Breast Cancer (March 2015): Molecular Oncology Tumor Boards

ASCO University
Mar 11, 2015 10:52 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. Dara Ross (Memorial Sloan Kettering Cancer Center) and Aditya Bardia (Massachusetts General Hospital).

Users 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 “Email me when this thread has replies.” option located at the bottom of this page.

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Please click here for supplemental resources related to the case.

Comments

10031

ASCO University
Re: Breast Cancer (March 2015): Molecular Oncology Tumor Boards
Mar 11, 2015 9:55 AM

Patient Case

Age/Sex: 55/F

Medical History: A 55-year-old woman was diagnosed with infiltrating mixed ductal/lobular carcinoma. She underwent right mastectomy with lymph node dissection. Surgical pathology revealed Stage 1 T2N0M0. She received 4 cycles of cytoxan and adriamycin followed by tamoxifen for 5 years.

15 years later, she underwent urgent MRI spine for evaluation of acute ‎back pain. MRI spine revealed compression deformity of the L4 vertebral body and enhancing lesions in the L1 vertebral body, L4 vertebral body, left iliac bone, and left sacrum, most consistent with metastatic disease. See attached for additional details.

Type of Tumor: Breast Cancer

Relevant Markers:
CA 15-3 = 338.6 (pre-treatment)
CEA = 2.9 (pre-treatment)

Co-morbidities:  Hyperlipidemia

10061

ASCO University
Re: Breast Cancer (March 2015): Molecular Oncology Tumor Boards
Mar 11, 2015 9:56 AM

Discussion Questions

  1. What would be the next step(s) in management? Is bone biopsy recommended in a patient with suspected metastatic breast cancer who has a known history of primary breast cancer?
  2. What would be recommended systemic therapy option for management for ER+ metastatic breast cancer?
  3. Should molecular profiling of the tumor be performed? If so, what are the genes of clinical interest?


10066

Daniel G. Haller, MD, FASCO
Re: Breast Cancer (March 2015): Molecular Oncology Tumor Boards
Mar 11, 2015 11:46 AM

Has she had a recent mammogram or other imaging of remaining breast?

10071

ASCO University
Re: Breast Cancer (March 2015): Molecular Oncology Tumor Boards
Mar 11, 2015 12:38 PM

Patient Case Update

The patient had undergone prophylactic left mastectomy in the past, pathology of which was negative for malignancy. Physical exam during clinic visit showed no abnormal findings.

10036

Anis Toumeh, MD
Re: Breast Cancer (March 2015): Molecular Oncology Tumor Boards
Mar 11, 2015 3:05 PM

1- I would definitely consider obtaining a biopsy and test for ER / PR and HER2. This could well be a distant recurrence of her primary hormone receptor positive disease but also could be of a different biology ( Triple negative or HER2 disease). I also think that, based on her symptoms, a palliative intervention for the L4 lesion / compression may be worthwhile. Kyphoplasty probably. Would complete staging with PET-CT scan / Brain MRI (if signs or symptoms exist)

2- Frontline treatment would depend on the disease ( HR+, HER2 or TNBC). For minimally symptomatic hormone receptor positve disease in the abscense of a visceral crisis, first line hormonal therapy is very reasonable. This would be in the form of Non-steroidal AI plus or minus Palbociblib. One could also consider the combination of Fulvestrant and Arimidex ( although the dose of Fulvestrant used in the SWOG and FACT trials was 250 and patients with no prior exposure to hormonal therapy benefited the most ). I personally would consider Fulvestrant and Arimidex combination. Despite the impressive PFS data from PALOMA-1 trial, no OS benefit has been demonstrated yet, in addition to the risk of neutropenia and alopecia. Bone targeted therapy will be in my plan too in the form of Zoledronic Acid or Donesumab.

10076

Daniel G. Haller, MD, FASCO
Re: Breast Cancer (March 2015): Molecular Oncology Tumor Boards
Mar 12, 2015 10:14 AM

Certainly, given the 15 year DFI since the original breast surgery, repeat tissue is required for both diagnosis and remeasuring of biomarkers.  Although one assume she was ER/PR+ initially since she received tamoxifen, knowing her current status, with HER2 is imperative, as would CXR, CT to establish breadth of metastatic disease.

10081

ASCO University
Re: Breast Cancer (March 2015): Molecular Oncology Tumor Boards
Mar 12, 2015 11:38 AM

Patient Case Update

The primary tumor was ER positive, PR positive, HER2 negative.

10041

Gilberto Lopes, MD, MBA
Re: Breast Cancer (March 2015): Molecular Oncology Tumor Boards
Mar 12, 2015 11:50 AM

Discussion Questions

  1. What would be the next step(s) in management? Is bone biopsy recommended in a patient with suspected metastatic breast cancer who has a known history of primary breast cancer?

A biopsy is clearly indicated to determine the etiology of the lesion, and if confirmed that it is breast cancer, to clarify its hormone receptor and HER2 status, which will help guide therapy. For patients who have received adjuvant treatment, it is expected that 20-25% might have a different hormone or HER2 status. This patient´s presentation with metastases 15 years after the original diagnosis and treatment would be consistent with ER+ breast cancer. 

2. What would be recommended systemic therapy option for management for ER+ metastatic breast cancer?

If staging work-up does not show visceral metastases (or shows low-volume visceral disease), hormonal therapy would be indicated. An aromatase inhibitor would be appropriate treatment, alongside a bisphosphonate or denosumab. In the US, palbociclib, a CDK 4 and 6 inhibitor, has been approved based on an improvement of 10 months in PFS and is certainly an option to be added to an AI. If the disease is HER2 positive, anti-Her2 therapy can be added to the AI. 
3. Should molecular profiling of the tumor be performed? If so, what are the genes of clinical interest?

At this time, hormone receptor and HER2 testing are the main molecular markers that have clinical implication. In the future, and as a patient goes through the available standard therapies, molecular profiling may prove of benefit. Most likely to be helpful in the near future include alterations in the PI3K and MTOR patwhays.


10046

Filipa Lynce, MD
Re: Breast Cancer (March 2015): Molecular Oncology Tumor Boards
Mar 12, 2015 5:02 PM

I agree with what was written before. Molecular profiling at this point would not have clinical implications. Is she postmenopausal? Although average age of menopause in the US is 51, some women continue to menstruate until later. Implication for choice of hormonal therapy if clinically appropriate.

10051

Helmy M. Guirgis, MD
Re: Breast Cancer (March 2015): Molecular Oncology Tumor Boards
Mar 15, 2015 3:34 PM

Breast cancer case with bony lesions Presumably the initial tumor was hormone positive. Is there any recent CT scan to document the absence of another malignancy? If CT scan is negative and the patient refuses bone biopsy, I would start her on AI and follow.  

10086

Dara S. Ross, MD
Re: Breast Cancer (March 2015): Molecular Oncology Tumor Boards
Mar 16, 2015 5:35 PM

Course Faculty Response

Biopsy of the suspected metastasis should be performed in order to confirm the diagnosis and determine the status of the biomarkers ER, PR and HER2. ASCO/CAP guidelines recommend ER, PR and HER2 testing on every primary invasive breast cancer and on metastatic sites (if stage IV and specimen is available) in order to guide decisions regarding therapy. Classically, treatment decisions are based upon the histologic subtype, grade and stage of the tumor in addition to the biomarker status. With the development of improved molecular profiling assays with faster turnaround times, the identification of “driver” and “actionable” somatic genetic alterations (i.e. point mutations, copy number alterations or gene fusions) in key oncogenes and tumor suppressor genes now play an essential role in the diagnosis and treatment of many cancers, such as lung adenocarcinoma, and this is evolving in the treatment of breast cancer as well. 

Breast cancer is a heterogenous disease histologically and at the molecular level. The most common recurrent molecular alterations in breast cancer involve the genes TP53, PIK3CA and GATA3. The molecular profiles vary for ER-positive and ER-negative tumors and can be further characterized amongst the intrinsic subtypes (luminal A, luminal B, HER2-enriched and basal-like). Molecular alterations involving the PI3K/AKT/mTOR pathway occur in approximately 30% of invasive breast tumors and specific mutations may serve as potential drug targets. PI3K is a heterodimer composed of 2 subunits - an 85 kDa regulatory subunit (p85) and a 110 kDa catalytic subunit which consists of 4 isoforms. The PIK3CA gene encodes the isoform p110α and mutations in PIK3CA are found in multiple tumor types. The most common mutations (“hotspots”) involving the PIK3CA gene in breast cancer involve amino acids E542 and E545 in the helical domain and H1047 in the kinase domain of p110α, all of which result in gain of enzymatic function. PIK3CA is the most commonly mutated gene in luminal A and luminal B breast cancers, at 45% and 29% respectively (TCGA. Nature 2012). Additional somatic alterations which lead to hyperactivity of the PI3K pathway include mutations in AKT1, amplification of AKT2, and loss of the phosphatase PTEN. Various molecular profiling platforms, including next generation sequencing, multiplexed hotspot mutation panels, Sanger Sequencing and fluorescence in situ hybridization (FISH) can be used to identify these genetic alterations which may allow patients to participate in a clinical trial. 

The tissue available for biomarker testing and molecular profiling is important to consider when planning the next step in management. If a bone biopsy will be obtained with the intent of confirming the biomarker status and performing molecular testing it is important to communicate this to the Pathology department. Specimens labeled as “bone” almost always require a decalcification procedure which is necessary for rendering an accurate diagnosis in the submitted tissue. The decalcification solution unfortunately makes the tissue unsuitable for molecular testing due to nucleic acid degradation. In addition, decalcification solutions may alter the ER, PR and HER2 results and lead to weaker or negative staining. Solutions to this problem include: 1) perform a concurrent fine needle aspiration (FNA) so that the cytology material can be used to prepare a cell block, and/or 2) perform an additional core biopsy for molecular test purposes which can be processed without decalcification. In addition, providing the Pathology department with the history of breast cancer and the need for ancillary molecular studies up front will prevent additional immunohistochemical work-ups to determine the site of origin of the metastasis. 

The primary tumor or metastatic tumor (preferred) can be sent for molecular profiling. When tissue is received in the Molecular Pathology department the tumor percentage will be evaluated. It is important to be familiar with the technical/analytical sensitivity of the molecular profiling assay being performed. The technical sensitivity of an assay will determine the minimum amount of tumor cells which should be present in the submitted tissue in order to exclude the possibility of a false negative result. Assays performed in a CLIA-certified lab will be validated for technical sensitivity for the different specimen types being tested. An understanding of these limitations is always important when interpreting molecular results. 

10091

Aditya Bardia, MD, MPH
Re: Breast Cancer (March 2015): Molecular Oncology Tumor Boards
Mar 16, 2015 5:37 PM

Course Faculty Response

In general, restaging with CT chest/abdomen/pelvis and bone scan would be recommended for evaluating extent of disease. PET scans are not routinely recommended for breast cancer.

In addition, biopsy of the metastatic site should be considered for:

  1. confirmation of diagnosis of metastatic adenocarcinoma
  2. repeat ER/PR and HER2 receptors as there can be a receptor switch (tumors can become ER-) in about 10-20% of breast tumors.


For this patient, bone biopsy was obtained which revealed ER+/PR+/HER2- adenocarcinoma consistent with breast origin. Restaging CT scans and bone scan revealed loculated left pleural effusion and widespread bony disease.  No visceral metastasis were seen.

In general, endocrine therapy would be recommended as first line for management of HR+ breast cancer. The role of CDK 4/6 inhibitors will be reviewed in a later post.

Molecular genotyping of the tumor could be considered, though role not fully established in breast cancer (as opposed to lung cancer or melanoma). If patient interested in clinical trials, molecular profiling could help in stratified clinical trial enrollment.

This patient was very interested in clinical trials. Molecular profiling was obtained for the patient which revealed PIK3CA mutation (discussed below).

10096

ASCO University
Re: Breast Cancer (March 2015): Molecular Oncology Tumor Boards
Mar 16, 2015 5:45 PM

Patient Case Update

How tissue was acquired/preserved:  Paraffin embedded tissue from the metastatic bone and tumor resection. See molecular pathology report for details. 

Testing Platform/Molecular Profiling: See attached

Treatments initiated: Letrozole with a PI3K inhibitor (on a clinical trial)

10101

ASCO University
Re: Breast Cancer (March 2015): Molecular Oncology Tumor Boards
Mar 16, 2015 5:46 PM

Discussion Questions

  1. What is the role of PIK3CA mutation in mediating resistance to endocrine therapy? What the common toxicities to watch out for when treating with PI3K inhibitors?
  2. If the patient progresses on the PI3K inhibitor, should re-biopsy and molecular profiling be performed on additional metastatic sites?


10106

Dara S. Ross, MD
Re: Breast Cancer (March 2015): Molecular Oncology Tumor Boards
Mar 23, 2015 9:43 AM

Course Faculty Response

Studies have shown that hormonal and PI3K signaling pathways cooperate in breast cancer and mutations leading to hyperactivity of the PI3K pathway can be associated with resistance to anti-estrogen and anti-HER2 therapies. Biopsy at the time of progression of disease is becoming more common in order to explore mechanisms of resistance and new therapeutic options in various tumor types. This is routine in patients with lung adenocarcinoma who have developed acquired resistance to tyrosine kinase inhibitors however in breast cancer the clinical significance of this information is still evolving. The comparison of molecular profiles (and the variant frequencies of each mutation) of primary tumors and subsequent metastatic tumors has provided insight into tumor heterogeneity and the evolution of various clonal and subclonal populations in disease progression. 

A recent article (Juric D et al. Nature 2015) studied the genomic evolution in a patient with breast cancer with a PIK3CA mutation who received treatment with BYL719 (PI3Kα inhibitor). Material was obtained from 14 metastatic sites and sequencing was performed. In comparison with the pre-treatment tumor, all metastatic lesions showed copy number loss of PTEN. The metastases that showed resistance to treatment had additional PTEN alterations, including the loss of PTEN expression. This study showed that with the continued inhibition of PIK3CA, additional genomic alterations emerged leading to PTEN loss as an alternative mechanism for activation of the PI3K pathway. 

Other mutations associated with resistance to endocrine therapy that may be identified in metastatic lesions are somatic alterations involving the ESR1 and FGFR1 genes. Point mutations in the ligand binding domain of ESR1 may be seen in patients treated with anti-estrogen therapy. In addition, amplification and overexpression of FGFR1 may contribute to poor prognosis in luminal A and luminal B breast cancers and lead to subsequent endocrine therapy resistance. This provides further information into the evolution of tumors over time and therapeutic resistance. 


10111

Aditya Bardia, MD, MPH
Re: Breast Cancer (March 2015): Molecular Oncology Tumor Boards
Mar 23, 2015 9:45 AM

Course Faculty Response

The PI3K/AKT/mTOR and cyclin D–CDK4/6–INK4–Rb pathways have been implicated in resistance to endocrine therapy. Accordingly, there is an increasing interest in targeting this pathway with PI3K and CDK 4/6 inhibitors. The FDA recently provided accelerated approval to CDK 4/6 inhibitor, palbocliclib, as a 1st line therapy along with letrozole for metastatic HR+ breast cancer. A number of clinical trials are investigating the efficacy of PI3K inhibitors in HR+ breast cancer.

While the toxicity of PI3K inhibitor is a bit dependent on the specific PI3K inhibitor, particularly whether it is a pan-PI3K or an alpha-selective PI3K inhibitor, in general hyperglycemia is one of the most common observed adverse effect of PI3K inhibitors. Hyperglycemia is an on-target effect of PI3K inhibition, and it is important to note that Insulin should generally not be used to treat hyperglycemia (unless urgent) as it can potentially fuel growth of the tumor.

From a research perspective, a repeat biopsy would be informative as it could provide insights into mechanism of resistance (discussed nicely by Dr. Ross). However, clinically that can be difficult as a number of patients have bone-only metastasis which can be difficult to biopsy (and re-biopsy). There is emerging interest in utilizing circulating tumor cells (CTCs) and circulating DNA (ctDNA) as potential tools for “liquid biopsy”.  

10056

Nathan M. Shumway, DO, FACP
Re: Breast Cancer (March 2015): Molecular Oncology Tumor Boards
Mar 24, 2015 8:52 AM

How do you think use of upstream inhibitors of PI3K (i.e. mTOR inhibition/Everolimus) that are already in use will complement the newer and more specific PI3K inhibitors in the treatment of metastatic breast cancer?

10116

Aditya Bardia, MD, MPH
Re: Breast Cancer (March 2015): Molecular Oncology Tumor Boards
Mar 25, 2015 9:34 AM

Course Faculty Response

Good question. PIK3CA signaling activates Akt which in turn activates mTOR and there has been interest in looking at downstream inhibitors, particularly mTOR inhibitors such as everolimus, among patients whose tumors harbor PIK3CA mutation. In the BOLERO-2 trial, which investigated exemestane with everolimus, versus exemestane, both groups (with or without PIK3CA mutation) derived benefit from everolimus. Surprisingly, a greater benefit from everolimus treatment was seen among patients with minimal tumor alterations in PIK3CA, (among others),  while those with multiple alterations had less  benefit (Hortobagyi et al. ASCO 2013).  One could speculate various reasons for these observations, including kind of specimens (primary versus metastastic), effect of prior treatments, difference in inhibiting oncogene directly (versus indirectly), and the increasing appreciation that signaling pathways in the cell are a complex interplay of multiple feeds and compensatory loops. Should one therefore consider combination of multiple inhibitors, such as mTOR with PI3K, or mTOR with CDK 4/6 etc? These questions are being investigated in ongoing clinical trials.

10121

Dara S. Ross, MD
Re: Breast Cancer (March 2015): Molecular Oncology Tumor Boards
Mar 26, 2015 3:33 PM

Course Faculty Summary

Thanks to everyone who participated in this discussion. In summary, these are my individual interpretations based off of the available information:

  1. Mutations: The detection of “driver” and “actionable” somatic genetic alterations in breast cancer by molecular profiling is an evolving process and may influence how patients with Stage IV breast cancer are treated. 
  2. Molecular Profiling Platforms: There are different platforms that can be used for molecular testing of breast carcinomas. Identification of the “hotspot” mutations in the PIK3CA gene can render a patient eligible for clinical trials in the setting of advanced metastatic disease. The genes of clinical relevance should always be stated on the requisition when submitting material to the Surgical Pathology and Molecular Pathology departments. An understanding of the different platforms offered for molecular profiling, including the genes being analyzed and the technical/analytical sensitivity for each assay, is important when interpreting Molecular Pathology reports.
  3. Communication: Communication with the Pathology department is essential when performing biopsies for ER, PR, and HER2 testing and molecular profiling. Bone biopsies that undergo decalcification are not suitable for molecular testing. The technical sensitivity of an assay should be stated in reports with an additional disclaimer if the tumor percentage in the submitted material is suboptimal for the test and the possibility of a false negative result cannot be excluded. 
  4. Heterogeneity: Breast tumors are heterogeneous. Our understanding of the therapy related genomic evolution in breast tumors continues to expand as more sequencing data is accumulated on primary tumors and their subsequent metastases. 


10126

Aditya Bardia, MD, MPH
Re: Breast Cancer (March 2015): Molecular Oncology Tumor Boards
Mar 26, 2015 3:35 PM

Course Faculty Summary

I would also like to thank everyone who participated in this discussion. In summary, these are my individual interpretations based off of the available information:

  1. In a patient with suspected metastatic breast cancer, a biopsy of the metastatic site should be considered for confirmation of diagnosis and repeat ER/PR and HER2 receptors as receptor switch can be observed.
  2. The PI3K/AKT/mTOR and cyclin D–CDK4/6–INK4–Rb pathways have been implicated in resistance to endocrine therapy. The FDA recently provided accelerated approval to CDK 4/6 inhibitor, palbocliclib, as a 1st line therapy along with letrozole for metastatic HR+ breast cancer.
  3. Currently there is no FDA approved PI3K inhibitor for breast cancer but there a number of ongoing clinical trials investigating the efficacy of PI3K inhibitors in HR+ breast cancer. 
  4. Hyperglycemia is an on-target effect of PI3K inhibition, and it is important to note that Insulin should generally not be used to treat hyperglycemia (unless urgent) as it can potentially increase growth of the tumor.
  5. There is emerging interest in utilizing circulating tumor cells (CTCs) and circulating DNA (ctDNA) as potential tools for “liquid biopsy”.  

10131

ASCO University
Re: Breast Cancer (March 2015): Molecular Oncology Tumor Boards
Mar 26, 2015 3:38 PM

Thank you to Drs. Ross and Bardia 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 opportunity to claim CME credit on ASCO University by clicking here.

Please check back in mid-April for a new case in this series related to chronic lymphocytic leukemia.   


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