Metastatic Breast Cancer

Introduction

• Virtual Molecular Tumor Board
• Patient: Metastatic breast cancer
• Atrium Health
• Presented by: Dr. Julie Fisher

Initial Diagnosis and Treatment

A 55-year-old Caucasian woman noted a palpable lump in her left breast in August 2008.

• Diagnostic breast imaging revealed a 1.6 cm x 1.2 cm x 1.0 cm spiculated mass corresponding to the area of palpable concern
• Ultrasound-guided core biopsy showed poorly differentiated invasive ductal carcinoma: ER+, PR+, HER-2-Neu 2+ by immunohistochemistry (equivocal) and negative by FISH (ratio: 1.46)
• September 2008: Initiated dose-dense doxorubicin/cyclophosphamide
• Patient was found to have metastasis to the lung and liver after two cycles

Clinical Progress & Treatment History

• December 2008: Liver biopsy shows ER+ 100%, PR+ 100%, HER-2-Neu 3+ by IHC
• December 2008-May 2009: paclitaxel/bevacizumab
• May 2009-August 2009: capecitabine/bevacizumab
• September 2009-November 2011: letrozole, disease progression
  • Biopsy shows ER+ 90%, PR+ 90% and HER-2-Neu 3+ by IHC
• November 2011-April 2013: fulvestrant/trastuzumab; trastuzumab held in January 2013 due to decline in EF, disease progression
• May 2013-October 2013: paclitaxel/lapatinib; paclitaxel stopped due to neuropathy
• October 2013-January 2014: anastrozole/lapatinib
• February 2014-January 2015: trastuzumab emtansine (T-DM1)
• January 2015-March 2015: docetaxel/trastuzumab/pertuzumab (CLEOPATRA)
• March 2015-August 2015: eribulin/trastuzumab/pertuzumab
• August 2015-February 2016: trastuzumab (after optimal response)
• February 2016-October 2016: vinorelbine/trastuzumab/pertuzumab
• October 2016-December 2016: gemcitabine/trastuzumab/pertuzumab
  • Liver biopsy shows ER 1+/40%, PR-, HER-2-Neu nonamplified
  • Specimen sent for genomic panel testing (December 2016)
  • Consideration for clinical trials, including ASCO TAPUR
• January 2017-March 2017: carboplatin
• March 2017-June 2017: doxorubicin liposomal
• August 2017-November 2017: pembrolizumab (received two cycles, but ultimately removed from therapy after persistent abnormal LFTs)
• *Therapy change due to disease progression unless otherwise noted.

Liver Imaging

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Pathology Images – Liver Core Biopsy

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Genomic Panel Testing

Potential Treatments

• December 2016

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Results

• December 2016

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Tumor Mutational Load

• December 2016
• Tumor mutational load (TML) is a measure of the total number of non-synonymous mutations per coding area
  • A non-synonymous mutation is a change in the DNA sequence that results in the alteration of an amino acid
• Emerging data suggests TML could be used to predict response to immune checkpoint inhibitors across various tumor sites
• High TML correlates to better response to immunotherapy.

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Biomarker Testing

Results

• December 2016

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Treatment on TAPUR Trial: Pembrolizumab

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• Prospective, non-randomized clinical trial (NCT02693535)
• Assesses safety and efficacy of targeted therapies
• Therapy is selected based on genomic testing results
  • Allows off-label access based on biology, not tumor site
• PD-1
  • An inhibitory immune checkpoint receptor expressed on T cells, PD-1 induces signaling that inhibits T-cell proliferation, cytokine release and cell death
• PD-L1
  • A PD-1 ligand that serves as an immunosuppressive signal
  • Expressed in many malignancies, including breast cancer
• Pembrolizumab is a monoclonal antibody against PD-1; as a result, the immune system is not hindered from targeting cancer cells
• There is evidence of efficacy in patients with metastatic, triple-negative breast cancer
• Patient received first cycles of pembrolizumab
  • Significant fatigue, intermittent abdominal pain
  • Initial follow-up scans stable
• Second dose held twice due to LFT abnormalities
• Ultimately removed from protocol because of LFT abnormalities
  • Transitioned to supportive care only

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Discussion

• This molecular tumor board case describes a patient with metastatic breast cancer who survived for 10 years after diagnosis
• Her disease course was notable for disease biology that evolved over time
  • Initial diagnosis in 2008: ER+/PR+/HER-2-
  • Metastatic disease demonstrated later in 2008: ER+/PR+/HER-2+
  • Repeat biopsy of metastatic disease in 2011: ER+/PR+/HER-2+
  • Repeat biopsy of metastatic focus in 2016: weakly ER+, PR-, HER-2-
• It is not uncommon for these markers to change over time in patients receiving ongoing treatment; it is therefore valuable to obtain repeat biopsies of metastatic foci periodically
• Evolving results may influence systemic treatment recommendations
• Her initial treatment included a combination of cytotoxic and endocrine therapies
• After HER-2 amplification was demonstrated, HER-2-targeted agents were utilized
• When repeat biopsy showed non-amplification of HER-2, she resumed cytotoxic therapy alone
• Ultimately, genomic profiling revealed the following alterations:
  • PIK3CA
  • PTEN
  • TP53
  • TLE3
  • AR/ER/HER2
  • CHEK
• In November 2017, ASCO TAPUR expanded to offer pembrolizumab to patients with metastatic breast cancer and a high tumor mutation burden
• This offered a non-cytotoxic option to this heavily pretreated patient with chemo- and endocrine-resistant disease
• She ultimately received 2 cycles of treatment, achieving stable disease per RECIST criteria
• She continued to experience significant fatigue and general debilitation
• Four months after enrolling in the clinical trial, she elected to pursue comfort-based care alone
• The patient enrolled in hospice care and passed away shortly thereafter, nearly 10 years after her initial diagnosis