune therapy clinical trial on heavily pretreated, PD-L1–positive, triple-negative breast cancer patients yielded response rates of 19% with use of PD-1/PD-L1 inhibitors (Keynote-012).

   Since our patient has MLH1 mutation with somatic mutation overload, she has a chance of good response with PD1 inhibitors.

   Identification of the “hotspot” mutations in the PIK3CA gene can render a patient eligible for clinical trials in the setting of advanced metastatic disease.

14471

Anupma Nayak
Re: Breast Cancer (April 2017): Molecular Oncology Tumor Board
Apr 21, 2017 8:14 AM

Course Faculty Response

5. What targeted therapeutic options would you recommend and what are the potential biomarkers of response based on patient’s test results?

As Dr. Calfa stated, the role of immune checkpoint inhibitors in breast cancer therapy is being heavily investigated in research and clinical trial settings. Some of the initial results are indeed very promising and like any evolving therapeutic strategy it raises certain questions such as, who should be the ideal candidate for immunotherapy or in other words if we have any biomarker to predict response to immunotherapy?

   We do not have any well-defined biomarker for predicting response to immunotherapy in breast cancer. Immunological markers such as, tumor infiltrating lymphocytes (TILs), CD8+ cytotoxic T cell density, and intra-tumoral expression of PDL-1 by immunohistochemistry (IHC) in pretreatment tumor specimens are though being used in research and clinical trial settings.

   At present, PDL1 IHC test is FDA approved as a companion diagnostic for using Nivolumab or Pembrolizumab (PD1 inhibitors) only in patients with nonsquamous NSCLC and advanced melanoma. From the technical standpoint, accurate measurement and scoring of PDL1 is challenging and has many pitfalls. There are many antibodies for PDL-1 available commercially but their affinities and specificities vary because they were developed without any cross-comparison. There are no set guidelines for the optimal cut-off for positivity. A few clinical trials have used positive cut-off for staining as low as 1% and have shown significant response rates. Similarly, some studies have reported decent response with PD1/PDL1 inhibitors in patients with PDL1 negative tumors, questioning the use of this marker as an absolute selection criterion for therapy. There are studies showing that PDL1 expression in multiple tumors from single patients can vary over time and by anatomical site. Additionally, prolonged specimen fixation and inappropriate tissue handling before fixation can alter the PDL1 epitopes and thereby staining result. Because of these reasons PDL1 IHC is not yet considered a definitive biomarker for decision making in treating breast cancer patients with immunotherapy.

   In parallel to immunological biomarkers, researchers are also studying genetic biomarkers of response to immunotherapy. Activation of PI3K/Akt pathway through deletion or loss of PTEN is linked with upregulation of PDL1 expression. Hence, loss of PTEN detection by IHC or FISH method can serve as an alternative predictive marker. Tumor mutational load is another promising concept currently being used in clinical trials studying immune checkpoint inhibitors. Dr. Le and colleagues from Johns Hopkins University hypothesized that mismatch repair deficient tumors being rich in mutations present neoantigens to hosts immune system and therefore would be more responsive to immune check point inhibitors. The authors conducted a phase II clinical trial in which Pembrolizumab was administered to three groups of patients with progressive metastatic disease that had worsened despite prior treatment: MMR-proficient metastatic colorectal cancer (25 patients), MMR-deficient metastatic colorectal cancer (13 patients), and other MMR-deficient non-colorectal cancers (10 patients). A huge difference in response rates (62 vs. 0%) and disease control rates (92% vs. 16%) was observed between MMR-deficient and proficient colorectal cancers. In the group of MMR-deficient non-colorectal cancers (excluding CRCs), the overall response rate was 60%. Moreover, responses were sustained and without significant toxicity. Continuing forward, clinical trials are ongoing to test the safety, tolerability and efficacy of PD-1 inhibitors in patients with recurrent MMR-deficient TNBCs.

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Anupma Nayak
Re: Breast Cancer (April 2017): Molecular Oncology Tumor Board
Apr 21, 2017 8:17 AM

Course Faculty Response

6. Based on the germline mutation found, what additional testing/counseling would you offer?

   The germline mutation in the MLH1 gene is consistent with a diagnosis of Lynch syndrome.

   Lynch syndrome is an autosomal dominant high penetrance hereditary cancer syndrome caused by germline mutation in one of 4 MMR genes (MLH1, MSH2, MSH6, or PMS2) or deletions in the EPCAM gene. The lifetime risk for developing colorectal cancer approaches 10 - 80% in individuals carrying a mutation in one of these genes. These individuals are also at heightened risk of developing other cancers including endometrial (16 - 60%), gastric (2% to 30%), ovarian (24%), pancreatic, urethral, brain, small intestine cancers and sebaceous gland adenomatous polyps and keratoacanthomas.

   There is not sufficient evidence yet to support increased risk for breast cancer in Lynch syndrome.

   Per NCCN guidelines this patient and family members should be referred for genetic counseling and advised increased surveillance. At-risk relatives, can undergo predictive genetic testing to avoid unnecessary procedures.

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Carmen Julia Calfa, MD
Re: Breast Cancer (April 2017): Molecular Oncology Tumor Board
Apr 21, 2017 8:19 AM

Course Faculty Response

6. Based on the germline mutation found, what additional testing/counseling would you offer?

   I agree with Dr. Nayak that this patient and her family should be referred for genetic counseling. Relatives should be advised about possible inherited cancer risk, options for risk assessment and management. At-risk relatives can either go for increased cancer surveillance per NCCN guidelines or opt for predictive genetic testing to avoid unnecessary screening procedures.

   I would like to emphasize here current ASCO recommendations in handling germline testing results (Robson et al. 2015).

“ASCO supports the communication to patients of medically relevant incidental germline findings from somatic mutation profiling conducted in the clinical setting. Only laboratories equipped to provide analytically and clinically valid results should conduct secondary analyses to identify germline variants. Laboratories that are not resourced to provide clinically valid information from secondary analysis of the normal sample in tumor-normal subtractive analyses should only report tumor-associated variants and should not be obligated to seek germline variants. Oncology providers should communicate the potential for incidental and secondary germline information to patients before conducting somatic mutation profiling and should review the potential benefits, limitations, and risks before testing. Providers should carefully ascertain patient preferences regarding the receipt of germline information and allow patients to decline receipt of germline information. This may require referral for additional counseling to help the patient clarify his or her preferences. In the setting of tumor-normal sequencing, laboratories conducting secondary analyses should develop mechanisms to report only somatic results for patients who choose to decline receipt of germline findings. ASCO supports research to determine how to best deliver pretest education, support patient preferences, and understand outcomes of providing incidental and secondary germline information with somatic testing.”

Anupma Nayak
Re: Breast Cancer (April 2017): Molecular Oncology Tumor Board
Apr 21, 2017 9:19 AM

Dr. Calfa has raised a very important point here. Oncologists and pathologists should be aware of the ethical issues associated with germline genetic testing and should strictly follow the ASCO recommendations.