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Musings of a Cancer Doctor

Wide-ranging views and perspective from George W. Sledge, Jr., MD

Wednesday, November 6, 2019

The European Society of Medical Oncology's 2019 Annual Meeting, held in Barcelona, had several interesting themes related to breast cancer. First and foremost, the CDK 4/6 inhibitors held sway. But there were also interesting stories related to novel immuno-oncology approaches to triple-negative breast cancer. While perhaps not immediately applicable, these were provocative and may show the way forward for this continuing unmet medical need. Finally, a further update on the TAILORx trial examined the fate of patients with a high Oncotype Dx recurrence score.

Let us begin with the CDK 4/6 inhibitors. Two large, randomized controlled trials presented overall survival data, and the news here is good. MONARCH 2 is a trial in ER-positive, HER2-negative endocrine therapy-resistant advanced breast cancer that randomly assigned patients in a 2:1 fashion to either abemaciclib plus fulvestrant or placebo plus fulvestrant. (As a conflict-of-interest statement, I was the principal investigator for this trial and had the pleasure of presenting the data in Barcelona.)

MONARCH 2 now has fairly extensive follow-up (approaching a median of 4 years at data cut-off) and has a statistically significant (p = .0137) and clinically relevant improvement in overall survival, with a 9.4 month increase from 37.3 to 46.7 months. Pleasingly, benefit was seen in both patients with visceral metastasis and patients with primary endocrine therapy resistance, both previously tough groups to treat. Toxicity is similar to that reported at the initial progression-free survival presentation at the 2017 ASCO meetings, with the exception of an emerging signal for interstitial lung disease and deep venous thrombosis, both fortunately relatively rare events.

Immediately after the presentation of MONARCH 2, Dennis Slamon, MD, PhD, of UCLA (this year's Lasker Award winner for his groundbreaking HER2 work) presented the results of the MONALEESA 3 trial. Similar to MONARCH 2, this trial randomly assigned patients to either ribociclib plus fulvestrant or placebo plus fulvestrant. The trial differed from MONARCH 2 in a number of ways: MONALEESA 3 was limited to postmenopausal patients (MONALEESA 7 having previously focused on premenopausal women), and patients could be receiving either first-line or early-relapse plus second-line therapy, unlike MONARCH 2's requirement for endocrine therapy resistance.

Though the data are still emerging (follow-up time on this trial is a median 39.4 months), a clear survival advantage was seen in MONALEESA 3. Median survival was 40 months in the control group and has not yet been reached in the combination arm, but a landmark analysis at 42 months shows a 58.2 percent overall survival in the combination arm versus a 45.9 percent rate in the control arm. Survival benefits were seen in both the first- and second-line settings.

So where are we with the CDK 4/6 inhibitors after ESMO? We now have overall survival data from several trials in addition to the two just presented. MONALEESA 7, the premenopausal frontline metastatic ribociclib trial, has demonstrated an overall survival advantage. PALOMA 3 has demonstrated a survival advantage in the endocrine therapy-sensitive population for palbociclib plus fulvestrant (though, disappointingly, not in the endocrine-therapy resistant population). Overall the trend from emerging data is clear: CDK 4/6 inhibitors improve both progression-free and overall survival, and by clinically meaningful amounts. I find it reasonable to consider these standard treatment options for patients receiving endocrine therapy for advanced breast cancer. I'm still not certain that any of the three CDK 4/6 inhibitors has a clear advantage over any of the others; trial outcome differences may reflect the differing populations enrolled rather than differences in drug efficacy.

That is not to say that we have answered all the questions we might ask regarding this class of drugs. We still await the overall survival results from several phase III trials, which will add to our knowledge regarding the relative benefits of these agents. We have just scratched the surface in terms of studies of mechanisms of resistance. We do know whether there will be importanct efficacy differences between these agents, though there are clearly differences with regard to toxicity. Currently attempts to compare these drugs from an efficacy standpoint rely on cross-study comparisons, and such comparisons are dangerous given the different enrollment criteria and patient populations treated on these trials. And we do not have any good sense, other than an anecdotal one, whether crossover from one CDK 4/6 inhibitor to another upon progression will provide benefit. This will depend, of course, on whether these agents have common resistance mechanisms. And the biggest question of all: will these agents, which have now proven their worth in advanced breast cancer, improve disease-free survival in the adjuvant setting, increasing the likelihood of cure?

We think of CDK 4/6 inhibitors primarily in terms of estrogen receptor-positive, HER2-negative breast cancer. But preclinical data suggests that some the combination of HER2-targeted therapy with CDK 4/6 inhibition may prove synergistic in HER2-positive breast cancer. This has led to the use of these agents in clinical trials for advanced, drug-resistant HER2-positive breast cancer; one of these, monarcHER, was presented at the meeting by Sara Tolaney, MD, MPH, of Dana-Farber Cancer Institute.

The monarcHER trial was a randomized phase II study that enrolled hormone receptor-positive, HER2-positive patients who had received at least two prior HER2-directed therapies, one of which must have been T-DM1. A total of 237 patients were randomized to either abemaciclib plus trastuzumab plus fulvestrant (Arm A), abemaciclib plus trastuzumab (Arm B), or trastuzumab plus the investigator's choice of chemotherapy. The trial's primary endpoint was progression-free survival. There was a statistically significant improvement in PFS comparing Arm A and Arm C, with a delta of 2.6 months. Overall response rate was also improved comparing Arm A to Arm C (35.7% vs. 15.9%).

These results are not stunning. But are they the beginning of something new in the HER2 space? Expecting a great deal in third-line or greater advanced HER2-positive breast cancer may be asking too much for any drug. Might the combination have shown greater activity in an earlier line of therapy? Perhaps we'll see.

Triple-Negative Breast Cancer

The other great area of interest for breast cancer at this year's ESMO involved triple-negative breast cancer. The recent approval of atezolizumab in combination with nab-paclitaxel for PD-L1-positive front-line metastatic breast cancer, based on the Impassion130 trial, was one of the first steps forward in many years for this difficult-to-treat disease.

This year's ESMO meeting saw another interesting take on immuno-oncology for triple-negative breast cancer, this time in the neoadjuvant setting. Peter Schmid, MD, PhD, of the Barts Cancer Institute, presented the results of the KEYNOTE-522 trial, wherein patients with newly diagnosed TNBC with either T1CN+ or T2-4 Nx disease, regardless of PD-L1 status, were randomly assigned to receive either neoadjuvant carboplatin plus paclitaxel followed by anthracycline (doxorubicin or epirubicin) plus cyclophosphamide, with either concomitant checkpoint inhibition with pembrolizumab 200 mg q3w or a placebo. Patients then underwent surgery, and patients in the pembrolizumab arm continued therapy for another nine 3-week cycles.

The primary trial endpoint, pathologic complete response, favored the addition of pembrolizumab, with a pCR rate of 64.8 percent versus 51.2 percent (p = 0.00055). Benefit was seen whether or not a patient was PD-L1-positive. Interestingly, looking just at the control arm of the study, PD-L1-positive patients have a higher pCR rate to chemotherapy than do their PD-L1-negative colleagues (54.9% vs. 30.3%). This implies that (similar to studies of tumor infiltrating lymphocytes in the adjuvant TNBC setting) the immune system plays an important role in response to chemotherapy.

What do we do with this data? The FDA recognizes pathologic complete response as a valid surrogate for drug approval in breast cancer. Is the 13.6 percent difference in pCR rate seen in KEYNOTE-522 not just statistically significant but clinically important? Should pembrolizumab be considered the new standard of care in the neoadjuvant triple-negative breast cancer setting?

It is an important question. The use of pathologic complete response rates as a surrogate for clinical benefit has proven controversial. A basic question—namely "what increase in pCR rate is needed to give what improvement in distant disease-free survival?"—is unanswerable when one crosses over into a novel therapeutic realm. Checkpoint inhibitors are toxic, expensive drugs, so we might wish for further follow-up in KEYNOTE-522 (event-free survival is still immature) before declaring victory.

And what do we make of the unimportance of PD-L1 as a biomarker for neoadjuvant pembrolizumab? In the metastatic TNBC setting, biomarker-negative patients failed to benefit from atezolizumab. Is the neoadjuvant setting different from the adjuvant setting, or is atezo different than pembro? We still have a great deal to learn. Biomarkers have always been tricking, and PD-L1 is no different. Hope Rugo, MD, of UCSF revisited Impassion 130 through the lens of PD-L1, looking at three different immunohistochemical measures of PD-L1, analyzing their analytical concordance with each other and estimates of clinical activity.

To cut to the chase, concordance was not great (64% and 69%, respectively, vs. the SP-142 assay used in the trial). As a medical oncologist, I rarely think about what antibody is used to perform immunohistochemistry on the tissues we send to the lab. But assay accuracy clearly matters, and one wonders how much of the differences one sees in clinical trials (or in the real world of the clinic) is a function of variable or imperfect testing.

Revisiting TAILORx

Finally, Joseph Sparano, MD, at Albert Einstein College of Medicine, gave an update on the TAILORx trial. TAILORx is the gift that keeps on giving for those interested in genomic assays in patients with lymph node-negative, ER-positive breast cancer. The ESMO 2019 data focused on patients with a high Oncotype Dx recurrence score (defined as a recurrence score of 26 or above). Patients entering TAILORx with a high recurrence went into a registry and were encouraged to receive chemotherapy, which most did, with a grab bag of chemotherapy regimens, followed by endocrine therapy. With 5-year median follow-up on 1,389 patients, freedom from distant recurrence was 93 percent, a better-than-expected result and an improvement on older 1980s-era NSABP results. This presentation, like the earlier abemaciclib paper, was simultaneously published in JAMA Oncology (2019; doi:10.1001/jamaoncol.2019.4794).

So that was the news from Barcelona, that lovely Catalan city on the western edge of the Mediterranean. Barcelona is architecturally famous for the work of Antoni Gaudi, and his Sagrada Familia Basilica, one beautifully weird piece of work, remains unfinished more than a century after the foundation stone was laid: the Catalans seem constitutionally incapable of finishing the work. It could be a metaphor for breast cancer research: a strange, often other-worldly, yet highly valuable task that never seems quite finished. But we may hope that both the basilica and breast cancer are getting closer to completion.


Tuesday, February 5, 2019

One of my favorite oldie-but-goodie songs, written by Jerome Kern for a 1930s musical, is "Smoke Gets in Your Eyes." I like the 1959 Platters version the best (you can Google it), but every version shares these Otto Harbach lyrics:

They said someday you'll find

All who love are blind

Oh, when your heart's on fire

You must realize

Smoke gets in your eyes

As I finish writing this issue's column, it's late in 2018 and the fires have recently been contained in Northern California. The quaintly named "Camp Fire," though some distance from Palo Alto, turned the local air into a sooty, unbreathable, sickly mess. The local schools (including Stanford) briefly closed their doors; the air quality measures having set record highs for the Bay area. For some brief period, we had the worst air quality on the planet—worse than Beijing, worse than New Delhi, worse than just about any place but Chico, Calif., near the fire's epicenter.

No one is sure exactly how the fire began, though it's been suggested that it was caused by a sparking high-voltage power line near Camp Creek Road in Butte County (hence the "Camp Fire" name). Regardless of how it started, it spread quickly. At one point, it was growing at the rate of a football field a second. In its path was Paradise, whose 26,000 inhabitants barely had time to pack their cars and flee the oncoming firestorm. Paradise was surrounded by forest, and the forest was dry due to a prolonged lack of rain. Not everyone made it out, and we heard sickening tales of bodies found in cars and under burned-out homes. The cadaver dogs have earned their keep. Over 200 square miles of land burned. For an exceptionally well-written look at what happened in Paradise last month, I suggest Kyle Dickman's "Paradise Lost" in Outside magazine (available at outsideonline.com).

While the firefighters were still struggling against the blaze, we were blessed with a visit from the President, who informed us that the fires and the bad air quality were our fault because we had failed to sweep up all the dead trees and brush like they do in cold, wet, subarctic Finland. He admitted that maybe there was something called global warming, but he didn't think it was to blame for the prolonged drought or the millions of dead trees that litter the California landscape. Never mind that it was federal land that surrounded Paradise, and, therefore, his responsibility. Never mind that the hot, dry Diablo winds barreled through the area like a fire-spewing freight train. No, it was the state of California's mismanagement. And besides, he needed to get back to tweeting about something more important, like the Mueller investigation. And so, he left.

The dictionary defines smoke as "a visible suspension of carbon or other particles in air, typically one emitted from a burning substance." And that is just about right: The sun's disk lacked its usual sharpness, the hills across the Bay were obscured, and my bicycling to work no longer seemed like the healthy thing to do like it had a few weeks before. The air tasted bad. You just wanted to stay indoors. The local emergency rooms saw the expected surge in asthmatics and COPD patients. My Thanksgiving vacation—out of California—came as a welcome respite. By the time I returned, the rains had come, and the firefighters finally got some well-deserved rest.

Judgements of Modern Science

An Air Quality Index of 246, the local paper told us, is the equivalent of smoking a half-pack a day or more of cigarettes. I find this comparison to cigarettes interesting. Unlike my former Indiana home, few Californians smoke (or not tobacco, anyway). It's not considered a rational or cool thing to do.

Climate denialists, of whom the leader of the free world is one, remind me ever so much of those who denied the link between cigarettes and lung cancer. The parallels abound: An industry (tobacco or energy) views the judgements of modern science as the enemy of their profits. It buys a few stooges—often aging, second-rate has-been scientists—to trumpet denialist views, casting doubt in the public sphere wherever possible. It creates shadowy "institutes" that, in turn, issue misleading policy reports masquerading as dispassionate analysis. The industry co-opts politicians (such as the representatives of the tobacco-growing states in the 1950s and 1960s or the coal-producing states of current times) who work to defeat sensible measures that might ameliorate the problem. The media, always interested in the concept of fairness in the airing of alternative viewpoints, treat the denialists as intellectually equivalent to real scientists rather than as the frauds and con artists they are.

I remember the previous denialists because they belonged to my extended family. My relatives all grew tobacco in North Carolina, and were decent, church-going folks who would not intentionally harm a soul. Unless, of course, that soul was addicted to nicotine, in which case they were fair game. They denied the linkage in part because they were basically good people, and to believe that they were willingly causing the death of others would have meant that they were, in fact, not good people. It was easier to believe that tobacco did not cause lung cancer, or at least that there was some scintilla of real doubt that one might cling to like a life preserver in stormy waters.

I also knew, during medical school and as a house officer, physicians who smoked like furnaces. Most of them are dead now, many of lung cancer or heart disease. Few of them openly derided the linkage; they read the same medical journals the rest of us did. But they had all the equivocations one could ask for: Maybe cigarettes were not causal themselves, and smoking was linked to some innate biologic trait, something genetic perhaps, that was causal. Maybe filtered cigarettes would solve the problem. Maybe there was some safe amount you could smoke. It wasn't an addiction, it was "habituation" to nicotine, because it was wrong to call good, upstanding smokers (like the head of pulmonology at one hospital where I trained) drug addicts.

One of my faculty smoked two packs a day and got a chest X-ray every 3 months, with the intent of resecting the first non-calcified mass that showed up—not a denialist per se, but a fantasist nevertheless. And, of course, not being total hypocrites, few smoking physicians told their patients to quit. Their addiction prevented them from being good doctors. But, like I said, most of them are dead now.

Cigarette smoking denialists pretty much all went radio silent years ago, though the Vice President of the United States has the wonderful distinction of having been a cigarette smoking denialist before he became a climate denialist. He doesn't talk about cigarettes anymore, presumably because that would just make him look ridiculous. It's when the ridiculous, the irrational, finally looks ridiculous and irrational to all that we move on, and perhaps we are close to reaching such a tipping point for climate change.

Human Nature

Most of us are practical climate denialists in our profligate use of energy. I cannot imagine that our descendants will thank us for this, or for our unwillingness to take meaningful steps to halt the melting of polar ice caps, the creation of vast deserts, and the evolutionarily massive extinction of wild species now occurring. "What were they thinking?" is the common refrain of every generation for preceding generations. Be it slavery, or racial or religious bigotry, or misogyny, or some unnecessary and destructive war, we all look back and see someone basically different, almost alien, wearing strange clothes and stranger beliefs, rather than realizing that we are staring into a mirror. We keep making dumb mistakes, just different ones. It is human nature. But this time we are messing with an entire planet.

And, who knows...maybe the planet is getting back at us with the conflagrations. One strange thing about the recent fires, and the ones that burned down much of the Sonoma and Napa Valley's last year, was how the sky looked. It had a yellowish-orangish hue. It never looked clean. I realize that large portions of China must be like this every day, but it was unsettling for an area accustomed to clean air for a generation or more.

This is not the first time in human history that the air has looked wrong. As reported in a recent issue of Science, in the year 536 a massive volcano erupted in Iceland, covering much of the northern hemisphere with a sickly fog. The Byzantine historian Procopius wrote that "the sun gave forth its light without brightness, like the moon, during the whole year." Crops failed, starvation was rampant, and the weakened population then experienced the outbreak of the Bubonic plague, killing up to half of the inhabitants of the Eastern Roman Empire. The eruption left characteristic traces in ice cores from the Colle Gnifetti glacier in the Swiss Alps, which have now been analyzed, allowing for the identification of its Icelandic origin.

As bad as that was, the dinosaurs experienced something worse. Some 66.043 +/- 0.011 million years ago an asteroid struck at Chicxulub on Mexico's Yucatán Peninsula with an impact a billion times the energy released at Hiroshima and Nagasaki. Though hotly debated, one possible outcome of this was a global firestorm. Chicxulub generated an enormous amount of soot debris over a global level. I don't know if they measured an Air Quality Index in those days, but I imagine it was even worse than what we got with the Camp Fire. The amount of smoke may well have led to a sort of "nuclear winter" sufficient to causing freezing temperatures for several years, tanking food chains and ending the dinosaur's long reign. The survivors were not T. rex and its relatives, but rather low-life, also-ran, tiny scavengers called mammals. I cannot even imagine how the sky looked, but I suspect my ancestors were hiding in some underground lair, so they probably weren't looking.

Health Impact of Fire Smoke

I experienced the Camp Fire from a relatively safe distance, and 2018 was not 536 nor 66 million years ago, for which I am grateful. The long-term health effects of so-called "wildland fire smoke" is, to quote a recent review, uncertain, as "research on the health effects of this mixture is currently limited." I can't imagine it is good for you. Firefighters got to see the Camp Fire up close, and to spend extended periods exposed to the worst of the smoke and soot. We think of firefighters as brave because they run into burning buildings, but the acute dangers might be outweighed by chronic health effects.

What happens to the firefighters over a lifetime? The largest study to date, conducted by the National Institute for Occupational Safety and Health, concluded that firefighters experience statistically higher rates of cancer (mostly digestive, oral, respiratory, and urinary cancers) than the general population. Mesotheliomas are twice as common among firefighters, for instance. Earlier this year, Congress passed a law, signed by the President, establishing a CDC-led registry that will examine the long-term links between workplace exposures and cancer for firefighters. I doubt that the exposures in an urban environment translate particularly well to a wildfire scenario.

The Camp Fire is out now, and the courage, dedication, and hard work of the firefighters have contained the residual blazes, though I do not doubt that we will see something similar once again, perhaps next year or the year following. In the meantime, let's hope no smoke gets in your eyes.

Thursday, December 20, 2018

As I write this at the end of the year, "Best Books" lists are coming out. I always enjoy matching my favorites against those of the reviewers for the New York Times and similar worthies. Which books are a person's favorites tells you a great deal about what type of books that person likes. The "best books" lists are, if you will, psychology tests as much as sober judgments.

I also have a sneaking suspicion that the reviewers have their own guilty pleasures, hidden from public view like the stacks of Harlequin romance novels I found under my mother's bed when she moved into the nursing home. Mine, too, exist and will remain hidden under my metaphorical bed. So don't bother asking.

That being said, a few of my own favorites from 2018:

Bad Blood, by John Carreyrou

Bad Blood is an almost novelistic rendition of the story of Elizabeth Holmes and Theranos. Holmes, who comes across as a sociopath in over her head, was a Stanford undergrad dropout whose grand vision for diagnostic testing failed to match the reality of the modern clinical pathology laboratory, or for that matter scientific reality in general. Her fraudulent activities, overlooked by the company's shamefully ignorant, neglectful Board of Directors and a fawning press, were eventually revealed by the author, a Wall Street Journal reporter. I appreciated the local color, which included restaurants I have eaten at in Palo Alto, but even more I appreciate this as a Silicon Valley story par excellence. Absolutely fascinating.

Educated, by Tara Westover

Westover is the child of rural Western survivalist fundamentalists, and her story of how a hard-won education liberated her from a life of intellectual and financial poverty is inspiring. There is a school of thought among economists that the best way to reduce global poverty is to increase the education of women, and this book is powerful support for the idea.

She Has Her Mother's Laugh, by Carl Zimmer

Zimmer, one of our better science writers, takes us through a lively history of genetics from its earliest days through to CRISPR/Cas-9 gene editing. A big thick popular science book filled with wonderful vignettes, some inspiring and some heartbreaking. I learned many of these stories in school or subsequently, but there was much that still informed and surprised me.

Babylon Berlin, by Volker Kutscher

This is not a new book, but rather a translation of a 2007 German police procedural novel, subsequently turned into a marvelous recent series you can stream (with English subtitles) on Netflix. Set in the final years of Weimar Germany, it is both a compelling mystery and an excellent description of the rise of fascism and the insidious dangers of a hyper-polarized political system.

These Truths, by Jill Lepore

Lepore is both a Harvard history professor and a fine essayist for the New Yorker, and her book is a magisterial look at the history of the American republic, and the progressive evolution of human freedom.

Chernobyl, by Serhii Plokhy

I was attending a breast cancer conference at the Banff Springs Hotel in Canada when the Chernobyl story broke in 1986, and I'll always remember the televised news of the nuclear catastrophe and the Soviet's feeble attempts at damage limitation. Plokhy tells the story with verve, intelligence, and no little compassion. It is as much the story of the failure of a political system as it is of a reactor failure, for as Plokhy demonstrates the two were inextricably linked.

The Imposter, by Javier Cercas

Cercas is a wonderful Spanish writer who I have admired for a long time. His specialty is the writing of novelistic histories of the 20th century, with a focus on Spain's troubled past. This book focuses on a fraud who fooled most of Spain into believing he was a Holocaust survivor. But it is also an exploration of the nature of truth, of our capacity for self-deception and the ease with which a compelling narcissist can fool an entire country. It is a great follow-up to his Soldiers of Salamis, also well worth the read.

Transcription, by Kate Atkinson

This book is a spy story that stretches from World War II into the Cold War. Set entirely in England and delivered with Atkinson's usual wonderful grasp of dialogue and character, it has a final twist that left me speechless.

Podcast of the Year

I spend a fair amount of time listening to podcasts, mostly while bicycling to and from work. While there are many fine podcasts that I might recommend, my vote is for a medical one. Going Viral: The Mother of All Pandemics is an investigation of the Spanish Flu epidemic at the end of World War I. A great mix of science and history, centered around modern research regarding the how's and whys of the flu virus. Well worth the listen.

Monday, December 10, 2018

By George W. Sledge, Jr., MD

 San Antonio is the largest breast-only cancer meeting every year, and arguably the most impactful. The meeting was started 4 decades ago by my mentor, Bill McGuire, and rapidly became the premiere venue for presenting both clinical and laboratory research. This year has been a good one both for breast cancer biology and treatment, with data that is immediately applicable to the clinic. I'll focus on just a few key take-home messages, involving treatment advances in HER2-positive, ER-positive, and triple-negative breast cancer, as well as the emerging science of genomics.

T-DM1: Best in Show

The highlight of the Symposium, from a clinical standpoint, was the presentation of the KATHERINE trial (please don't ask me what the acronym stands for). The trial started with a well-known observation: if you treat a patient with neoadjuvant therapy, and her surgery specimen demonstrates significant residual cancer burden for HER2-positive disease, she is at significant risk for early recurrence of breast cancer. This setting is one in which it is rational to apply novel therapeutic interventions in hopes of diminishing recurrence of disease. The high event rate with short follow-up times makes this an ideal study population.

KATHERINE, presented by Charles Guyer, MD, on behalf of an international group of investigators, randomized HER2-positive patients with significant residual cancer burden after neoadjuvant HER2-targeted therapy to either trastuzumab or to T-DM1 out to a year of total HER2-targeted therapy. The results, published simultaneously with the oral presentation in the New England Journal of Medicine, are striking (2018; doi:10.1056/NEJMoa1814017). T-DM1 improved invasive disease-free survival (the study's primary endpoint) by an impressive 11.3% at a median 41 months of follow-up; similar improvements were seen for distant disease-free survival, and overall survival—though early—is also trending in a positive way.

This represents a major win in HER2-positive breast cancer, and T-DM1 now joins the list of HER2-targeted therapies that improve outcome in the setting of micrometastatic disease. I suspect that this approach will receive rapid approval by the FDA and become the new standard of care in the post-neoadjuvant population. It will likely obliterate the use of post-neoadjuvant pertuzumab and/or neratinib, as pointed out by discussant Dr. Eric Winer, MD, and may well reduce the use of doxorubicin-based therapy as well.

All therapies have side effects. T-DM1 has both financial and therapeutic toxicity. In the study, T-DM1 patients had a significantly increased number of severe adverse events compared to the control trastuzumab arm, though the most important of these were reversible and relatively rare thrombocytopenia and transaminitis. But the benefits clearly outweigh the harms for the average patient considering such therapy.

The PHARE trial presented a long-term update on duration of therapy. PHARE tested duration of trastuzumab with a non-inferiority design, and the new 10-year results mirror the previous 6-year results in not rejecting the possibility of inferiority. A similar trial did reject, though the results are similar enough to PHARE and the major difference is the allowed confidence intervals for noninferiority. The T-DM1 results will likely render both trials irrelevant for high-risk populations, at least in resource-rich countries.

Stellar Results From SOLAR-1

PI3 kinase inhibitors have had a rough go of it. Though PI3K is a central node for several growth factor receptor pathways, and though PIK3CA is frequently mutated in both ER-positive and HER2-positive breast cancers, trials of PI3K inhibitors have largely been a bust, with minimal improvement in progression-free survival accompanied by significant toxicity, particularly in the form of hyperglycemia.

This meeting saw the presentation of the SOLAR-1 trial, a phase III randomized controlled trial of the selective PI3K alpha inhibitor alpelisib, comparing alpelisib plus fulvestrant to fulvestrant alone in metastatic ER-positive breast cancer. Though the trial recruited both PIK3CA-mutant and wild-type patients, the presentation focused on the patients with mutated tumors. In patients without prior CDK 4/6 inhibitor therapy, the addition of the study drug improved progression-free survival from 6.8 to 11 months. Overall survival trended positive but is immature for a truly confident analysis.

As with other members of this class of drugs, hyperglycemia represents a significant class effect, and a common management problem for patients and clinicians. I suspect real life, with older and less healthy patients, will offer up even greater hyperglycemia challenges for this agent. Nevertheless, this is the cheeriest trial presentation to date for a PI3K inhibitor, and the drug appears headed for the FDA.

An interesting side experiment in this trial involved the measurement of the mutation using ctDNA. Plasma ctDNA measures of PIK3CA mutations were highly concordant with tumor measures, and correlated well with PFS, suggesting that a simple blood test might allow us to "PIK" patients for this drug. Indeed, ctDNA was superior to tissue biopsy in predicting benefit.

In a related manner, this year's meeting saw a surge in ctDNA and circulating tumor cell presentations. None of these were definitive, though the gestalt from them was that this is a field that is rapidly heating up, both for surveillance for recurrence and progression, as well as prediction of therapeutic benefit for targeted therapy. The genomics field is rapidly progressing, and as prices fall and knowledge accumulates we are edging towards a day where liquid biopsies will guide treatment selection.

Immuno-Oncology for Triple-Negative Breast Cancer

Earlier this year, at the European Society of Medical Oncology meetings, we saw the first positive phase III trial of a checkpoint inhibitor in triple-negative breast cancer. The IMpassion 130 trial was updated (or cloned) for San Antonio, and though not much has changed, the results are worth describing. IMpassion 130 compared nab-paclitaxel alone to the same plus the PD-L1 inhibitor atezolizumab in first-line metastatic breast cancer. The trial enrolled patients with both PD-L1 positive and negative tumors.

Quite simply, there was no benefit seen for PD-L1 negative patients, and a statistically significant progression-free survival benefit for PD-L1 positive patients, from 5.0 months for the placebo arm to 7.5 months for the atezolizumab arm. Other biomarkers, such as CD8 and stromal TILs, added nothing to PD-L1 as a predictor of benefit. Though the presentation suggested an impressive overall survival benefit, with an increase from 15.5 to 25 months, these results are immature and were not supposed to be formally tested per the original hierarchical study design.

One concern arising from the initial data presentations is that the progression-free survival results do not, to date, look like what we would hope for: a true plateau in the PFS curves, such as seen in melanoma. This no doubt reflects the fact that, while we think of TNBC as the "heavily mutated" form of breast cancer, its mutational burden pales in comparison to melanoma, lung cancer, and MSI-high colorectal or endometrial cancer. Just not enough funny epitopes on the cell surface. Nevertheless, this is the first compelling evidence for therapeutic benefit of a checkpoint inhibitor in breast cancer. I cannot wait to see further follow-up.

Genomics

There were several wonderful presentations looking at the genomics of metastatic breast cancer. The genomic landscape of metastatic disease is now beginning to come into focus as data from hundreds of patients (many involving paired samples) become available. To summarize what this year's meeting suggested, comparison of primaries with metastases shows an increase (though not across the board) in tumor mutational burden and in specific mutations that represent potential therapeutic targets. The driver mutations identified represent a tractable number from a therapeutic standpoint, not dozens or hundreds, which is reassuring for drug developers. One presentation by Dr. Angus suggested that roughly a quarter of analyzed metastatic genomes had alterations for which FDA-approved drugs are available.

Within the past year, we saw the FDA approval of broad genomic panels, which also carry the Medicare imprimatur. As mentioned above, we are also beginning to see evidence that ctDNA is applicable to evolving breast cancers. These point to a number of fairly straightforward conclusions: first, that we will be able to measure tumor evolution in more-or-less real time, particularly that Darwinian selection induced by drug therapies; second, that we should be able to determine from such studies what treatments are best suited to keeping the patient's tumor in check.

Evolutionary biologists speak of the "Red Queen Hypothesis," derived from Lewis Carroll's Through the Looking Glass, in which Alice says "Now, here, you see, it takes all the running you can do, to keep in the same place." The Red Queen Hypothesis describes the evolutionary situation in which predator and prey co-evolve. Our "hunted" patients would like to stay several steps ahead of their vicious predator. Increasing knowledge of the genomics of metastasis, linked (for certainly it must be) to well-done therapeutic trials, should allow us to co-evolve, and perhaps get a bit ahead, of the pursuing beasts.

My Stanford colleague Christina Curtis, PhD, presented an updated analysis from the METABRIC consortium. METABRIC, published several years ago in Nature, used genomics to divide breast cancers into several integrative subtypes with prognostic significance, but never found its way into routine clinical use. At this year's meeting, Curtis and colleagues presented a detailed, clinically well-annotated update focused on several ER-positive integrative subtypes with increased risk of distant metastasis. These represent a substantial portion (roughly a quarter) of ER-positive patients and are associated with specific oncogenic drivers that could well serve as therapeutic targets, such as the fibroblast growth factor receptor and S6K1. Trials are in development to evaluate whether these findings will translate to clinical practice.

On a sadder note, we learned at San Antonio of the death of Charles Coltman, MD. Chuck led the clinical program where I trained in San Antonio, and had a distinguished career as a clinical trialist, primarily in the lymphoma field. A somewhat gruff, hard-charging ex-military man (we called him "COL. T Man, though never to his face), Chuck was a passionate advocate for clinical trials, serving for many years as head of the Southwest Oncology Group. He also co-chaired the San Antonio Breast Cancer Symposium for many years, first with Bill McGuire and then with Kent Osborne. I learned a lot about being an oncologist from him, and I mourn the passing of one of our field's giants.


Wednesday, December 5, 2018

A few months back, I attended a breast cancer meeting in Portugal. I started my last morning in Lisbon at 7:00 a.m. I knew from past experience that it always took more time to pack than I expected, particularly when I had been away from home for several days. There is something about being in a room I do not know, with socks and pants and shirts and keys and books randomly distributed on every previously empty table top, windowsill, and bathroom sink. I have left clothes and computer cords in many hotels over the years. So I spent a half hour packing the night before.

The flight to Newark was your usual United Airlines extravaganza. Halfway across the Atlantic the flight crew discovered that the ground crew in Lisbon had not serviced the toilets. Bad news, obviously, with no drink service for the last few hours and lots of nervous fidgeting by old folks. But the end result was that the plane got moved to the front of the line at Newark, so we landed 20 minutes early. No dark cloud without a silver lining.

I got off the plane, cleared customs, and headed for my flight to San Francisco. At Newark, the three terminals are connected by a light rail called Airtrain. I got on at Terminal B, headed for Terminal C. It wasn't a good time to ride Airtrain. It moved at a slow crawl. I could easily have outpaced it had there been a parallel walking path. And then, to make matters worse, the train went past the station stop, overshooting by about 30 feet. We sat there for a half hour, though in the mind it seemed far longer. When you want to get home after a long trip, time slows to a crawl as such inconveniences accumulate.

I got off the train, went through airport security, and walked to Gate 133 in Terminal C, arriving in the middle of boarding. After I sat, the pilot came on the intercom. There was some bad weather between New Jersey and California, but the crew had been working diligently on how to sneak around the thunderclouds, and he was certain we would arrive on time if not a bit early. A few minutes later, the doors were closed, and the plane readied for takeoff. It was at this point that one of the cabin crew noted, in the words of the pilot, and I kid thee not, that the plane had a defective life raft doohickey.

He assured us that it would only take 10 minutes to get this fixed. It was a trivial maintenance issue, not a major flaw. Now when an airline employee tells you that there will be only a 10-minute delay you know that they are being economical with the truth, to use Mark Twain's apt formulation. The next thing we heard was a flight attendant 's voice—I guess the pilot was too busy being embarrassed to share bad news—informing us that the flight was expected to land 40 minutes late.

Now, the above might be mistaken for another rant about the misery-inducing qualities of modern air travel: toilets that don't work because some employee couldn't be bothered to do his job, run-down airport facilities confirming the general perception of American civic decomposition, airline pilots bragging about how smart they are shortly before the flight gods punish that hubris with a "mechanical," and the courageous passing off of the delivery of bad news to a more junior employee. And, well, yes, those are all true. But that wasn't really my point.

My point was that all of these involved time, and my perception of time. When I travel, my overall sense of well-being largely revolves around when I unlock my front door, and that event is the summation of many small events. Because I fly a fair amount, I have missed flights, spent nights in awful airport hotels, hotels that I arrived at hours after my flight was supposed to have taken off, sat on tarmacs for hours all over the world, sat waiting for the gantry to roll down to the jet while local ground crews enjoyed late-night snacks, and stood for an hour in a long, winding taxi line. These all involved time, and my perception of it.

What is time? This turns out to be surprisingly difficult to define in any other than the most trivial of turns. The best physics is able to tell us is something like "time is what clocks measure." Yet time is the center of modern physics. Newton thought of time as a universal, what is now called Newtonian time. A standard 18th century meme was that of a clockwork universe, and God was the master clockmaker.

And then along came Einstein, who shattered Newtonian time. Time was a matter of your frame of reference. The faster you travel, the slower time moves. Einstein's time created the famous twin paradox, wherein one twin goes on a spaceship traveling close to the speed of light while the other stays here on Mother Earth. When the young space traveler returns, he finds a gray-hair sibling, even though only months have passed for the galactic traveler.

And while we haven't sent any astronauts away anywhere near the speed of light, time dilation is a real phenomenon, experimentally proven again and again, and practical for everyday life. The GPS and time clock measures my iPhone performs so effortlessly require adjustments for the time dilation caused by the satellites transmitting signals. They move fast enough around the earth, and so regularly, that if we did not make the adjustments our phone clocks would be off and Google Maps would tell me to turn left at the wrong street corner.

Most of the population is blissfully unaware of the physical reality of time dilation, or its effects on their lives. No doubt many would reject the very possibility of such effects as being either irreligious or a violation of plain old common sense, rather like some reject the Big Bang theory or the theory of evolution. But facts are stubborn things, and the universe is run by Einstein's playbook, not Newton's.

When I say "most of the population is blissfully unaware," I am not just talking about non-physics majors. There are populations of patients who experience their own personal time dilation, with altered perception of time, and while these alterations aren't associated with traveling near the speed of light, they are still eminently fascinating.

Take, for instance, the delightfully named but quite rare Alice in Wonderland Syndrome (AIWS). In AIWS, patients experience the sensation of visual distortions of body size (smaller), distance of external objects (farther away), auditory distortions (louder) and, finally, the sense that the passage of time is altered. To the AIWS patient, people may speak more quickly and things happen faster. Or, in some cases, that things move incredibly slowly. These alterations confer an altered sense of velocity (which, of course = distance/time) as well. AIWS has a very Einsteinian feel to it, if not an Einsteinian explanation.

AIWS patients have episodic attacks of time distortion. In one reported case in the neurologic literature, average reaction times increased during AIWS attacks, then returned to normal afterwards. There has been many a lecture or faculty meeting I've sat through where I wished I had the "time speeding up" version of the syndrome. Alas, I appear afflicted with "time slowing to a crawl" AIWS.

The "time slowing down" sensation is common in times of stress. I was driving home on an icy road a few years ago when my car spun out and headed for a tree. Time, or my perception of it, slowed. I saw the car approaching the tree at an agonizingly slow pace. I seemed to perceive every little branch and pine needle. Then the car hit the tree, my glasses flew off my face, and time sped up again.

It all happened in a few seconds, of course, but it seemed to go on a long time. That "time slowing down" experience was studied a few years ago by David Eagleman, now a Stanford neuroscientist, in a genuinely cool experiment conducted at an amusement park. Volunteers were raised 150 feet into the air and then dropped into a net, so-called SCAD jumping. It is a terrifying experience, apparently, and the perception that time slows down is a common one.

But does the SCAD jumper really see things in slow motion? In Eagleman's experiment, the jumpers wore perceptual chronometers, which flash numbers so briefly that one cannot perceive them under normal circumstances. If things really slowed down for the SCAD jumper, he should be able to read the numbers. Alas, this is not the case. The numbers are still a blur. Eagleman suggests that what has changed is not perception of time, but rather memory processing.

How do cancer patients perceive time? A 2011 Dutch study compared healthy cancer survivors with advanced cancer patients. Unsurprisingly, the healthy focus on the future, and the ill on the present. Somewhat to my surprise, patients with advanced disease experience the speed of time as being far slower than do healthy survivors. It is a frightening thought: being caught in a personal, inexorable horror where time slows to a crawl.

The neurologic basis of time perception has only been studied in recent years. Sofia Soares and her colleagues at the wonderfully named Champalimaud Centre for the Unknown in Lisbon, Portugal, have shown that manipulating midbrain dopamine neurons alters behavioral sensitivity to time. Transient activation or inhibition of dopamine neurons, in turn, slows down or speeds up time estimation. Does the cancer patient's experience of time have something to do with this phenomenon?

Ever since H.G. Wells, time travel has been a standard science fiction trope. The second law of thermodynamics seems a reasonable bar to traveling backwards in time: entropy is a beast. And even if you could, the paradoxes might get you: prevent your grandmother and grandfather from meeting, and you don't exist; if you don't exist, you can't prevent them from meeting, so you exist after all.

But I still can dream. Maybe I'd stay a day longer in Lisbon, have some fun in that lovely city, and avoid an awful flight. But then I'd be subject to the Airline Paradox: avoid one miserable air travel experience, and the universe artfully conspires to create an equally awful one. It seems an unalterable universal law, first discovered (perhaps) by Einstein while awaiting a flight from Berlin to Paris. Spooky action at a distance, or something similar.