Metastatic Breast Cancer

Reviewed on July 22, 2024

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+…

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

Pathology Images – Liver Core Biopsy

Enlarge  Figure 1-4: December 2016: Metastatic carcinoma with focal glandular differentiation, consistent with metastasis from primary breast cancer
Figure 1-4: December 2016: Metastatic carcinoma with focal glandular differentiation, consistent with metastasis from primary breast cancer
Enlarge  Figure 1-5: December 2016: Higher power magnification shows focal mucin production and intermediate grade histology December 2016.
Figure 1-5: December 2016: Higher power magnification shows focal mucin production and intermediate grade histology December 2016.
Enlarge  Figure 1-6: Immunohistochemical stain for estrogen receptor shows positive weak nuclear staining in a subset of the tumor cells (1+, 40%)
Figure 1-6: Immunohistochemical stain for estrogen receptor shows positive weak nuclear staining in a subset of the tumor cells (1+, 40%)

Genomic Panel Testing

Potential Treatments

  • December 2016

Results

  • December 2016

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.

Biomarker Testing

Results

  • December 2016

Treatment on TAPUR Trial: Pembrolizumab

  • 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

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

 

References

  • https://www.carismolecularintelligence.com/wp-content/uploads/2016/12/TN0291-v1_Total-Mutational-Load-Immunotherapy-REVERSED-PAGES.pdf
  • http://mct.aacrjournals.org/content/16/11/2598
  • https://www.tapur.org/sites/tapur.org/files/03.2018_General_TAPUR_Overview.pdf
  • http://ascopubs.org/doi/10.1200/JCO.2015.64.8931
  • http://ascopubs.org/doi/10.1200/JCO.2011.37.2482
  • http://ascopubs.org/doi/10.1200/jco.2012.30.27_suppl.92