On Wednesday, the morning General Session at SABCS focused on tumor sequencing and analyzing genomic changes in breast cancer tumors. The word of the morning was “heterogeneity,” or lack of uniformity. Heterogeneity may be the ‘theme’ of the conference – we’ll see as we get further in.
Breast cancer is an incredibly complex disease, and each new category of breast cancer contains any number of sub-categories which repeat—something like astrophysicists’ search for the smallest molecule.
The first study, TransCONFIRM (all citations are below), reported by Dr. Rinath Jeselsohn, sought a genetic marker to identify a subgroup of patients with advanced breast cancer for whom fulvestrant is effective after prior endocrine treatment has failed. This was exploratory analysis that found 37 genes that may be predictive of better outcomes. These findings now need validation through a second study.
Dr. Mike Dixon presented an in-depth genomic analysis of hormone positive breast cancer, looking at the genetic mutations which characterize this breast cancer subtype. By understanding the genetic mutations, the hope is to develop a tool to help doctors in clinic predict which patients will respond to endocrine (hormone) therapy as well as to understand resistance to hormone therapy so therapy can be tailored appropriately for each patient.
One of the most surprising revelations to me during this session was how tumors change. Even though I am familiar with the data showing that different parts of a tumor can express differently, as well as data showing that metastatic tumors can be of different types, I was somewhat dumbfounded to realize that the tumor samples can themselves switch from basal to luminal A and back again—effectively changing cancer subtype! These changes coincide with response to hormone therapy so that as molecular subtypes change with response, we find that responders all likely end up luminal A. This means that baseline analysis alone is insufficient to predict endocrine response, as we need to evaluate the tumor in an ongoing basis during treatment. Finally, the study identified four genes that may predict response to hormone therapy and have clinical relevance.
One of the aims of the POETIC study is similarly to find out if there are mutations that indicate a poor response to treatment, in this case aromatase inhibitors. This study further underscored the heterogeneity of tumors. Somatic mutations are those mutations that a cell acquires which are then passed to the next generation of cells when the cell divides. Some somatic mutations lead to cancer. Over time, the next generations of cells can acquire additional mutations (referred to as sub-clonality). In this way, cancer cells evolve in an iterative process of clonal expansion, genetic diversification and clonal selection. This characteristic of cancers to evolve and diversify is precisely what makes them so difficult to treat and can lead to treatment resistance or failure.
The last paper I want to report on focused on genomic sequencing of tumors presented by Ryan Hartmaier, PhD., from the University of Pittsburgh. This comprehensive study of tissue samples of six metastatic breast cancer patients attempted to understand the genomic changes in metastatic breast cancer.
Genomic changes in metastatic disease are not well understood and mutations of metastasis don’t match primary tumor mutations. The author explained that the reason mutations don’t remain constant in breast cancer has to do with the number of mutations. The primary tumor has many different heterogeneous mutations. This heterogeneity is reduced in post-surgical therapy so that just a few of the mutations survive. In other words, as treatments for some cancers decimate some of the cancer clones, there is a Darwinian survival-of-the-fittest kind of process that occurs to narrow, or select, which cancer clones continue. These surviving mutations seed metastasis and then go on to mutate in new ways in their new locations. Thus the primary tumor single nucleotide variants (or SNVs) are often not detected in metastasis.
So what do all these tumor mutations and changes mean? Will we be able to predict responsiveness to treatment—saving women toxicity of ineffective or unneeded treatments, avoiding delay in adjusting treatment when they don’t work, finding the best treatments for each patient, etc? While predicting responsiveness to treatment was not the only thing of value in these studies, it is of immediate and urgent interest to women and their doctors.
S1-01. TransCONFIRM: The correlative analysis of breast tumors from patients with advanced hormone receptor positive disease identifies a genetic signature associated with decreased benefit from single agent fulvestrant
Jeselsohn RM, Barry WT, Zhao J, Buchwalter G, Guarducci C, Migliaccio I, Biagioni C, Bonechi M, Laing N, Rukazenkov Y, Winer EP, Brown M, Di Leo A, Malorni L. Dana Farber Cancer Institute, Boston, MA; Translational Research Unit, Hospital of Prato, Istituto Toscano Tumori, Prato, Italy; “Sandro Pitigliani” Medical Oncology Unit, IstitutoToscano Tumori, Prato, Italy; AstraZeneca Pharmaceuticals, Macclesfield, United Kingdom.
S1-03. Identification of base pair mutations and structural rearrangements acquired in breast cancer metastases including a novel hyperactive ESR1-DAB2 fusion gene specifically in hormone-resistant recurrence
Hartmaier RJ, Puhalla SL, Oesterreich S, Bahreini A, Davidson NE, Brufsky AM, Lee AV. Women’s Cancer Research Center, University of Pittsburgh Cancer Institute & Magee Women’s Research Center, Pittsburgh, PA; Department of Pharmacology & Chemical Biology, University of Pittsburgh, Pittsburgh, PA; Department of Human Genetics, University of Pittsburgh, Pittsburgh, PA.
S1-04. Exome sequencing of post-menopausal ER+ breast cancer (BC) treated pre-surgically with aromatase inhibitors (AIs) in the POETIC trial (CRUK/07/015)
Gellert P, Segal CV, Gao Q, Li T, Miller CA, Mardis E, Martin L-A, Holcombe C, Skene A, Bliss J, Robertson J, Smith I, Dowsett M, POETIC Trial Management Group and Trialists. Institute of Cancer Research, London, United Kingdom; The Genome Institute at Washington University, St Louis, MO; Royal Liverpool University Hospital, Liverpool, United Kingdom; Royal Bournemouth Hospital, Bournemouth, United Kingdom; Royal Marsden Hospital, London, United Kingdom; University of Nottingham, Nottingham, United Kingdom; POETIC Trial Management Group and Trialists.
S1-05. In-depth genomic analysis of ER+ breast cancers during development of endocrine resistance
Dixon JM, Turnbull AK, Fan C, Parker JS, He X, Arthur L, Martinez-Perez C, Renshaw L, Perou C. University of Edinburgh, Edinburgh, United Kingdom; Comprehensive Cancer Centre, Chapel Hill, NC.