Breast Cancer (February 2016): Molecular Oncology Tumor Boards

ASCO University
Feb 10, 2016 9:49 AM

User 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. This month’s topic is led by Drs. Deborah Dillon (Brigham and Women’s Hospital) and Tiffany Traina (Memorial Sloan Kettering Cancer Center). 

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Supplemental resources related to the case are attached for reference.  



ASCO University
Re: Breast Cancer (February 2016): Molecular Oncology Tumor Boards
Feb 10, 2016 9:52 AM

Patient Case

Your 58 year old patient with a previous history of Stage 1 triple negative breast cancer (TNBC) presents to you for routine follow up and notes a new palpable right supraclavicular lymph node for ~1 week associated with a sore throat. Her teenaged daughter has had “mono” and she has attributed the lymph node as related to a viral illness. She otherwise feels well and is without localizing complaints. She denies fever, weight loss or fatigue, aside from that related to recent holidays.  

Medical History: Hypertension and osteopenia. 

Social History: Married, 2 teenaged daughters, homemaker. Never smoker.

Family History: Maternal aunt with postmenopausal breast cancer. Paternal uncle with pancreatic cancer. Paternal grandfather with prostate cancer. No history of ovarian cancer or other malignancy in the family. She is of German, Irish, Lithuanian descent. 

Prior Oncology History:  In early 2013, she was diagnosed with a right-sided Stage 1 (T1 (1.4cm) N0) breast cancer detected on routine screening mammography. She underwent right breast conservation surgery which revealed a 1.4cm invasive ductal carcinoma, moderate to poorly differentiated. ER 0% PR 0% HER2 2+ FISH not amplified. Zero of 4 sentinel lymph nodes were involved. She received dose dense AC x4 followed by dose dense paclitaxel and went on to receive radiation therapy.  

Physical examination: Well appearing with normal vital signs. HEENT exam notes mild pharyngeal erythema without exudates. Right lower neck is remarkable for a 2.5cm nontender, firm, somewhat fixed lymph node in the medial supraclavicular space without overlying skin changes. There are no other palpable lymph nodes in cervical or axillary regions bilaterally. Remainder of exam is without pertinent findings, including breast examination. 

Laboratory Data: CBC within normal range with normal differential, comprehensive metabolic panel within normal range.

Radiographic imaging was performed. An ultrasound of the supraclavicular region at the bedside identified a highly suspicious 2cm supraclavicular LN as well as ipsilateral enlarged internal mammary LN. CT neck/CAP with contrast remarkable for a 2.6cm supraclavicular lymph node, subcentimeter right subpectoral nodes, a right parasternal soft tissue mass/nodes in right internal mammary location with direct extension into sternum and chest wall anteriorly. A lytic lesion was noted within the ischium and several ~1cm bilateral pulmonary masses were seen. 


ASCO University
Re: Breast Cancer (February 2016): Molecular Oncology Tumor Boards
Feb 10, 2016 9:53 AM

Discussion Questions

  1. Choice for site of biopsy? LN vs. Bone and merits/pros/cons for tissue for molecular profiling vs. confirmation of distant recurrence?
  2. Would you recommend clinical genetics consultation for BRCA testing?  Expanded panel testing? 
  3. What additional tests would you ask of your pathologist?


Anis Toumeh, MD
Re: Breast Cancer (February 2016): Molecular Oncology Tumor Boards
Feb 10, 2016 11:58 AM

1- Clinically, this is more likely to be a distant recurrence of her disease (within 2-3 years of diagnosis). As per ASCO guidelines (Van Poznak et al. JCO 2015) biopsy of metastatic site is recommended to confirm the diagnosis and to test for ER/PR and HER2 as in up to 10% of cases, a change in receptors status may happen.  I think biopsy of the supraclavicular node will help confirm the diagnosis and also provide tissue for molecular profiling as the decalcification of bone biopsy material for the analysis of ER, PR, and HER2 may alter the results. 

2- According to NCCN, women with triple negative breast cancer who are 60 years old or younger should be referred for genetic counseling and  have genetic testing. The patient's family history is suggestive of a possibility of breast and ovariac cancer syndrome. 

My question here is that with the availability of panel testing, how would one decide on testing for BRCA1-2, PALB2 only vs doing the panel? 


ASCO University
Re: Breast Cancer (February 2016): Molecular Oncology Tumor Boards
Feb 13, 2016 1:37 PM

Thank you Dr. Toumeh for you input. A follow up response by the faculty will be posted on February 15th which will address your question.


Deborah Dillon
Re: Breast Cancer (February 2016): Molecular Oncology Tumor Boards
Feb 15, 2016 9:45 AM

Course Faculty Response

From the pathology perspective, the site of biopsy determines to some extent the quality of tissue acquired and what types of further studies can be performed. Although biopsy of one of the bone lesions can allow histologic confirmation of metastatic disease, bone biopsies present some limitations in terms of further immunohistochemical assays, FISH or molecular profiling. In order to make thin sections of bone for histologic examination, the tissue needs to be decalcified, generally using strong acids that can destroy protein antigens in the tissue. For this reason, while a positive result on immunohistochemistry can be helpful in a bone biopsy, reduced antigenicity and false negative immunohistochemical results are common in decalcified tissue. Biopsy of a non-bony metastatic site will yield the most reliable IHC results and also preserve options for FISH and other molecular testing.

Another consideration at this point is to be sure the biopsy will provide sufficient material for all studies required. Although biopsy of some metastatic sites will yield considerable tissue for analysis, most needle biopsies provide quite limited material for further study. Production of H&Es for standard histopathology and analysis of ER/PR and HER2 and any other markers needed to confirm metastasis can easily take up to ten 5-micron sections. Although there may be a small amount of tissue remaining in the paraffin block, it may be insufficient for further molecular studies once the block is remounted to section again at a later date.  If the oncologist wants to prioritize tissue for molecular analysis, this should be communicated upfront to the pathologist, who may be able to institute processing procedures to conserve tissue for molecular analysis following standard of care pathologic examination. 


Tiffany A. Traina, MD
Re: Breast Cancer (February 2016): Molecular Oncology Tumor Boards
Feb 15, 2016 9:47 AM

Course Faculty Response

Dr. Dillon has nicely discussed the pathology considerations for site of biopsy. From a medical oncology perspective, I would prefer to biopsy a site that would confirm distant metastasis rather than locoregional given the implications for goals of therapy. This is understandably balanced by the potential risk of accessing certain distant lesions and the limitations of molecular analysis on tissue as discussed above.

With respect to clinical genetics consultation, 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.  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.

Finally, when arranging for biopsy of the selected suspicious lesion, I would communicate with my Interventional Radiologist and Pathologist my clinical suspicions and needs. For example, goal of biopsy is to confirm or rule out metastasis, with sufficient material for standard special stains including ER, PR and HER2. Beyond this, I would aim for adequate material to facilitate tumor genomic profiling and request immunohistochemical testing for the androgen receptor.



ASCO University
Re: Breast Cancer (February 2016): Molecular Oncology Tumor Boards
Feb 15, 2016 9:51 AM

Patient Case Update

She underwent a core needle biopsy of the right supraclavicular lymph node. Pathology revealed a poorly differentiated carcinoma with apocrine features (Image 1). ER <1% PR 0% HER2 1+. Androgen Receptor 80% nuclear staining (Image 2).

BRCA testing was performed and was negative. 

She declined tumor genomic profiling at this time as she had concerns that testing might uncover a germline variant that could suggest hereditary risk to cancer or other illness. 


ASCO University
Re: Breast Cancer (February 2016): Molecular Oncology Tumor Boards
Feb 15, 2016 9:52 AM

Discussion Questions

  1. What clinical or pathologic features may have suggested the tumor would test AR+?  Are there standard AR tests available? 
  2. Does the AR positivity influence your choice of 1st line chemotherapy?
  3. Given AR positivity, are there targeted therapy options for therapeutic consideration? 



Deborah Dillon
Re: Breast Cancer (February 2016): Molecular Oncology Tumor Boards
Feb 19, 2016 9:48 AM

Course Faculty Response

The fact that our patient's tumor is triple negative with apocrine features strongly suggests that it belongs to the subset of TNBCs that has been called "molecular apocrine" or "luminal androgen receptor" type (Niemeier LA et al. 2010; Doane AS et al. 2006; Farmer P et al. 2005). Interestingly, these ER/PR-negative cancers show gene expression patterns similar to those of ER positive cancers but are characterized by androgen receptor signaling (Lehmann BD et al. 2011; Robinson JL et al. 2011).  Dr. Traina's decision to request AR testing opens up new treatment options for this patient whose tumor strongly expresses the androgen receptor.

Although there are no formal guidelines for the measurement of AR expression and various studies have used different antibodies, dilutions and cutoff points, it appears that well over half of all breast cancers show some degree of AR expression. In a recent report from the Nurses' Health Study, 77% of breast cancers were found to be positive for AR by IHC (Dako AR441 at 1:200 with a 1% cutoff). This included 88% of ER+ tumors, 59% of HER2+ tumors, and 32% of TNBCs (Collins LC et al. 2011).    

Both phase II clinical trials targeting androgen receptor have used a somewhat more stringent cutoff point of at least 10% staining for a positive result. In the phase II trial testing bicalutamide as treatment for ER–/AR + breast cancers (TBCRC011) a positive result was defined as AR > 10% (Dako AR441 at 1:300). Using this cutoff, 12% of TNBC patients screened were positive for AR (Gucalp A et al. 2013). The enzalutamide phase II trial also used a cutoff of AR >10% (Traina et al SABCS 2014 Poster P5-19-09).  In this study, a larger proportion of TNBC patients screened were positive for AR (55%). It is encouraging that this study also showed high concordance between the Dako AR441 antibody and Ventana SP107.

At this time, the best cutoff point to use for selection of patients for treatment with an AR antagonist is not known. The significance of other AR alterations in breast cancer, such as amplification and mutation, is also uncertain and further work is needed in this area. A missense mutation in AR conferring enzalutamide resistance has recently been described in prostate cancer (Joseph JD et al. 2013; Korpal M et al. 2013). It is not clear at this time if similar mutations may also arise in breast cancer patients treated with enzalutamide or other second-generation antiandrogens.



Tiffany A. Traina, MD
Re: Breast Cancer (February 2016): Molecular Oncology Tumor Boards
Feb 19, 2016 9:54 AM

Course Faculty Response

This patient’s radiographic imaging suggests distant disease with numerous >1cm pulmonary masses and bone lesions. Perhaps PET imaging would increase confidence in this as the site of biopsy chosen (supraclavicular LN) technically constitutes locoregional recurrence. One could also consider biopsy of the bone to establish involvement of a distant M1 site with metastatic breast cancer. For the sake of discussion, let us presume she has metastatic, AR+TNBC. She has received prior anthracycline and taxane in the adjuvant setting and now has recurrent disease >2 years from diagnosis. This long disease free interval together with her excellent KPS and lack of symptoms from her disease encourage me to consider clinical trials for the first line treatment of her TNBC.  

Outside of a clinical trial, we can turn to the TNT study for guidance on management of TNBC in the first-line setting (Tutt et al). This study randomized patients with TNBC or with known BRCA mutations to either carboplatin or docetaxel. Overall, there did not appear to be a significant difference between the taxane or platinum in terms of response or PFS. In the small subset of patients known to carry mutations in BRCA, the use of carboplatin achieved a higher response rate and longer median PFS. For our patient, in the absence of a BRCA  mutation, I would consider weekly paclitaxel as a first line option. This is supported by  data from CALGB 40502 (Rugo et al, JCO 2015), where ixabepilone was inferior to paclitaxel and nab-paclitaxel was not superior with a trend towards inferiority in 1st line treatment of metastatic breast cancer; these trends were consistent in the subset with TNBC as well. And although she previously received taxane in the adjuvant setting, I would not rule our weekly paclitaxel considering her nearly 3 year disease free interval. 

The fact that her tumor tested AR-positive opens the door to consider endocrine approaches which target the androgen receptor. Retrospective series have suggested that response to chemotherapy for AR+ TNBCs is poor (Asano et al BJC 2016). We now have data from 2 multicenter prospective phase II trials that establish proof of concept and activity of oral AR antagonists. First, TBCRC011 showed that bicalutamide achieved a clinical benefit rate (CBR) at 24 weeks of 19% in patients with AR>10% TNBC. More recently, the next generation AR antagonist, enzalutamide, was shown to achieve CBR at 16 weeks of ~35% in the evaluable patient population with AR>10% TNBC.  Furthermore, median PFS from this study was significantly longer in patients receiving enzalutamide in the first or second line setting. For these reasons, I would be open to consideration of treatment on a clinical trial utilizing an AR antagonist as an option. 


Aditya Bardia, MD, MPH
Re: Breast Cancer (February 2016): Molecular Oncology Tumor Boards
Feb 21, 2016 7:26 PM

Thank you fot the excellent summary Dr. Traina. I would support the decision to enroll in a clinical trial. Could you shed some light on potential clinical trials to consider for AR+ TNBC? Also, is there any data on efficacy of standard chemotherapy (taxol or platinum) in AR+ metastatic TNBC? In the neoadjuvant setting, AR+ TNBC has a lower response to conventional chemotherapy agents than AR- TNBC (Loibl S et al 2011).


Tiffany A. Traina, MD
Re: Breast Cancer (February 2016): Molecular Oncology Tumor Boards
Feb 22, 2016 8:52 AM

Course Faculty Response

Dr. Bardia: There are several ongoing trials testing novel AR-targeted therapies, alone or in combination, for the treatment of advanced AR(+) TNBC. A selection of actively recruiting trials are listed below with their registration number:

  1. Palbociclib in combination with bicalutamide for the treatment of AR+ metastatic breast cancer (NCT02605486)
  2. A Open-Label Study to Evaluate the Safety, Tolerability, Pharmacokinetics, Pharmacodynamics and Efficacy of VT-464 in Patients With Advanced Breast Cancer (NCT02580448) 
  3. Taselisib and Enzalutamide in Treating Patients With Androgen Receptor Positive Triple-Negative Metastatic Breast Cancer (NCT02457910)

With respect to your question regarding chemotherapy choice in AR+ metastatic TNBC, we have several data sets from the neoadjuvant setting which show that AR+ TNBC has a lower rate of pathologic complete response (~10%) in contrast to basal-like TNBC which approximates 50%. However, we lack predictive data that would allow us to choose one particular chemotherapy agent over another based on AR expression. For this reason, we must use best clinical judgment supported by the literature. 



Deborah Dillon
Re: Breast Cancer (February 2016): Molecular Oncology Tumor Boards
Feb 24, 2016 9:58 AM

Course Faculty Summary

Thank you to everyone who participated in this discussion. My key takeaways for this case are noted below:

  • Decalcification of bone biopsies may lead to false negative IHC results and failed FISH and other molecular analyses.
  • Androgen receptor is expressed to some degree in more than half of all breast cancers.
  • There is no standardized test for androgen receptor. Further work is needed to understand the optimal cutoff point and the significance of other AR alterations.


Tiffany A. Traina, MD
Re: Breast Cancer (February 2016): Molecular Oncology Tumor Boards
Feb 24, 2016 10:01 AM

Course Faculty Summary

I would also like to thank everyone for their participation in this discussion. My key ideas from this case based on the available information are as follows:

  • TNBC is heterogeneous in molecular profile and drivers of the disease

  • ~ 55% of patients with TNBC had AR>10% staining by IHC in the Ph II enzalutamide trial, suggesting that this target may be more prevalent than previously considered.

  • Targeting the androgen receptor may offer a well tolerated, endocrine approach for the treatment of TNBC

  • Clinical trials are encouraged for this subset of patients with AR-driven TNBC. Examples of ongoing studies include: bicalutamide in combination with palbociclib (NCT02605486), enzalutamide with or without an oral PI3K inhibitor (NCT02457910) and the phase I/II trial of VT464, an oral combined AR antagonist and CYP17 inhibitor which reduces androgen production (NCT02580448)



ASCO University
Re: Breast Cancer (February 2016): Molecular Oncology Tumor Boards
Feb 24, 2016 10:04 AM

Thank you to Drs. Dillon and Traina for leading the discussion of this case and also to all of those who contributed to the conversation! The forum is now closed to further comments but users have the ability to claim credit by clicking here.

Please check back in mid-March for a new case in this series related to lymphoma.