Breast cancer is not so much a disease as it is a universe: endlessly complex, huge, and continuously evolving. 2014 saw fascinating glimpses of where the new biology of breast cancer is taking us, as well as some important clinical advances.
Genetics and Biology
Let's begin by looking at several fascinating stories involving biology and genetics. Physicians have, since the mid-1990s, screened patients for mutations in BRCA1 and 2. Such testing was expensive, controlled by a single company, and occasionally confusing (the dreaded “Variant of Unknown Significance”).
The landscape of genetic testing is now in hyper-evolution. The Supreme Court's invalidation of the Myriad patent has led to multiple new diagnostic companies entering the field, with a consequent fall in prices. At the same time, so-called “panel testing” has come to the fore, with broader sweeps of the human genome than just BRCA 1 and 2.
Kurian et al (J Clin Oncol 2014 Jul 1;32(19):2001-9) looked at panel testing in a population of women referred for genetic testing who proved to be BRCA-mutation-negative.
Overall, 11.4 percent of these women harbored another mutation associated with a human cancer (including ATM, BLM, CDH1, CDKN2A, MUTYH, MLH1, NBN, PRSS1, and SLX4), though many of these were mutations not typically thought of as predisposing to breast cancer. Many of these were “actionable” mutations in that they would normally lead to some diagnostic or therapeutic intervention.
One mutation that drew particular scrutiny this year was PALB2. This somewhat low-frequency mutation had been known for some time to be associated with a higher rate of breast cancer, though until the paper by Antoniou in the NEJM (2014;371:497-506) the strength of this association had not been recognized. The authors estimated that a patient harboring a PALB2 mutation carries a risk of developing breast cancer of 35% by age 70. This makes PALB2 as being a heavy hitter in terms of breast cancer risk.
Tumor genomics, like host genomics, continues to excite. My favorite breast cancer genomics paper in 2014 was a Nature paper by Wang and colleagues at MD Anderson (Nature. 2014 Aug 14;512:155-60) looking at single cell genomics. The original genomics studies involved looking at populations of breast cancer cells within a tumor. The technology has now improved to the point that one can isolate single cancer cell nuclei and perform deep sequencing.
The world revealed by single cell sequencing is fascinating and frightening. Looking at ∼50 cells per tumor, the authors stated “No two single tumor cells are genetically identical.” Heterogeneity reigns at the single cell level, and certainly goes a long way to explaining the ineffectiveness of current therapies for metastatic breast cancer: the whack-a-mole phenomenon of compensatory resistance is common when a cancer has a multitude of mutations.
In one triple-negative breast cancer studied, 374 clonal mutations were seen across the cancer, with an additional 154 subclonal mutations, a quarter of which are predicted to affect protein function. Such studies suggest that there are hard limits to kinase-based approaches for many breast cancers.
One of my favorite papers this year, published in JAMA (312:902-14), was a population-based study (189,734 women) of contralateral prophylactic mastectomy. Bilateral mastectomies have increased significantly in recent years (from 2.0% to 12.3% between 1998 and 2011 in California), particularly in younger women. This is the result of increased genetic testing, increased use of breast MRIs, changes in plastic surgery techniques, and increased public awareness (the “Angelina Jolie effect”).
But does contralateral prophylactic mastectomy improve outcome? The answer, as the JAMA study clearly demonstrates, is no. When compared with lumpectomy and radiation therapy, 10-year overall survival is virtually identical. Interestingly, unilateral mastectomy is inferior to both bilateral mastectomy and lumpectomy plus radiation therapy, perhaps suggesting that patients with more aggressive cancers are more likely to undergo mastectomy than lumpectomy.
Breast Cancer Subtypes
Breast cancer, as we have realized for the past decade or more, is a collection of diseases, with distinctive biologies and (more-or-less) specific treatments. Describing breast cancer therapy necessarily requires an understanding of breast cancer subtypes. 2014 brought us interesting new information regarding the main subtypes.
In estrogen receptor positive disease, the field awaits the completion of large phase III metastatic trials (some of which may report out in 2015) for approaches involving CDK 4/6 inhibition and HDAC inhibition, both of which have had promising results in underpowered randomized Phase II trials.
While we hold our collective breaths awaiting such results, 2014 saw the presentation (at ASCO and San Antonio, and in a recent NEJM publication) of the SOFT and TEXT trials in premenopausal estrogen receptor positive breast cancer. These trials asked straightforward yet important questions: should tamoxifen continue as the standard of care for premenopausal ER-positive disease in the adjuvant setting, or should (as smaller, earlier studies suggested) we add ovarian suppression to the mix? And, if ovarian suppression adds something, should it be combined with tamoxifen or with an aromatase inhibitor?
SOFT (N Engl J Med. 2014 Dec 11. [Epub ahead of print]) randomized patients to tamoxifen alone, tamoxifen plus ovarian suppression, or exemestane plus ovarian suppression. While ovarian suppression did add significant benefit or the overall group (which contained a substantial portion of low-risk, node-negative patients), planned subset analyses revealed a significant benefit for the more high-risk subgroup of women who had received chemotherapy and remained premenopausal. Here the rates of freedom from breast cancer at five years were, respectively, 78 percent (tamoxifen alone), 82.5 percent (tamoxifen plus ovarian suppression), and 85.7 percent (exemestane plus ovarian suppression).
The age breakdown in SOFT was also of interest. In women younger than 35, freedom from breast cancer at five years was 67.7 percent for tamoxifen alone, 78.9 percent for tamoxifen plus ovarian suppression, and 83.4 percent for exemestane plus ovarian suppression. This is an impressive difference, though the number of patients analyzed in this subset was small.
Ovarian suppression in premenopausal women is not without a price; premature menopause carries significant symptomatic burdens regarding hot flashes, sexuality, and bone health. Understanding that, the data would certainly suggest that exemestane plus ovarian suppression should be part of the treatment discussion for high-risk premenopausal women (defined as women receiving chemotherapy and those under age 35 in the study).
2014 was a year of both triumph and disappointment in the HER2-positive world, as physicians tested novel combinations of HER2-targeting agents. On the disappointment side of the ledger, the long-awaited ALTTO trial, presented at the ASCO annual meeting's plenary session, failed to demonstrate a significant benefit for the addition of lapatinib to adjuvant trastuzumab. In addition to representing the failure of a drug, the trial results called into question the suggestion that neoadjuvant trials would represent a valuable surrogate for adjuvant trial results, a hypothesis that had led to an FDA draft document for preoperative drug development.
What the ALTTO trial clearly did not do was put a damper on HER2 combinations. The CLEOPATRA trial, originally published in 2013, demonstrated a progression-free survival advantage for the addition of the monoclonal antibody pertuzumab to trastuzumab. This year's European Society for Medical Oncology meeting updated the trial results, and the results were stunning. Front-line metastatic HER2-positive patients randomized to the combination of docetaxel, trastuzumab, and pertuzumab lived a median of 56.5 months, versus the 40.8-month median for docetaxel and trastuzumab.
This is a stunning result. In the past 15 years, survival for metastatic HER2-positive disease has almost tripled, and is now at least equivalent to, or perhaps superior to, that of ER-positive disease.
Pertuzumab has already entered the neoadjuvant setting as a result of an FDA approval, and more standard adjuvant trials (including combinations with T-DM1) are ongoing. If the results of these trials mimic those of CLEOPATRA, then HER2-positive disease may cease to be a major public health hazard. If so, this will represent a signal accomplishment for the breast cancer clinical trials community.
Along the lines of “science by press release,” we are told that there is a positive “late adjuvant” trial for the small molecule HER2 inhibitor neratinib, and that the MARIANNE trial has failed to show additional benefit for the addition of T-DM1 to pertuzumab in the metastatic setting. Both of these results should be presented more formally in coming months.
Triple-Negative Breast Cancer
With real advances in ER-positive and HER2-positive breast cancer (and even more within our short-term reach), triple-negative breast cancer remains stubbornly recalcitrant. For practical purposes, treatment remains confined to chemotherapy, and advances in the past decade (e.g., eribulin in the metastatic setting) have had only a minimal effect on overall outcome.
Recent years have explained why this is the case: genomic studies have identified triple-negative breast cancer as a subtype dominated by genomic chaos. Combined with the lack of our favorite breast cancer targets (ER and HER2), this genomic instability dooms our treatment approaches to rapid failure in all too many cases.
Are we beginning to find our way out of this morass? Perhaps. Numerous drug targets have been identified based on subsetting of triple-negative breast cancer. Last month's San Antonio Breast Cancer Symposium saw two interesting triple-negative presentations that may point the way forward.
First, Andrew Tutt and colleagues presented the results of the TNT trial. TNT randomized front-line metastatic breast cancer patients to either docetaxel (100 mg/m2 every 3 weeks) or carboplatin (AUC of 6 every 3 weeks). Platinating agents have been around since the 1980s, and taxanes since the 1990s, but neither had been tested head-to-head prior to TNT.
This would have been a quite boring Toothpaste A vs. Toothpaste B chemotherapy trial were it not for the biologic correlates included by the investigators. While overall the trial was a wash, with no significant difference in progression-free or overall survival, in BRCA1/2 mutation carriers, carboplatin was the clear winner over docetaxel (68% vs. 33% response rate, p =.03). And while carboplatin had a mediocre progression-free survival in BRCA wild-type patients (3.1 months), PFS was twice as long in BRCA 1/2 mutants (6.8 months). DNA damage repair clearly matters when one is using a DNA-damaging agent.
Secondly, while finding the right place for an old drug is clearly of value, we do need new approaches to triple-negative. Rita Nanda and colleagues offered us a glimpse of the future with their Phase Ib study of the checkpoint inhibitor pembrolizumab (an anti-PD-1 IgG4 monoclonal antibody) in triple-negative breast cancer.
Using PD-L1 positivity as the trial's gateway, an overall response rate of 18.5 percent was seen in a smallish (27 evaluable patient) cohort. Short follow-up and small numbers, but several robust and durable responses were seen.
Similar results, albeit with an even smaller Phase I study, were seen with another checkpoint inhibitor called MPDL3280A. Immuno-oncology appears poised to spill over from melanoma and lung cancer into triple-negative breast cancer: more to come, I am sure, but 2014 appears to be a transitional year between receptor-based approaches that have dominated the past decades and newer approaches that may bring us closer to a cure.