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Musings of a Cancer Doctor

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

Friday, June 19, 2020

By George W. Sledge, Jr., MD

The American Society of Clinical Oncology's 2020 meeting was held, not in Chicago, but virtually, the citizens of Oncoville scattered around the world like refugees from some vast cataclysm or natural disaster. No, wait. That's not a metaphor. There actually was a natural disaster. COVID-19 haunted the halls of McCormick Place, and the rest of us avoided it, well, like the plague (a phrase that has taken on new meaning).

I take notes at ASCO and similar meetings by tweeting. I can then go back later and see what thoughts I had in the moment about a particular study. It requires a certain discipline that I might not otherwise be capable of, and it keeps me busy when my mind might otherwise wander. Halfway through the meeting, I tweeted a brief list (brief because of Twitter's character limit) of pros and cons for the virtual meeting; of all my tweets at the meeting, it got the most responses. If you are not my Twitter follower, let me repeat them for you.

On the pro side, the virtual meeting meant that there actually was an ASCO Annual Meeting. I can't thank the ASCO staff enough for pulling this off on such relatively short notice. I'm sure it involved a Herculean effort on their part. Maintaining the continuity of the world's premiere cancer meeting in the midst of a pandemic is reason for celebration and gratitude.

The talks themselves had parallel video and Power Points. I appreciated this; getting to hear the speaker is one thing, but getting to linger over the data is another, and the virtual meetings' format allowed for both. Also—and this was an unexpected bonus—I could always pause watching and eat dinner between presentations. It was definitely more relaxed in that sense, and several responses to my tweet pointed out the calming nature of not having to sprint across the convention center between talks at different venues. Like any of my friends needed the exercise.

But for me, the cons outweighed the pros. The video presentations only worked about half the time. One reply to this tweet said "You must have special pull. Mine only worked 30% of the time." I assumed this was a bandwidth issue. Over 40,000 people visited the virtual meeting, and I suspect this overloaded the system. This was an irritant, if a minor one, as I could switch to the slide set. I suspect that the technology will continue to improve in future years.

There were two larger issues. First, it felt like homework. I don't know any other way to put it. When I sit in the audience at ASCO, and some great data pops up on the screen, there is a current of excitement that flows through the convention hall. That electric sensation disappeared when I plodded through breast cancer talks at home. It was simply less fun. Not ASCO's fault, nor the presenters, but there it is.

But the biggest issue for me was that I miss my friends. Societies socialize. They bring together diverse groups from around the globe, people we haven't seen during the year, and we get to hang out and talk. Sometimes that talking is about family and friends, sometimes about oncopolitics, and sometimes it involves how to interpret the talk we've just heard and how to apply the results to the next trial we're designing or the patient we'll see on Monday morning in clinic. I cannot count the number of times that a research project began in casual conversation in the lobby of the Chicago Hilton or outside Hall D.

ASCO is also an efficient place to hold meetings. My schedule often involves 15 or 20 side meetings. They're not all worthwhile. Most meetings don't amount to much in the long run: you can't meeting your way to a cure. But collectively, they always added something to my knowledge and forwarded my research agenda. And that disappeared along with the handshakes and hugs, another COVID casualty.

All of which is a long-winded way of saying I hope this isn't the permanent way we do the ASCO Annual Meeting. I think having a virtual meeting in parallel to the "real" meeting has value, and I trust it will continue, for the benefit of our many colleagues who cannot attend. But I want to be back in Chicago, as long as I and my colleagues all receive an effective coronavirus vaccine.

Breast Cancer at ASCO

As for breast cancer at the meeting, there are annual meetings which represent great leaps forward, with bold paradigmatic shifts that fundamentally alter how we understand or treat the disease. Think of these as discovering a new continent. And there are years which can best be characterized as "filling the empty holes on the map." This was, by and large, the latter.

One breast cancer presentation made it to the Plenary session. Seema Khan presented the ECOG/ACRIN group's E2108 trial. By way of Conflict of Interest statement, I'm the senior author on this presentation. This trial addressed, and perhaps answered, the question of "what do we do with the breast when a patient presents with metastatic disease. Patients with stage IV disease received several months of initial systemic therapy and were then randomized to either local-regional therapy or to no local-regional therapy and continued systemic therapy. With fairly long follow-up, there was no difference in overall survival.

Two previous trials from Turkey and India had addressed the same question, and another similar trial is ongoing, so the final answer might not be in yet. Local-regional therapy in the setting of stage IV disease can have objectives other than overall survival, such as preventing catastrophic local failure and relieving psychological stress. But for the moment I do not think any physician should walk into a room with a patient and claim that local-regional therapy will prolong life by so much as a day.

Unlike many trials at the annual meeting, there was no nifty new biologic tested nor any deep pockets of Big Pharma support pushing E2108 to conclusion. The trial was a labor of love, ably designed and led by Northwestern's Dr. Seema Khan. It was the sort of trial that the National Clinical Trials Network is well-suited to conduct, answering an important question that would otherwise remain occult.

HER2-positive breast cancer was an important focus for ASCO 2020. Certainly, the most important of the trials presented was HER2CLIMB, a trial examining the highly HER2-selective receptor tyrosine kinas inhibitor tucatinib. This trial was important for two reasons, one of which was a game-changer for a major unmet medical need. First, the trial (which randomized patients to receive trastuzumab and capecitabine with or without tucatinib) had previously shown an overall improvement in progression-free and overall survival.

But what made HER2CLIMB special was its focus on brain metastasis. HER2-positive breast cancer is trophic for the central nervous system, yet the vast majority of trials conducted in this disease actively excluded patients with CNS metastasis, or required treated, stable or responding brain metastasis as entry criteria. In contrast, HER2CLIMB allowed patients with both treated and untreated brain metastasis (though it excluded leptomeningeal disease), and thereby allowed us to evaluate the effect of tucatinib on the brain. Both CNS-PFS (progression-free survival in patients with brain metastasis) and overall survival in patients with brain metastasis favored the tucatinib arm of the trial, with a 1-year landmark analysis showing a median survival of 18.1 versus 12 months, and CNS-PFS of 70.1 percent versus 46.7 percent.

This is not to say that we have solved the problem of brain metastasis in HER2-positive disease. But tucatinib represents a real step forward, and the willingness of the study sponsors to tackle this huge unmet medical need is laudable. This is a drug that I suspect will rapidly progress from the later line setting of this trial to a more frontline metastatic setting or the (neo)adjuvant setting. Perhaps more importantly, future trials in the advanced disease setting will now be judged against a drug with efficacy in the central nervous system. This will be a spur to further drug development in this area.

Tucatinib was not the only new HER2-positive agent examined at ASCO 2020. One group of researchers from China evaluated the role of pyrotinib, a pan-ErbB receptor tyrosine kinase inhibitor in metastatic HER2-positive patients, all of whom had received prior trastuzumab and taxanes and/or anthracyclines, and up to two prior chemotherapy regimens for metastatic disease. Patients received capecitabine with either lapatinib or pyrotinib. The pyrotinib arm outperformed the lapatinib arm, with a significantly increased progression-free survival of 12.5 versus 6.8 months (P < 0.001, hazard ratio of 0.39). Overall survival results were immature but trending in favor of pyrotinib.

While it is always nice to have another new agent, this trial had significant limitations, largely related to differences in the population seen. Patients in the West have generally seen trastuzumab, pertuzumab, and T-DM1 before they reach a receptor tyrosine kinase inhibitor, so the applicability of these results to a HER2-positive patient in my clinic is uncertain. It is also hard to know where to place this agent in the setting of other recently approved (and highly efficacious) agents such as tucatinib and the antibody drug conjugate trastuzumab deruxtecan. We now have a cornucopia of HER2-targeting agents for metastatic disease and ordering all of them in the absence of comparative data is a problem.

There were a number of interesting but non-transformative adjuvant or neoadjuvant HER2 trials. An update on the KAITLIN trial, which had previously demonstrated the superiority of T-DM1 over trastuzumab in the post-neoadjuvant setting residual disease setting, failed to demonstrate any particularly useful biomarkers for T-DM1 benefit, though high HER2 expression in the residual setting predicted worse trastuzumab outcome, as did low PD-L1 expression.

Another trial, TRAIN-2, studied neoadjuvant chemotherapy with or without 3 cycles of anthracyclines. Anthracyclines added nothing to efficacy, worsened quality of life, and were associated with more delays and dose reductions. I believe, and have thought for some time (since the CLEOPATRA trial data became available), that anthracyclines no longer have a place in HER2-positive breast cancer.

Do we need to use chemotherapy at all in the HER2-positive early disease setting? In the provocative PHERGain trial with immature results, Dr. Javier Cortes and his colleagues used FDG-PET scans in a response-adapted strategy to eliminate chemotherapy in patients having an excellent imaging response. The trial hasn't followed patients long enough to judge disease-free and overall outcomes, but it points to a future in which we might appropriately eliminate chemotherapy altogether for some HER2-positive patients, as we have done with many early stage ER-positive patients.

ER-positive disease at the ASCO annual meeting is best characterized as a series of interesting disappointments. The greatest of these didn't occur at the meeting, but in a parallel press release announcing that the PALLAS trial had been declared futile by its data safety monitoring committee. PALLAS was a large, well-conducted adjuvant trial testing the role of the CDK 4/6 inhibitor palbociclib in early-stage disease. Sadly, and strangely, it had no role, despite impressive results in the metastatic setting.

One piece of evidence corroborating the PALLAS results was presented. The FELINE trial (my favorite acronym at this year's meeting) randomly assigned patients to letrozole plus either ribociclib or a placebo with a primary endpoint of PEPI score, a commonly used measure of endocrine response in prior neoadjuvant endocrine therapy trials. There was no difference between the two groups, unless one draws comfort from a p value of 0.96, nor was there any difference with regard to clinical or imaging responses. Of course, the breast need not be a surrogate for micrometastatic disease, but the FELINE results were not catnip for CDK 4/6 inhibitor fans.

These failures (briefly) left the field at a loss. Was PALLAS (and, to a lesser extent, FELINE) a failure of one drug, or of one trial (trial design is important), or a failure for the larger CDK 4/6 inhibitor field? I've tended to think that the CDK 4/6 inhibitors were all essentially the same, based on the similar trial hazard ratios in the front- and second-line settings, so I was concerned that this might be a failure of CDK 4/6 inhibitors rather than of one drug or one trial. Fortunately, the answer came quickly, in another press release announcing that the monarchE trial of adjuvant abemaciclib was positive for its primary endpoint.

We will, of course, need to await the published, peer-reviewed results of these trials to come to any real conclusions. Knowing the magnitude of benefit, as well as the extent of toxicity is crucial, and learning why one trial failed and another succeeded will be of interest, if only to my fellow breast cancer geeks. Nevertheless, there is joy in Mudville tonight.

Dr. Cynthia Ma presented the Alliance ALTERNATE neoadjuvant endocrine trial, which randomized patients to anastrozole alone or to fulvestrant plus anastrozole. In results reminiscent of the (generally forgotten) combination of tamoxifen and anastrozole in the old ATAC trial, the combination was no better than single-agent aromatase inhibitor with regard to the trial's primary endpoint of estrogen sensitive disease rate (ESDR).

And finally, let's take a look at triple-negative breast cancer, where there were a number of interesting results. The KEYNOTE-355 trial randomized frontline metastatic triple-negative breast cancer patients to chemotherapy alone, or to chemotherapy plus the checkpoint inhibitor pembrolizumab, with co-primary endpoints of progression-free and overall survival. Chemotherapy type was at the physician's discretion, and patients were eligible regardless of PD-L1 status. Pembrolizumab improved progression-free survival only in patients with a CPS score greater than or equal to 10 (i.e., in patients with significantly elevated PD-L1 scores), going from 5.6 to 9.7 months. Overall survival data are immature. These results are generally consistent with the IMpassion 130 trial results that led to the approval of atezolizumab for metastatic frontline triple-negative breast cancer.

The other quite interesting triple-negative breast cancer result came from a Chinese cooperative group's SYSUCC-001 trial, which examined maintenance capecitabine therapy. The trial consciously used a metronomic approach to capecitabine, giving 650 mg/m2 twice daily for an entire year following standard adjuvant chemotherapy. With 5 years of follow-up, disease-free survival was 83 percent in the capecitabine arm compared to 73 percent in the control arm, with similar distant disease-free survival improvements. Overall survival results are immature, but trending in favor of the capecitabine arm. These results remind one of the CREATE-X trial results in the post-neoadjuvant residual disease setting. Capecitabine may play a special role in triple-negative breast cancer, and I await this trial's peer-reviewed publication and mature overall survival results with great interest.

Reviewing ASCO highlights is always fraught with hazard. You may miss what's important or offend your friends for failing to discuss their study. Often what is really important is an abstract chosen for a poster presentation where the data was immature at the time of submission, the results were preliminary to a larger definitive trial. In the past, I could always say: "No matter—they'll update us at next year's meeting." I hope that's the case. I miss Chicago, and my friends from around the world, and I so want next June to be something approaching normal. Until then, stay healthy, my friends, and avoid those little COVID beasties.

Friday, May 8, 2020

By George W. Sledge, Jr., MD

"When they come to write the history of this epidemic, what do you think they'll say?" asked my brother Jeff when we spoke recently.

His question got me thinking about epidemiology stories I've heard over the years. Epidemics often have key stories attached to them. These stories become shorthand for the meanings we derive, or at least for the memories we retain across time. Let's call them Epi stories.

The first use of the word itself, from the Greek epi (on) and demos (people) comes from Homer. In Homer's Iliad Agamemnon, leader of the Achaeans in their war against Troy, robs the temple of Apollo, and kidnaps the daughter of the priest Chryses. In response to Chryses' prayers, Apollo sends a plague to the Achaeans, sickening them as they waited in their ships on the shores near Troy. If this sounds familiar, think of the role cruise ships (where crowded groups shared and spread COVID-19) played in the early part of the current pandemic. "On the people," indeed. Hippocrates used Homer's word to describe outbreaks that occurred intermittently to populations, a case of science taking its clues from literature.

The Iliad is only the first in a long line of creative works devoted to epidemics. Thucydides' History of the Peloponnesian War has an extensive section devoted to the epidemic that ravaged Athens, fatally weakening the first democracy and taking the life of its great leader Pericles. Giovanni Boccaccio's Decameron, written just a few years after the Black Death killed half of Europe, follows 10 sexy young people people "sheltering in place" in a Florentine villa while telling great stories. Daniel Defoe's Journal of the Plague Year, written several decades after the last visitation of the bubonic plague on England in 1665-66, is a stunning portrayal of what it was like to live through such an event. Irresponsible Londoners avoided social distancing, bought fake plague cures from con men, and resorted to panic buying. Then, as now, front-line workers "went about their employment with a sort of brutal courage," to quote Defoe. And, of course, Edgar Allan Poe's The Masque of the Red Death tells of the frightening suddenness with which a crowded banquet room can become the nidus for an explosion of disease, though it is mostly just a great atmospheric horror story.

In more recent times, we have Katherine Anne Porter's wonderful Pale Horse, Pale Rider, a semi-autobiographical fictionalization of what it was like to come down with, and barely survive, the 1918 influenza pandemic. At one point, the protagonist imagines herself fleeing death on her horse:

"Come now, Graylie, she said, taking his bridle, we must outrun Death and the Devil…The stranger swung into his saddle beside her, leaned far towards her and regarded her without meaning, the blank still stare of mindless malice that made no threats and can bide its time…The stranger rode beside her, easily, lightly, his reins loose in his half-closed hand, straight and elegant in dark shabby garments that flapped upon his bones; his pale face smiled in an evil trance, he did not glance at her. Ah, I have seen this fellow before, I know this man if I could place him. He is no stranger to me."

Nor a stranger to us, now, that mindless malice, that pale face.

My other favorite in modern writing is Albert Camus' The Plague, his great novel in which an epidemic overtakes Oran, killing residents in their thousands and paralyzing civic life. The book is an extended metaphor for World War II and the French resistance to German occupation, an occupation experienced by the courageous young resistant Camus. One of the book's main heroes, Dr. Rieux, tries early in the novel to convince the authorities that this disease must be taken seriously, that this is not business as usual, but to no avail. One of the recurring themes of Epi stories is that we never learn, never deal effectively with epidemic disease until it is upon us, and that is often too late.

The AIDS epidemic, of course, developed its own extensive literature, with works such as Tony Kushner's Angels in America, and a host of novels, and Tom Hanks's Oscar-winning Philadelphia. AIDS was a slow-motion epidemic, and we view it in a different way than an acute outbreak like COVID-19. I've not seen any social stigma attached to coming down with COVID, probably because of its lack of a sexual connotation, though racism has reared its ugly head. Post-AIDS we have Steven Soderbergh's prescient 2011 movie Contagion, where a pandemic begins with a bat zoonosis. Epi stories are as old as Western literature and as new as recent Hollywood blockbusters or Steven King potboilers.

But the Epi stories I like best are the stories doctors share, stories based in the epidemics themselves rather than in some fictional representation. One thinks of that striking moment when the Bubonic plague came to Europe in 1347. A Mongol army, besieging a Genoese trading outpost on the Black Sea, was thwarted by a stout defense and strong walls. That army had brought the bubonic plague from the Asian steppes and was dying outside the walls. And then some Mongol commander had the clever idea of catapulting dead plague victims into the fortress.

In no time at all, the defenders started to die of the Black Death. Genoese businessmen packed up their goods, got on their ships, and fled, carrying the plague bacillus with them to Constantinople and Italy, and eventually throughout the Mediterranean basin and across Europe. A later outbreak eventually reached as far as Iceland.

One Epi story, still important today, is that epidemics love globalization, love long-distance travel. We were fooled by MERS and SARS and Ebola into thinking that these dangerous infectious diseases essentially belonged to other places, even other times, and that we were somehow protected by distance and our way of life. I remembered SARS largely because it briefly struck Toronto and led to cancellation of that year's American Association for Cancer Research meeting. An inconvenience, I thought at the time, and then gave it no more thought. Silly me.

In fact, as the infectious disease community has long known, the modern way of life represents our Achilles' heel: rapid jet-spread of disease across the globe, and fragile global medical supply chains. Wuhan supplied much of the world's N95 masks, and Lombardy the nasopharyngeal swabs used for viral detection, both sent around the world using just-in-time delivery schedules, right up until the moment when those schedules no longer made sense and the nickel-a-mask savings provided by modern globalization vanished. Epidemics have their own deadly ironies.

A favorite Epi story involves John Snow, the intrepid British obstetrician who tracked an 1854 outbreak of Cholera to London's Broad Street Pump. The "Broad Street Pump" metaphor is well-beloved by physicians: when you know the cause of a disease (cigarettes for lung cancer), remove the pump handle (as Snow convinced reluctant authorities to do) and you can end the epidemic.

It's a great metaphor, and worked for cholera, but not for COVID-19. It would work just fine for tobacco-induced diseases, as tobacco is a classic pump handle for lung cancer and emphysema. Or perhaps, as was once suggested, for HIV and the AIDS epidemic. In the "Patient Zero" story, a sexually athletic flight attendant spread the disease across the world, a potent meme repeated in print and on TV in works such as And the Band Played On. Identify and quarantine Patient Zero and you halt the epidemic in its tracks, before it can—literally or figuratively—take off. Alas, that particular Epi story was wrong: the flight attendant, subsequent molecular analyses showed, was not "Patient Zero," nor anything close, in the history of the AIDS epidemic.

The older, related Epi story, and also a near universal meme, is that of Typhoid Mary. The Irish immigrant Mary Mallon (foreigners often take the blame for epidemics) was a cook at upper class homes and had a bad habit of infecting her patrons with Typhoid fever. Eventually identified as a recurring source of disease outbreaks, she was quarantined for almost 3 decades by New York Health authorities. We're currently wrestling with issues related to COVID-19 super-spreaders, of asymptomatic carriers (as was Mary) and with issues of re-infection and disease clearance. And, of course, with the tension between public health and individual freedom.

Tracking origins, as the current outbreak shows, can be hard: we think COVID-19 started in a bat and then somehow migrated through the Wuhan wet market into the Chinese population, but even this is somewhat fuzzy. The idea that it started in a laboratory (an American lab if you are a Chinese fantasist, a Chinese lab if you are an American one) seems ridiculous. And it's hard to remove the pump handle when nature is full of pump handles, or "Patient Zero"/ "Typhoid Mary" disease vectors. There are lots of animal viruses patiently waiting their turn to enter the human population, and with COVID-19 we didn't identify the infected in a timely enough fashion, due to the CDC's disastrous failure with testing assays.

The more useful Epi story, or at least more useful for the current outbreak, is the Philadelphia Victory parade of 1918. As the Great Influenza epidemic spread across the world late in 1918, public health authorities were faced with stark choices: business as usual or mandatory social distancing. Health authorities in St. Louis shut down the city, while the chief public health official in Philadelphia, a well-meaning physician put in his job by and answering to the local political machine, allowed a World War I Victory parade to go forward. A ship from England (ships again!), loaded to the scuppers with the infected, had just docked at the port, and disease carriers were released just in time for the parade. Soon the citizens of the City of Brotherly Love were dying in their thousands. St. Louis was far less affected.

What impresses, at least impresses a medical oncologist used to dealing with diseases that develop over years or decades, is the vital importance of timing when one shuts down a city or a country. Too soon, and the economic consequences are devastating. They are devastating even if done right on time, as the collapse of the world economy shows. But too late, and you get Philadelphia in 1918, or Milan or New York City or New Orleans in 2020. Looking at 1918's Philadelphia Victory Parade, and Mardi Gras in 2020, one can wonder how far we have actually come in learning the meaning of some Epi stories.

We still wrestle with our basic ignorance of the natural history of a new disease, just as our ancestors did. We still have to learn and act on the fly, based on incomplete information and imperfect models. We still have decisions made by politicians who seem inherently suspicious of science, or worse, feel the need to politicize every public health action, as if coronavirus actually cared what political party one subscribed to. Despite ample warning from public health officials, we still managed to be woefully unprepared to provide basic medical necessities to health care workers and patients.

We still, or a substantial number of us do, view these outbreaks as supernatural occurrences, and assume that the deity will protect us if we are sufficiently virtuous, so that it is appropriate to avoid social distancing guidelines on Sunday morning. We seem unable to put aside our petty nationalism in the face of global medical and economic catastrophe. Deep inside us, I'm forced to conclude, lurks an atavistic Medieval mindset. And that frightens and appalls me. Pandemics bring out the best in some of us—ER docs and ICU nurses—but some of the worst in others.

So, to answer my brother's question, when they come to write the history of these times, when they tell new Epi stories, the stories will be the same old ones. I hope, dear readers, that we all remain healthy long enough to share them

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

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.