The Evolution and Importance of Hereditary Breast and Ovarian Cancer (HBOC) Genetic Testing

This topic has a lot of meaning for me personally, having undergone the testing and knowing many people who have been impacted by HBOC. I wanted include on my personal blog this post, pasted below, that I wrote as part of my consulting work with Fabric Genomics on October 25, 2021.

Breast cancer is the most common cancer for women (other than skin cancer), with over 300k cases diagnosed this year in the U.S.  Ovarian cancer, is less common, approximately 20k cases per year, but is far more deadly.  In both cases, early diagnosis is critical to achieving positive outcomes. Mammography is an effective test for breast cancer but still misses approximately 20% of cancers, and there is no effective screening for ovarian cancer.

In 1996, screening for pathogenic variants in the BRCA1 and BRCA2 genes, both associated with hereditary breast and ovarian cancer (HBOC) syndrome, became the first genetic test offered clinically for cancer risk assessment.  Pathogenic variants in the BRCA genes are associated with high rates of cancer relative to those without the variants. Pathogenic variants in BRCA1 confer a greatly elevated risk of breast cancer and ovarian cancer and a small but significant elevated risk of pancreatic cancer. There is also limited evidence for association with prostate cancer. Pathogenic variants in BRCA2 confer an elevated risk of breast cancer (especially ER+ cancer) and ovarian cancer and a small but significant elevated risk of pancreatic and prostate cancers. There is also limited evidence for association with melanoma and leukemia.1

Researchers estimate that somewhere between 1 in 300 and 1 in 800 people have a pathogenic variant in the BRCA1 or BRCA2 genes. Some ethnic groups, however, are more likely to have mutations in these genes. Approximately 1 in 40 people of Ashkenazi Jewish descent have a BRCA mutation.  Because HBOC is an inherited syndrome, a family history of breast, ovarian, and certain other cancers is a significant risk factor. If one parent has a BRCAmutation, their children will have a 50% chance of inheriting the mutation.

As the cost of performing BRCA testing has declined over the last 25 years, the recommended population of those for whom screening testing is indicated has expanded broadly – initially from those with a strong family history of breast and ovarian cancer to those at risk by virtue of being of Ashkenazi Jewish descent to potentially even broader segments of the population.2  The knowledge gained from risk screening for HBOC can be life-saving – knowledge of one’s BRCA status can allow for risk reduction measures, including more frequent and extensive radiological testing and prophylactic oophorectomy, hysterectomy, and mastectomy.  Angelina Jolie’s sharing of her personal decision to undergo prophylactic surgeries, as well as broader awareness of the potential benefits has empowered many women to take greater control of their cancer risk.

But what if we are not talking about the risk of potential cancer in a healthy individual but rather the value of genetic testing in patients with a diagnosis of breast or ovarian cancer?  In these cases, BRCA testing can still provide important information. First, a patient with a BRCAmutation is at increased risk of developing additional cancers. Testing provides potentially life-saving information to other family members who may also have inherited the pathogenic variant. Finally, there is compelling research showing that adjuvant treatment with the PARP inhibitor olaparib (Merck/AstraZeneca’s Lynparza) significantly delayed cancer progression in germline BRCA1/2-mutated, early-stage, HER2-negative breast cancer patients.3  A benefit was also seen specifically in the reduction of breast cancer recurrence in the PARP inhibitor group – 59 patients died, versus 86 in the placebo group.  The data from this and other studies are proving the importance of all breast and ovarian cancer patients and their clinicians knowing their BRCA status.

With BRCA tests being prescribed by more doctors to more people, there is a parallel rise in the desire by local molecular laboratories to be able to offer these tests.  Lower cost NGS sequencers fit in the budgets of regional labs, and tools and services such as those from Fabric Genomics enable these labs to quickly and confidently start and scale up their HBOC testing making BRCA testing more readily available for all patients.   

  1. https://ask2me.org/resources.php.  Also Oncol Lett. 2019 Feb; 17(2): 1986–1995.PMCID: PMC6341769 doi: 10.3892/ol.2018.9770.  BRCA1 mutation in breast cancer patients: Analysis of prognostic factors and survival Joanna HusznoZofia Kołosza, and Ewa Grzybowska
  2.  JAMA Netw Open, 2020;3(10):e2022874 October 29, 2020 Cost-effectiveness of Population-Wide Genomic Screening for Hereditary Breast and Ovarian Cancer in the United States, Gregory F. Guzauskas, MSPH, PhD1; et al.. doi:10.1001/jamanetworkopen.2020.22874
  3.  N Engl J Med 2021; 384:2394-2405, Adjuvant Olaparib for Patients with BRCA1- or BRCA2-Mutated Breast Cancer Andrew N.J. Tutt, M.B., et al June 24, 2021  DOI: 10.1056/NEJMoa2105215

Genetic Testing for Inherited Cardiac Risk

Originally posted on April 29, 2021 as part of my consulting at Fabric Genomics

Heart disease is the leading cause of death for men and women in the United States.1  Many different types of heart disease can be inherited. Some common conditions such as high blood pressure or coronary artery disease run in families but are probably due to multiple genetic variations (polygenic). Each variation individually confers a small increased risk and likely works together in a complex manner to cause disease. Genetic testing is at the early stage of development for these cases (for instance polygenic risk analysis for hypertension is in development), however, there are a number of inherited heart diseases that are caused by just one or a few genetic changes.  Testing protocols for these diseases are well established.  These genes are both highly penetrant and deleterious and therefore are strongly linked to serious disease. Examples of these conditions include:

  1. Cardiomyopathies, such as hypertrophic cardiomyopathy (HCM), dilated cardiomyopathy (DCM), and arrhythmogenic right ventricular cardiomyopathy (ARVC) – these are conditions that affect the heart muscle and can lead to heart failure.
  2. Inherited arrhythmias – these are also inherited heart conditions that affect the electrical system of the heart, causing abnormal heart rhythms called arrhythmias. Examples include Long QT syndrome and Brugada syndrome. These arrhythmias can be deadly and may require changes in lifestyle or medical therapy. 
  3. Aortic dysfunctions (including aneurysms and dissections), are genetic conditions that affect the main artery, the aorta. Bulging of the wall of the aorta (aneurism) can lead to rupture of the vessel, while tears in the aorta can lead to separation of the inner and middle layers of the aorta (dissection). Both can be life-threatening.  Examples include Marfan syndrome, Loeys Dietz syndrome, Ehler Danlos syndrome. 
  4. Familial hypercholesterolemia is a condition with extremely high LDL cholesterol levels that greatly increase the risk of heart attack

In the past, knowledge of one of these inherited conditions has tragically come about from a sudden, often fatal, cardiac incident, frequently impacting young people at the prime of their lives.  Fortunately, with advances in Next Generation Sequencing (NGS) technology, it is now possible to test for these conditions.  Comprehensive cardiac risk panels cover all of these conditions.  Importantly, knowledge of the condition may significantly affect the treatment and management of the patient.  Specific medications, devices such as implantable defibrillators, and exercise and lifestyle interventions may be called for and can be very effective in extending lives.  

This testing is now at the point where it is cost-effective and makes sense from a public health point of view.  Guidelines are emerging and the latest version from the American Heart Association is described here. But all the major societies (including the American College of Cardiology, the American Heart Association, and the Heart Failure Society of America) recommend testing for those individuals with established or suspected clinical conditions.  Assays for these panel tests are widely available. Fabric Genomics provides software that facilitates the analysis of the sequencing results.  It provides a seamless workflow, taking the output from sequencing machines and carrying out secondary and tertiary analyses.  Given the significant growth in the volume of these tests, it is critical that interpretation can be done accurately yet efficiently.  AI-based software such as Fabric ACE is an example of such a tool while being fully ACMG compliant.  Fabric ACE has long been used for Hereditary Breast and Ovarian Cancer screening and a number of other hereditary risk gene groups and we are now seeing rapid growth in the cardiac space – exciting due to the large potential clinical impact.  Given the seriousness of these conditions, the actionability of a diagnosis, and the declining cost of the testing we expect to see significant growth in this testing and, hopefully, improved health and lifespan for those with these conditions.

  1. Centers for Disease Control and Prevention. Underlying Cause of Death, 1999–2018. CDC WONDER Online Database. Atlanta, GA: Centers for Disease Control and Prevention; 2018. Accessed March 12, 2020.

Where Pareto Doesn’t Apply – The NICU

One of my favorite posts I did as part of my consulting at Fabric Genomics. Originally posted on December 3, 2020

The use of AI in healthcare is gaining increased attention with the significant advances and widening clinical use in radiology and pathology and now increasingly in genomics. In all of these cases, there are vast quantities of data to consider that should, in fact, be considered as they could be clinically significant.

Beyond the technology in use, we do see certain diagnostic situations that have a need for AI interpretation assistance. To illustrate this, we provide two different diagnostic scenarios. For instance, in adult critical care the doctor’s diagnostic process supplemented by well-researched rubrics has proven resilient. These cases are rarely primarily genetic in nature and are much more impacted by natural aging, environment, infectious agents, and lifestyle. There is a fairly high concentration of causation and a Pareto-like distribution. In contrast, the NICU pattern is quite different, with much more likelihood of a direct genetic cause. NICU genetic conditions are frequently rare and require unique considerations.

Let’s take a prototypical case – an elderly man presents in the ER with shortness of breath. In this case, there are a few highly likely and perhaps 200 possible causes and the doctor has them roughly mentally ranked in order of frequency. The clinician reranks likely causes real-time based on information as it is revealed – history, demographics, test results, etc. The top few causes make up over 95% of the cases and can be selected with reasonable confidence and confirmed via additional testing. Perhaps a few additional low-probability but high-risk causes are tested for, and a diagnosis will be confirmed in the vast majority of cases. A large but manageable dataset is analyzed and iteratively reanalyzed by the doctor in what is essentially a human Bayesian process – adjusting the prior probability based on real-time data. How likely is it heart failure (as opposed to an infection) given that there is no fever? How does the likelihood change given a specific test result? And for the vast majority of diagnoses, the doctor has confirmed and managed that specific diagnosis many times before in their career.

By contrast, let us consider the case of a critically ill child in the NICU. While there are a few common causative elements such as preterm birth, in over 30% of the cases the child’s condition has a genetic basis. The fact that there is a high chance of a genetic cause immediately brings us into a different diagnostic equation implying many thousands of potential causes. The vast majority of genetic causes will not be identified by standard newborn assay screening as they are not on the standard diagnostic panels (and those take weeks). Even the most experienced pediatricians will have only seen and be personally familiar with a tiny minority of those diseases and, on the off chance that they are familiar with a particular genetic disease, the phenotypic presentations are often not fully expressed in the newborn.

The recent Baby Bear study1 led by Rady Children’s Hospital clearly showed the prevalence of rare genetic diseases in NICU cases. Per Appendix A of the study, “Thirty-five of the diagnosed genetic diseases are rare conditions with an incidence of less than one in one million births.Sixty-five of the 71 primary genetic diseases were diagnosed just once in the Baby Bear population.” Of course, given the rarity of these conditions, it is beyond the likely human clinical experience.

We also know that the choice of treatment matters greatly. Genetic, metabolic, and neurological disorders are highly specific, and the wrong or delayed intervention can have life-long consequences.

In the NICU, we ideally would aggressively seek all reasonably accessible diagnostic information and immediately explore all possible genetic causes rather than work our way slowly along a curve that lacks the steep Pareto shape. Time is often the enemy in these cases. Damage from seizures, nutrition acting as a metabolic poison, or invasive procedures can take place that could be avoided with an early, specific diagnosis.

Just as we treat a critically ill febrile patient with broad-spectrum antibiotics to not lose time with narrow therapeutic shots in the dark, we need a broad but fast approach to diagnosis.

Fortunately, with technology lowering the cost of NGS and with the support of AI algorithms such as Fabric GEM, this approach is coming into use. Multiple peer-reviewed studies2including Farnaes et al 2018 show significant clinical efficacy of this approach and even cost savings.3 The technology is here, it’s available and even economical. Now is the time to insist on its use for the NICU babies that depend on us.

References

1. https://radygenomics.org/wp-content/uploads/2020/06/PBB-Final-Report_06.16.20.pdf

2. https://www.nature.com/articles/s41525-018-0049-4

3. https://health.ucdavis.edu/health-news/newsroom/project-baby-bear-shows-genomic-sequencing-for-infants-in-intensive-care-yields-life-changing-benefits-and-medical-cost-savings-/2020/06

Women’s History Month Podcast

Melinda Byerly and her team at “Stayin’ Alive in Tech” have put together a cool compendium from their various podcast interviews in honor of Women’s History Month and I’m thrilled to be included – you can see the post here

 

Women's History Month EVENT_2

 

Stayin Alive in Tech Podcast – “Good Life”

I had the great pleasure of being interviewed by my former employee and colleague and dear friend Melinda Byerly on her podcast Stayin Alive in Tech – you can listen here.  It’s a bit of a career and experience retrospective – I hope you enjoy listening as much as I enjoyed the conversation.

 

Hiring Tech Talent for Startups

I was recently interviewed by Andrea Smith of CyberCoders on how to recruit and interview for startups.  The war for talent here in the valley is fierce – I shared some of my approaches in this interview.

https://www.cybercoders.com/insights/qa-with-laura-yecies-ceo-of-neuro-technology-company-syncthink/

 

The Beginner’s Mind

We often associate learning new skills with youth.  In fact, it is commonly assumed that if you don’t learn certain skills such as playing a musical instrument, a sport, or to speak a foreign language as a child, it’s “too late.”  As a culture we admire those who achieve excellence at a young age for instance a musical child prodigy or a business prodigy such as Mark Zuckerberg.  While their accomplishments are admirable why don’t we equally celebrate accomplishments, particularly learning later in life? Unfortunately many cultural and psychological constructs confound to keep us from learning new things as adults

I believe that’s why I found the concept of “Beginner’s Mind” so important when I began my journey of learning about Mindfulness.  Beginner’s Mind or “Shoshin” is a concept in Buddhism.  It refers to having an attitude of openness, eagerness, and lack of preconceptions when studying a subject or performing a task.  The key point is to suspend judgment or assessment when taking on a new activity.  Most children suspend this judgement naturally. Our society doesn’t expect them to be experts but more importantly, they don’t expect it of themselves.  The inner critic’s loud voice, that so often holds adults back, has not kicked in for most children.

If you think back to all the things that you learned as a child that you do well now, you typically journeyed along a path where you went from absolute clumsiness to unthinking expertise.  This applies to both mental and physical skills.  We were able to do this in part because of our mindset of Shoshin.  Nobody expects a new young violinist to play in tune and we tolerate that long, squeaky, out of tune period knowing, of course, that it is an unavoidable stage on the path to musicianship.  Mis-conjugation of a verb is almost cute by a child but can be horribly embarrassing for an adult.  Of course intellectually we know that adult learners go through that same awkward phases as do children and if we can only accept that phase in ourselves we could achieve and enjoy so much.  But somehow we can’t.  We often fear embarrassment but the reality is that most people are their own worst critics.

Holding ourselves to inappropriately high standards is an even greater risk when we are trying to relearn a skill.  I experienced this recently with my violin playing.  I studied the violin starting at three and a half and continued throughout high school and college.  When I applied to and attended a liberal arts college I decided that I would not be pursuing music as my profession though I still studied and played in college.  Once I became a parent and was juggling motherhood with graduate school and a career I could not find the time for my violin playing and the violin sat pretty much untouched for 28 years.  It wasn’t that I never thought about playing.  In fact I missed it – but knowing how rusty I was, the idea of playing at that level was intolerable to me.  Interestingly I continued to play the piano occasionally but since I had never been a very good pianist, it didn’t bother me as much to hack around.  I finally got over the hump through a combination of lucky circumstances and my mindfulness training.  The two lucky circumstances were my friendship with George Whitehill – a colleague in my Vistage group and meeting Claudia Bloom.  I witnessed George’s journey from pure beginner to accomplished pianist/composer and was seated at a wedding next to a wonderful and encouraging teacher Claudia Bloom.  Timing was fortuitous, my youngest son Adam was about to go to college and after talking to Claudia I realized that this was the time.  It was a painful first few months of lessons and practicing, especially when I realized that the piece I was working on was one I studied in 6th grade!  On the other hand, I also realized that once I mastered the technique required for that piece, I could play it with greater expression and, frankly, enjoyment than I had 40 years earlier, a humbling yet rewarding experience.

Like many others in the corporate world I did many Myers-Briggs tests and the results were consistently INTJ (though I moved closer towards ENTJ over time).  I always hated the “J” (judgement) label – I aspire to be an empathetic, accepting and tolerant person – I didn’t want to be judgmental and didn’t accept that I was until I realized during my first mindfulness class (and reading a wonderful book “How Good do We Have to Be”) that I was in fact judging.  I just most frequently pointed the judgement lens at myself and not always kindly.  It is hard indeed to find the right balance of setting high goals and standards, working and trying hard yet accepting our own imperfections, missed goals or awkwardness.  It is very hard to suspend judgement while we learn as adults.  The payoff, however, is limitless.

Baroque Chamber Ensemble – June Concert

The Palo Alto Baroque Chamber Ensemble

Joyce Malick, Director

featuring

Laura Yecies and Marianne Cooper in Bach’s Concerto in C Minor

and Music of Mozart, Ferrabosco, Still

Sunday, June 7, 2015  7:30 p.m.

Lucy Stern Center Ballroom- Middlefield at Embarcadero, Palo Alto

Admission is free – all ages welcome, program is about 1 hour

Refreshments following the Concertbaroque_2

Hitting our Stride

Last fall, Steve and I went back to Boston for our 25th HBS reunion.  We had an incredible turnout and great fun reconnecting with old friends from literally around the world. In addition, I just happily celebrated a milestone (50th) birthday.  Both of those events, I suppose, leads me to become more thoughtful on the topic of age and  work stage.

It was interesting to see the broad range of stages people were at in their careers. A few of our friends that were in semi or complete retirement mode.  At the same time many, particularly women, were just gearing up.   Several of our female friends were going back to work after some time focused on children with a few starting brand new enterprises.  For example it was great to reconnect with MaryAnne Gucciardi and discuss ecommerce strategies for her cool new startup DragonWingGirl.  Others hadn’t left the working world to parent but were clearly putting the pedal to the metal now that they are becoming “free birds” (a.k.a. empty nesters).  I could certainly resonate with that pattern.  While I have been continually intense in my career focus, the jump to entrepreneurship was a better fit for me when my kids were past the baby stage.

I am seeing a similar pattern outside of my alumnae network.  Since selling Catch.com as I have been exploring new startup ideas I have worked with, advised or met several 40’s and 50’s women embarking on an intense entrepreneurship journey.  Examples include Sarah Frisken of MadeWithMischief to Trish Costello of Portfolia and my former employees Tanya Roberts starting SheByShe and Melinda Byerly, founding Vendorsi.

I am thrilled to see such accomplished women as Janet Yellen (67) and Christine LaGarde (58) in literally two of the most powerful positions in the world.  While I cannot deny the uncanny abilities of Mark Zuckerberg in creating a multibillion dollar company in his 20’s, I must say that I’m glad that the leaders of the free-world’s financial system have a bit more experience under their belt!

Sadly, closer to home, another accomplished female economist, my cousin Pearl Kamer passed away at 74 during the height of her career.  The obituaries and eulogies, noted her impressive accomplishments as the foremost economist for the Long Island region.  They also remarked on what she was recently in the process of doing and what she could have still accomplished.  She clearly had more to contribute.  Her insights were astute – forecasting the real estate bubble and other key economic trends.

I get a thrill every time I see my former professor and thesis adviser Madeline Albright lecturing or on the talk show circuit making mincemeat of tricky questions or difficult presenters on the other side and I hope to have the opportunity to support Hillary Clinton running for and achieving the Presidency of the US.  The supreme court of our country includes among its three women an impressive octogenarian.  Ruth Bader Ginsburg must be one of the toughest human beings on the planet.  Not only has she survived two bouts with cancer she was back hearing oral arguments 12 days after pancreatic cancer surgery and didn’t miss a day of work when battling colon cancer.  While in law school and right after the birth of her daughter, Ginsburg’s husband was diagnosed with cancer.  She attended class and took notes for both of them; typed her husband’s papers from his dictation; and cared for their daughter and her sick husband – all while making the Harvard Law Review.

I am fortunate to have role models in my family for prioritizing continued work and contribution.  My great-uncle Frank Kamer (father of Pearl) practiced as an attorney until age 98.  Both of my parents, and my father-in-law, all in their 70’s, are actively practicing as physicians.  In fact, just a few months ago, my mother who worked as medical director of the North Shore Hospital Drug Rehabilitation program for more than 30 years was offered a promotion to lead an even larger program at a neighboring hospital

I aspire to follow in their footsteps.  While able to leverage my years of experience, I believe that I still have much to learn and contribute.  With each new technology, market or situation I find myself on a steep learning curve which is what makes work so exciting.  For this reason, I find biases such as the ones described here  and here to be so distressing and damaging.

This article provides a more nuanced and explanatory view and explores solutions.  As bad as the biases may be in real life, the fact that the media portrays them as completely pervasive makes their impact even worse.  In fact, the reality of startup land is much, much more diverse than the media portrayal.  This was clear to me even at the recent Launch festival here in San Francisco.

There are many great startups being founded and managed by 40 and 50 somethings.  In February, I visited Paula Long, my former board member at SugarSync, cofounder of Equallogic and now cofounder of the hot startup DataGravity.  DataGravity raised a $30million series B led by Andressen Horowitz – they are innovating at the intersection of storage and big data – exciting and critical fields today.  I didn’t see a single hoodie or masseuse at their office in Nashua.

Of course, in addition to startups being founded and led by this demographic, there are impressive members leading some of the biggest and most important companies in tech – HP, IBM, Xerox and beyond – eg GM to name a few.

Lets be sure to get the story of these women as publicized as the male 20 something story.  Half the battle towards ending these biases is awareness and information.  I believe that seeing these role models frequently and in a fair and reasonable light would encourage young women to stick it out in their careers during the challenging baby stage or maintain their skills part time or even simply dive back in later.  This pool of talent has so much potential and our society and they have so much to gain

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Life Is Not A Science Experiment

According to Wikipedia a scientific control is an “experiment or observation designed to minimize the effects of variables other than the single independent variable. This increases the reliability of the results, often through a comparison between control measurements and the other measurements.”

I recently read the  NYTimes article “The Opt Out Generation Wants Back In” and some of the ensuing discussion such as here.

I found myself engrossed in the individual stories – all of the women profiled were very clear about what they gave up and what the cost was – also what they gained and enjoyed.  For a variety of reasons, however, the losses were looming large in their minds.  There was a lot of implied “what iff’ing” going on – as if the alternate path was knowable.

I think it is human nature to compare ourselves and our decisions with others and that comparison often leads us to feel dissatisfied with our lot in life.  That comparison can feel particularly acute if one made the explicit choice to be on their current path and is observing the benefits others are accruing from the alternate choice.  We notice the benefits of their choice and the weaknesses of our own more readily than the inverse.

I am no exception to the tendency to “what iff.”  Could I have maintained my career opportunities if I traveled less and missed fewer school events?  How would that have affected my children – would they have noticed or remembered?  Fortunately I don’t find myself “what-iff’ing” my children’s general well-being being bettered by my not working – seeing who they are and what they are doing I feel very blessed.

As many of my friends are approaching the freebird aka empty nest state, I see a big range in satisfaction among those who opted out.  In some cases without regrets and looking forward to new activities professional and/or volunteer to occupy what used to be parenting time, in other cases with decidedly more ambivalent feelings.  The decision to stay home when kids were little and their job had little flexibility v. now that kids are older and their peers are in high-level and perhaps more flexible roles than expected may put that decision in a different light.

But the truth is that it is impossible to truly know what the alternate course would have yielded.  Life is not a science experiment where all variables but one can be held constant.  With a decision such as working outside the home v. staying home full-time or even the possibilities in between, the variable is clearly not independent.  It impacts all of our relationships in immeasurable ways.  Even the financial impact cannot be known for certain.

The most interesting part of all this to me is that there is any element of surprise.  I notice a sense of unreality filtering through the NYTimes interviews.  Almost as if there was an expectation for a “storybook” outcome – actually for both the opt-in and opt-out path takers.  Perhaps this contributes to the regrets and potential dissatisfaction.

More choices and more options for working parents are sorely needed but those options will still come with tradeoffs unless there is a built-in day-extender.

There is always a road not traveled.  By definition that road is not known and it is natural to be curious what it would have been like.  But the story does not (hopefully) need to end at midlife.  I believe strongly that regardless of past choices and the inherent challenges there is the opportunity to set new goals and forward objectives and embark on a different road.