	PARP inhibitors represent an exciting new class of anticancer agents and are currently being evaluating in phase III for a number of different indications. Clinically, PARP inhibitors demonstrate activity in tumors which lack a functional homologous recombination (HR) system and are being developed primarily for patients with germline BRCA1 or BRCA2 mutations and high-grade serous ovarian cancer. This review will discuss the clinical experience with PARP inhibitors so far and the current registration strategies being undertaken. In addition, the review will discuss the rationale behind the recent work combining PARP inhibitors with other targeted agents.

	The Role of PARP and Rationale for Its Inhibition in BRCA-Deficient Tumors

 Poly (ADP-ribose) polymerase (PARP) inhibitors are pharmacologic agents that inhibit the PARP enzymes within the cell. This class of agents represents an exciting potential therapy in patients with defects in the HR repair pathway. In particular, PARP inhibitors are being developed for patients with germline BRCA1 or BRCA2 mutations, although the spectrum of tumors that may be treated effectively by these agents may be larger than this specific population. This article will review: 1) the role of PARP within the cell and why its inhibition is effective in BRCA-deficient tumors; 2) an overview of key clinical trials which have been completed for PARP inhibitors and how they have guided clinical development of these agents; 3) the clinical potential for PARP inhibitors in combination with other targeted agents.

In all human cells, DNA is subjected to frequent damage secondary to environmental insults, toxic metabolites, and DNA replication errors. Single-stranded breaks (SSBs), defined as a loss on continuity in the deoxyribose sugar backbone in one strand of the DNA double helix with the possible loss of the nucleotide base at the site of the break,

 are one of the most frequent mechanisms of damage.

 Detection of SSBs and repair of SSB is thought to require the activity of PARP enzymes as cells that have lost PARP enzymatic activity accumulate SSBs in their DNA. As a consequence of failing to repair SSBs, double-stranded breaks (DSBs) in DNA occur as replication forks encountering SSBs either stall or collapse.

 Fatal if not repaired, 2 major DSB repair pathways have evolved: 1) HR, a largely error-free mechanism to repair DSBs; and, 2) non-homologous end-joining (NHEJ), which randomly attaches DSB together, leading to potentially significant new insertions, deletions, base-substitutions or translocations to a cell’s genome.

The initiation and completion of HR repair is highly dependent on intact BRCA1 and BRCA2 function; therefore, PARP inhibition can potentially lead to tumor cell death in BRCA1/2-deficient tumors. The exact mechanism by which PARP induces cell death in BRCA1/2-deficient tumors is uncertain with 4 mechanisms proposed. First, by failing to repair the DSB through HR, cellular apoptotic pathways are activated leading to cell death. Second, PARP inhibition increases the activity of the NHEJ repair pathway in HR-deficient cells through phosphorylation of DNA-dependent protein kinase substrates, leading to accumulation of genetic errors in essential cellular genes and eventual cellular death secondary to genomic instability.

 Third, it has been proposed that PARP inhibitors work by preventing the release of PARP/BER complex located at a SSB. This “PARP-trapped” BER-repair complex physically prevents progression of replication forks and is thought to require HR-dependent repair in order to remove from DNA.

 Finally, it has been proposed that stalled replication forks can be repaired by either DSB-repair HR or a PARP-dependent HR-repair mechanism, with PARP inhibitors preventing PARP-dependent HR repair.

 In cells which are HR-deficient, inhibition of the PARP activity prevents PARP-mediated HR repair of stalled replication forks, resulting in replication failure and synthetic lethality.

 Helleday’s review on this topic is recommended for any reader interested in further details regarding the mechanism of PARP inhibitors in cancer cells.

		Figure. Presumed Mechanism for Synthetic Lethality Using PARP Inhibitors in BRCA-Deficient Tumors

		Shapiro GI.  Biologic Principles of Targeted Combination Therapy: PARP-1 and Checkpoint Kinase 1 and augmentation of the DNA damage response.  Educational Session, Tumor Biology, American Society of Clinical Oncology, 2012, Chicago, IL. 

Although the focus of this review will be primarily for BRCA1/2-deficient tumors, one should be aware that PARP inhibition may be a theoretical treatment strategy for any tumor with HR-deficiency. Tumors with defects in RAD51, RAD54, DSS1, RPA1, NBS1, or the Fanconi Anemia Pathway should also demonstrate increased sensitivity to PARP inhibition, as well as those with loss of cell checkpoint control.

Phosphatase and tensin homolog (PTEN) deficiency may also result in increased chromosomal instability due to its role in controlling the expression of RAD51 and the cell cycle checkpoint.

Thus, in the future, PARP inhibitors may play a role in a number of genetic subtypes beyond BRCA1 and BRCA2.

Because of the strong interest in PARP inhibitors as a class, a number of pharmaceutical companies have designed PARP inhibitors and have tested them in a number of clinical scenarios. A summary of the agents and their side-effect profiles is shown in table 1. Currently, olaparib, rucaparib, niraparib and BMN673 have reached phase III. Initially thought to be a PARP inhibitor, there were encouraging early results for iniparib in combination with carboplatin plus gemcitabine for patients with triple-negative breast cancer (TNBC); however, this agent was not successful in phase III. Further work into the mechanism of action of iniparib strongly suggests that the drug is not a functional PARP inhibitor but instead works synergistically with chemotherapy to increase DNA damage.

 For this reason, iniparib will not be considered further in this review. In addition, PARP inhibitors have been evaluated as chemosensitizing and radiosensitizing agents, with veliparib primarily used in evaluation; this is beyond the scope of this review but has been extensively reviewed in the past.

 As olaparib, rucaparib and niraparib have been the most extensively studied, they will be the focus of this review.

Olaparib is a potent, orally administered PARP inhibitor with preclinical evidence of in vitro and in vivo activity in HR-deficient cell lines and in combination with alkylating agents.

 Following determination of the dose in phase I,

 3 separate phase II studies evaluated olaparib. In the first studies, olaparib was tested in patients with advanced ovarian cancer with known or suspected BRCA1 or BRCA2 mutations. Overall, 40% of these participants obtained at least a partial response (PR) and appeared to offer more clinical benefit in patients defined as platinum sensitive compared to those who were platinum resistant or refractory (69% vs 45% vs 23% respectively).

Because of these differences it has been proposed that platinum sensitivity in ovarian cancer may be mechanistically related in some way to loss of HR within the tumor cell and may be predictive for PARP inhibitor benefit. The second and third studies evaluated olaparib in confirmed BRCA1- and BRCA2-deficient breast and ovarian cancer, respectively. Both studies treated patients with either high-dose (400 mg twice a day) or lowdose (100 mg twice a day) olaparib; in both studies, high-dose olaparib resulted in superior clinical outcomes and was tolerable, suggesting that higher doses of PARP inhibitors are more efficacious; however, it should be noted that the studies were not randomized and prognostic factors may not be balanced between cohorts. In terms of clinical benefit, 400 mg twice a day of olaparib resulted in response rates of 41% and 33% in breast and ovarian cancer respectively, supporting the use of olaparib in these populations.

		Table 1. Summary of PARP Inhibitors Currently in Development

		BID indicates twice daily; MTD; maximally tolerated dose; LFT, liver function test

Given that TNBC and high-grade ovarian cancer share a number of pathologic features to breast and ovarian tumors with confirmed germline BRCA1 and BRCA2 mutations, it has been hypothesized that these sporadic cancers may have acquired deficiencies in HR repair and may also be sensitive to single agent PARP inhibitors.

 To evaluate this hypothesis, Gelmon and colleagues enrolled patients with TNBC or high grade serous ovarian cancer to receive olaparib 400 mg twice a day with subsequent stratification based on BRCA1/2 mutation status. This study is notable for obtaining a 24% response rate in patients without germline BRCA1/2 mutations. This finding is the first result in clinical trials demonstrating single- agent PARP activity in non—BRCA mutation carriers and offers the first suggestion that a “BRCAness” phenotype may be relevant clinically, although this has not been confirmed through further tumor analysis work.

Because the observations by Gelmon et al suggest the presence of a “BRCAness” phenotype, olaparib may represent a potential maintenance therapy for patients with platinumsensitive, high-grade ovarian cancer. Ledermann and colleagues randomized 265 patients with high-grade serous ovarian cancer to receive either olaparib 400 mg twice a day or placebo. Initially reported in the 

 the most recent interim analysis was reported in 

 A progression-free survival (PFS) was observed in both patients with or without germline BRCA mutations for olaparib compared to placebo, although the PFS was substantially longer in the BRCA-deficient population (BRCA-deficient: 11.2 vs 4.3 months; HR = 0.18; P <0.001) (BRCA-proficient: 7.4 vs 5.5 months; HR = 0.54; P = .0075).

No overall survival benefit has been observed at this point; however, given the number of treatment options available for patients with advanced ovarian cancer, this is not a surprising finding. Maintenance olaparib in combination with single agent carboplatin has also been tested with the combination offering superior PFS (12.2 months vs 9.6 months; HR = .51; 95% CI: 0.34-0.77; P = .0012).

As normal tissues are spared the toxicity of PARP inhibition due to functional HR activity, PARP inhibitors may represent a better tolerated and more efficacious treatment than standard chemotherapy options in patients with germline BRCA1/2 mutations. To assess this question, 97 patients with ovarian cancer with confirmed BRCA1/2 mutations were randomized in a 1:1:1 fashion to receive olaparib 400 mg twice a day, olaparib 200 mg twice a day, or liposomal doxorubicin at its standard dose. Although well tolerated, olaparib failed to demonstrate a PFS benefit compared to liposomal doxorubicin (HR = .88; 95% CI: 0.51-1.56; P = .66).

 This study illustrates some of the challenges that investigators have faced in designing clinical trials evaluating PARP inhibitors. As a topoisomerase II inhibitor, doxorubicin induces DSBs in DNA; theoretically, these types of agents are potentially more efficacious in the BRCA1/2 population than what might be predicted in a non-selected ovarian cancer population.

Because of the biology and chemotherapy responsiveness of BRCA-deficient tumors in general, this situation may be true with other chemotherapy agents as well.

In ovarian cancer, based on the observations of Ledermann et al, the current registration strategy for olaparib has been in the maintenance setting following platinum chemotherapy in both the first line (NCT01874353) and platinum-sensitive settings (NCT01844986) for patients with BRCA-deficient tumors. Olaparib is also being evaluated in phase III for patients with BRCA-deficient breast cancer and is being compared with a physician’s choice of cytotoxic agents (NCT02000622) as well as in the adjuvant setting (NCT02032923).

Rucaparib (AG-014699) is a potent inhibitor of PARP enzymes and was the first PARP inhibitor to be evaluated in clinical settings. Rucaparib was initially formulated for intravenous use with the goal of using it as a chemosensitization agent. Single-agent testing of the agent occurred only after the combination of it with temozolomide proved too toxic and once the drug was converted to oral formulation in order to permit continuous dosing.

 Rucaparib demonstrated clinical activity in BRCA-deficient tumors in doses above 300 mg daily, with a disease control rate of 70%, 2 complete responses and 7 PRs observed in breast cancer, platinum-sensitive and platinumresistant ovarian cancer.

 Rucaparib is also being evaluated in phase III as maintenance therapy for patients with platinum- sensitive ovarian cancer (ARIEL3; NCT01968213); unlike the phase III studies for olaparib, ARIEL3 is not requiring germline BRCA1/2 mutations for enrollment. At the current time, there is no registration strategy being undertaken for rucaparib in BRCA-deficient breast cancer.

	Novel Approaches to Utilizing PARP Inhibitors

Niraparib is a potent oral inhibitor of PARP-1 and PARP-2 and has been evaluated in phase I for BRCA-deficient as well as BRCA-proficient cancers. Clinical activity was observed at doses greater than 60 mg/day with the maximal tolerated dose determined to be 300 mg/day. A subset analysis of patients with BRCA-deficient tumors demonstrated responses in 8/20 ovarian cancers and 2/4 breast cancers.

 Niraparib is currently being evaluated in 2 phase III studies: 1) maintenance therapy in platinum-sensitive, BRCA-deficient ovarian cancer following at least two lines of platinum therapy (NCT018472774); and 2) single-agent therapy compared to physician’s choice of chemotherapy in BRCA-deficient breast cancer (NCT01905592).

Although PARP inhibitors represent an exciting potential treatment option for HR-deficient tumors, it should be recognized that this only represents a small proportion of all cancer and it is unlikely that PARP inhibitors will represent a broad treatment option as single agents. There have been a number of efforts, however, to functionally inhibit HR in cancer cells to allow PARP inhibitors to be used in tumors where initially no benefit would be predicted. Currently, there are 3 such approaches in clinical development.

First, it has been demonstrated in the preclinical setting that phosphatidylinositol-3-phosphate (PI3K) activity is required to maintain HR function and that the addition of the PI3K inhibitor BKM120 downregulated BRCA1/2 activity, sensitizing HR-proficient cells to olaparib.

 This concept has been developed in the clinical setting with early results presented at the 2014 American Society of Clinical Oncology (ASCO) Annual Meeting. Although there are encouraging signs of clinical activity, the study enrolled both BRCA-proficient and deficient tumors; without the pending pharmacodynamic analysis, it is not possible to determine at this time whether the combination is responsible for the observed benefit or whether the benefit is due to single-agent activity alone.

Second, as cyclin-dependent kinase-1 (CDK1) phosphorylates BRCA1 and this action is necessary for BRCA1 to efficiently form repair foci at sites of DNA damage and induce the necessary checkpoint arrest, administration of a pharmacologic CDK1 inhibitor could potentially stop HR in HR-proficient tumors; this hypothesis was confirmed in both in vitro and in vivo models.

 Based on this preclinical data, a phase I clinical trial evaluating the combination of veliparib with the CDK1 inhibitor SCH727965 in patients with advanced solid tumors which are HR-proficient is underway (NCT01434316). This trial is in dose escalation and results are not yet available.

Finally, another strategy has been to combine an antiangiogenic agent with PARP inhibitors. In preclinical models, it has been demonstrated that hypoxia down-regulates BRCA1/2 and RAD51 activity, creating a HR-deficient state within the cell; therefore, the utilization of an antiangiogenic agent could increase the clinical efficacy of a PARP inhibitor.

 At the 2014 ASCO Annual Meeting, Liu and colleagues presented phase II results for the combination of cediranib and olaparib in both BRCA-deficient and BRCA-proficient tumors. In this study, 90 patients were enrolled with 48 having BRCA-deficient tumors. The addition of cediranib to olaparib significantly increased the overall response rate (84% vs 56%; P = .008); in addition, responses were observed in BRCA-proficient tumors.

 This combination will be further developed, with phase III studies planned for the near future.

PARP inhibitors represent an exciting new class of anticancer agents and are currently being evaluating in phase III for a number of different indications. In the future, identification of resistance mechanisms and means of overcoming them will have increasing importance in order to maximize benefit. In addition, current work evaluating the combination of PARP inhibitors with other targeted agents appear very promising and have the potential to expand their use beyond BRCA1/ BRCA2-deficient tumors. It is very likely that within the next year, a PARP inhibitor will be approved for clinical use, something that patients with germline BRCA1/BRCA2 mutations, and their physicians, have eagerly been awaiting for the past several of years. 

 John F. Hilton, MD, medical oncologist, Dana-Farber Cancer Institute, Brigham and Women’s Hospital, and Harvard Medical School, Boston, MA.

 John Hilton, MD, 450 Brookline Ave, Boston MA, 02215

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Articles

PARP inhibitors represent an exciting new class of anticancer agents and are currently being evaluating in phase III for a number of different indications.

PARP Inhibitors for Breast and Ovarian Cancers

There is an ever-growing variety of social media platforms, which, depending on the reader, can be either exciting or not. For the enthusiastic early adopter, these channels offer a new experience and the chance to broaden social and professional circles. For others, the growth of social media is overwhelming, and with each new medium, they may become even less willing to explore any of them.

	Patients Are Online and They Want Information About You

However, it is important that clinicians engage with social media primarily because we risk our reputations by not knowing what is being said, shared, and discussed about us online. In this article we will expand on these points and provide steps to help harness the Web and manage your online public persona.

The Internet has become a staple of society, both on a local and a global scale. It has resulted in the formation of online platforms and communities, and has changed the ways we can interact with others. By some reports, there are almost 1.3 billion people on Facebook

 and 255 million monthly active users on Twitter.

Estimates are that 35% of adults in the United States have gone online to diagnose a health condition,

 and other data suggest that patients might be choosing their healthcare providers based on online peer reviews.

 As a testament to this, online physician rating sites are widely available and appear to be frequently utilized.

The reach of social media extends to clinicians as well. In the 2014 American Medical Association Insurance’s survey of over 4000 US physicians, social media usage was noted by 79% of those under age 40, 62% of those age 40 to 59, and 53% of those age 60 to 69.

 Some physicians have recognized the shift from traditional models of information seeking and sharing, and actively discuss healthcare issues in a public way. Physician-led blogs such as Kevin MD (www.kevinmd.com) and 33 Charts (33charts.com) publicly discuss issues that affect those that work within healthcare.

In the oncology space, online blogs also have gained in popularity. Connection (connection.asco. org), the American Society of Clinical Oncology’s (ASCO) forum for the exchange of views on topical issues in the field of oncology, was recognized for its relevance and credibility with a 2014 Award for Publication Excellence (APEX) for site content. The blog authors write frankly about issues relating to oncology practice. Readers are invited to comment on the public blog posts, which often leads to authors answering questions directly from the reading public.

In recognition of these shifts in information gathering and sharing both amongst clinicians and the wider public, as well as the evolving working relationship between clinician and patient, we will suggest ways to cultivate and monitor your online persona and methods to approach using social media in your daily life.

These issues are relevant to oncology because information seeking has been changed by widespread access to the Internet. Indeed, some data show that among those who search for cancer information, 55% turn to the Internet as their initial source; only 25% went to their healthcare provider first.

	Protecting Your Online Reputation: The Digital Footprint and Beyond

However,clinicians must not assume that all information that’s available is accurate. In today’s Internet culture, anyone can write, post, or tweet an article, opinion, or otherwise. This access to “unfiltered” information can be misleading to patients, or even dangerous. A recent example concerned the dissemination of cancer information reported from “John” Hopkins University,

 which necessitated a point-by-point vigorous defense by the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins University with input from its faculty.

The digital footprint is the track that remains online after you have engaged in any activities on the Web. Conceptually, it is integral to your online reputation.8 It has both a passive and an active component, and understanding both is important.

The “passive” component is generated by identifying information from your computer or mobile device and by the way in which you access the Internet (eg, via the unique identifier attached to the computer you use to go online — the Internet protocol address—and your Internet service provider). Furthermore, passive data are recorded in your Internet browsing history (which records the sites you visit) and in the “cookies” that are collected by websites (cookies are small pieces of digital information that enable a previously visited site to recognize you immediately). Such information can be potentially collected, stored, and indexed online. While these pieces of virtual information (or “metadata”) are not easily linked with you personally, they could be.

The “active” component of your digital footprint is a record of what you write, blog, tweet, or post online, whether that is the pictures you post on a site like Instagram or the video you post on YouTube. If you’re not careful, who you are in your private life may blur with the image you are projecting as a professional. This has led for some to call for a separation of professional and personal personas on social media, such as Mostaghimi and Crotty’s concept of dual passports,

 in which two different identities are utilized—one strictly for a professional presence and the other for personal activities. However, others have argued that such a separation is not only impossible (there is no anonymity on the Web), but may be unfair to the patients we serve because it robs those we care for of the opportunity of knowing us as people, not providers.

Whether clinicians choose to share their personal lives on social media sites is an individual choice. However, being cognizant that those reading your posts may indeed be your own patients is critical.

Taken together, the footprint is a key to your online reputation. Information shared online can be accessed widely and can give others an idea of who you are—both professionally and personally. Indeed, there may be very little distinction between them. If your reputation were solely under your control, it would not be worth worrying about. Unfortunately, it is not this easy&mdash;it takes work.

Although you cannot exclusively control your online reputation, there are various ways to curate it, and we propose a framework of four “Ds” to explain these steps: (1) discovery; (2) definition; (3) dissemination; (4) defense (

: All clinicians should actively monitor professional information available online; this can be done by performing an audit of what is readily available online about you, your practice, and your reputation, sometimes referred to as a “professional audit.” This involves conducting a Web-based search on the most common search engines (Google, Yahoo, Bing, and Ask). Search by your full name and various combinations of your name, along with your associated practice, institution, city, state, etc. Perform the same search on public websites that specialize in rating clinicians, professional society websites, patient-related websites, and content-sharing sites (

). An audit will give you a sense of what information is currently available and an indication of what potential patients and colleagues will see when they search for information about you or your practice.

		Table 2. Examples of Sites to Utilize for Personal and Professional Self Audits

					American Society of Clinical Oncology

					American Association for Cancer Research

 After gathering the search results, perform a thorough analysis. Use the information to visualize something of a “narrative arc” that represents the sum total characterization, sentiment, and tone of the information. With a clearer definition, decide whether that story is accurate or not. If you are satisfied with what is presented, no further action is necessary, although you should continue to perform these professional audits online at least every quarter or so. In most cases, clinicians will discover content that is either inaccurate or, in their opinion, unfair, making further action appropriate.

Curating your online reputation means actively disseminating the information you want to be available. This can be done by creating a digital “biography” to serve as your preferred narrative and placing it on multiple platforms (listed in 

) to increase the likelihood that the information you want to be seen actually appears first in search engines. In addition to creating a personal narrative, engaging in social media networks is another means to disseminate your professional presence.

		Table 3. Examples of Oncology-Specific Social Media Sites

					Treatment Diaries tweet chat (#treatdiarieschat)

					Hospice and Palliative Medicine (#hpm)

					American Society of Clinical Oncology (ASCO) Connection

					What We Talk About - Massachusetts General Hospital

					Dr. Len’s Cancer Blog - American Cancer Society

It is important that clinicians engage with social media, since reputations are at risk by not knowing what is being said, shared, and discussed online about them online.

Clinical Oncology in the 21st Century: Reflections on how Healthcare Providers Should Manage Their Public Personas on Social Media

Instructor, Department of Medicine, Harvard Medical School

		Staff Physician, Medical Oncology - Melanoma, Dana-Farber Cancer Institute

Over the past decade drug development in cancer has shifted to an increasingly gene target—based approach.

The development of drugs such as erlotinib for EGFR mutant non-small cell lung cancer (NSCLC) and vemurafenib for BRAF mutant melanoma have established the power of targeting genomically selected patient populations. A product of this success, however, is that most of the common (and druggable) genomic aberrations in cancer have now been targeted. While the power of targeted approaches remains, the subsets of patients harboring new targets is shrinking. For example, major clinical responses have been observed in urothelial cancers harboring FGFR alterations, but the frequency of these genomic changes is relatively low (10%-20%), in a relatively infrequent cancer (<12,000 cases of metastatic disease per year in the United States).

Similarly, inhibition of RET fusions in NSCLC appears to be a promising target; however, the incidence of these genetic abnormalities is only on the order of 1% of NSCLC.

This is even more worrisome in the context of everyday practice where genomic data are increasingly becoming available to patients and physicians. Many of these data remain both uninterpretable and irrelevant to the practicing physician. However, it has become common when reviewing results from genomic testing to find rare mutations that do seem to be actionable but for which there is no drug immediately available. The urgency of this problem has become more pressing given the development of research around “exceptional responders,” such as a complete response to the US Food and Drug Administration (FDA) approved medicine everolimus, in a patient with TSC2-mutant thyroid cancer.

At the same time that our genomic approaches are expanding, US healthcare is changing a great deal in the context of the reforms outlined in the Affordable Care Act (ACA) of 2010. The ACA is driving providers to organize systems around Accountable Care Organizations (ACOs) and appears to be on the verge of shifting to a bundled payment strategy. Additionally, there is a push for transition of all health records to electronic health record formats, as well as for patient data sharing across platforms. These changes are difficult in many circumstances but do provide for a framework that could improve drug development and patient access to targeted therapies in the future.

As providers and health systems consolidate for cost savings and organizational purposes, incorporation of cancer genomic testing for all patients is a goal that could become a reality. With economies of scale, incorporation of molecular testing and genomics could be included in the bundled payment and the size of the growing health networks could put price pressure on the cost of genomic assays. The electronic medical records of these larger health systems may have a greater potential to centralize and protect sensitive patient genomic information. Additionally, the connection of oncology practices throughout health networks could facilitate the development of virtual tumor boards for decision making regarding molecular testing and best practices in the application of targeted therapies for cancer.

The impact of these changes on patient care could be significant. If all patients underwent molecular profiling, it would likely be much easier to identify patients with rare or unusual genomic lesions. These patients could then be directed toward molecularly directed treatment options before receiving what are often ineffective second- and third-line therapies. Such changes could also improve access to more effective medicines in remote areas or for rare genomic alterations that would otherwise go untreated.

The upcoming changes to the health system could also have a major effect on drug development for rare molecular lesions. Scenarios could be imagined in which pharmaceutical companies contract with cooperative groups or large health networks in order to find the rare patients needed to validate a new targeted therapy. In some ways there are signs that the drug development community is embracing this direction already.

The NCI MATCH trial is an example of this.

 The NCI MATCH Trial is a master protocol in which several small phase II trials of targeted drugs will be administered to patients of different cancer histologies who harbor specific molecular aberrations and are located at medical centers across the country. A focus of MATCH will be on rare cancers—at least 25% of patients enrolled are expected to fill this definition. Industry is also showing signs of heading in this direction with the development of the Novartis Signature program

 as well as a Genentech multi-arm trial evaluating HER2, BRAF, EGFR, and Hedgehog pathway activation in patients for whom there is no approved targeted therapy.

 If the field continues to move in this direction, a transition may take place in which phase I trials could be completed quickly for safety and pharmacokinetics and then larger, adequately powered phase II studies could be rapidly accrued to assess the efficacy of the targeted drugs in specific molecular subsets.

Many barriers to such a future of drug development do exist. There is an obvious requirement for adequate protections to be put into place around sensitive genomic patient data in large electronic health networks. A drug development paradigm such as that described above would require collaboration between industry, the National Cancer Institute, cooperative groups, and large ACOs. Perhaps most difficult, the FDA would need to facilitate a drug approval process that could be simplified so that aspects of it could be completed outside of specialized or academic centers.

It is clear that there is great promise in targeted therapeutics for cancer and that the environment for healthcare delivery is rapidly changing. While many oppose some of the changes that have been proposed, there are also potential upsides that the medical community and those working in drug development could harness. I hope any of us in the cancer community who have influence will do their best to optimize the opportunities to bring these 2 changing landscapes together.

			Sequist LV, Cassier P, Varga A, et al. Phase I study of BGJ398, a selective pan-FGFR inhibitor in genetically preselected advanced solid tumors. Abstract CT326. Presented at the American Association for Cancer Research Annual Meeting 2014. Accessible at: http://bit.ly/1Dwq72l.

			Drilon A, Wang L, Hasanovic A, et al. Response to cabozantinib in patients with RET fusion-positive lung adenocarcinomas. Cancer Discov. 2013;3:630-635.

			Wagle N, Grabiner BC, Van Allen EM, Amin-Mansour A, Taylor- Weiner A, Rosenberg M. Response and acquired resistance to everolimus in anaplastic thyroid cancer. N Engl J Med. 2014;9;371: 1426-1433.

			National Cancer Institute. NCI molecular analysis for therapy choice program (MATCH) & pediatric MATCH. http://1.usa. gov/1vgzxeb.

			Novartis oncology. About signature. https://www.signaturetrial. com/en.

			Clinicaltrials.gov. A study evaluating Herceptin/Perjeta, Tarceva, Zelbroraf, and Erivedge treatment targeted against certain mutations in cancer patients. ClinicalTrials.gov identifier: NCT02091141. http://1.usa.gov/1tDjZEj.

Over the past decade drug development in cancer has shifted to an increasingly gene targetâ€“based approach. 

Could Healthcare Reform Speed Molecular Medicine Adoption?

“You should have surgery. It’s the best treatment for you.”

Although radiation therapy was a viable alternative to surgery,

these two sentences were enough to convince my father some years ago to elect to have surgery to treat his intermediate-risk prostate cancer. He summarily declined the urologist’s offer to facilitate a radiation oncology consultation. My father expressed confidence in his surgeon and chances for cure.

I have since seen that this experience is far more common than what I first would have thought. I regularly hear patients voice similar conclusory statements about treatment plans, and even if initially presented with an inferior or equivalent option, many strongly resist consideration of a different course when presented with supporting data.

Doctors are taught to think through medical decisions by listing a series of options, weighing the risks and benefits of each, and ultimately concluding on the superior option. This comparative maximization approach is drilled into us as medical students and residents. Many doctors, likewise, seem to present data to patients with the implicit assumption that patients will make decisions only after hearing and equally weighing all relevant data.

But for patients, medical decision making often significantly departs from this ordered framework and perhaps may be better understood as a negotiation where the patient is seeking to determine the “best deal” in response to challenging circumstances. Information often is presented to patients in a piecemeal fashion, not comprehensively. The first “offer” typically is made by one type of physician, with the patient then left to determine whether to pursue other options or move forward with the initial proposal.

Such circumstances may give rise to two decision-making biases that are well known in negotiations literature: the anchoring bias and the status quo bias.

Researchers at the Harvard Negotiation Project at Harvard Law School describe anchoring as a cognitive bias “that describes the common human tendency to rely too heavily on the first piece of information offered (the ‘anchor’) when making decisions. During decision making, anchoring occurs when individuals use an initial piece of information to make subsequent judgments. Once an anchor is set, other judgments are made by adjusting away from that anchor, and there is a bias toward interpreting other information around the anchor.”

Applying anchoring to the medical context, it may be that patients are more inclined to pursue the opinion of the doctor they heard first, simply because it was the opinion they heard first. Most physicians have anecdotal experiences with trying to reframe patient thinking after another physician recommended an alternate treatment plan. Patients in such situations often frame their questions as to how the “new” recommendation could be “better” than one they already have in hand. The source of the initial recommendation also is an important consideration—the opinion voiced by a trusted physician or family friend can be especially difficult for a newly met doctor to overcome, even when presenting with data on better outcomes.

A second bias seen in negotiations that may affect patient thinking is placing an overly high value on the status quo. When describing effects of this bias in negotiations, Deepak Malhotra, PhD, a Professor in the Negotiations, Organizations and Markets Unit and Max H. Bazerman, PhD, the Jesse Isidor Straus Professor of Business Administration, both from the Harvard Business School, recently noted that “people are more likely to be concerned about the risk of change than about the risk of failing to change and will be motivated to preserve current systems and beliefs. The status quo bias is a general source of opposition to change even when people regard the consequences of the change to be a net improvement.”

In the medical context, the status quo bias may offer an additional reason for why patients who already have scheduled a treatment plan may be especially resistant to subsequent proposals. A new cancer diagnosis is an emotionally challenging and intellectually confusing experience for any patient. Many patients obtain a great deal of comfort simply from having a “plan” of care established. To then propose a change, even if small, can be unsettling and thrusts patients into feeling out of control over their circumstances.

Studies looking at the relationship between prostate cancer patients’ ultimate treatment selection and specialty of their initial consulting physician are consistent with these anecdotal observations.

from a recent report shows treatment selected (prostatectomy versus radiation) was significantly correlated with whether the patient had seen only a urologist before setting an initial treatment plan or had seen both a urologist and radiation oncologist before making a plan.

 A recent SEER analysis likewise found that patients with low-risk prostate cancer were more likely to receive treatment if seen first by a urologist, especially if that urologist billed for the treatment received or graduated from training in earlier decades.

 Other reports have noted that when patients are seen in multidisciplinary clinics— consulting multiple specialists at once&mdash;they are more likely to pursue active surveillance, even when controlling for the number and specialty of physicians met in consultation.

 These data align with the notion that timing and source of medical information can cause patients’ treatment decisions to vary.

Such variations may have significant, negative consequences for individual patient results and the health care system more broadly. A wide body of research establishes that generally accepted treatment options can generate different costs and side effects, even when outcomes may be comparable. For example, a recent analysis of different treatments for low-risk prostate cancer found substantial variability in cost with only modest differences in quality-adjusted life-years (QALYs): Treatment costs ranged from $19,901 with robotic-assisted radical prostatectomy to $40,588 with combined external beam radiation and brachytherapy treatment, while QALYs only ranged from 10.3 to 11.8 among the different radiation and surgical treatments.

		Figure. Physician Visits Prior to Treatment for Clinically Localized Prostate Cancer

		Specialists who were seen prior to definitive treatment for 18,201 men who had a radical prostatectomy (A) and 35,925 men who had radiation therapy (B).

With respect to treatment morbidity, a recent analysis of 1655 men from the Prostate Cancer Outcomes Study within the first five years after treatment noted increased rates of urinary incontinence and erectile dysfunction among surgery patients and increased rates of bowel urgency among radiotherapy patients.

 Patients may not appreciate these distinctions if unduly influenced by anchoring or status quo biases.

In light of these concerns, physicians can and should seek to ensure biases seen in negotiations do not impair their patients’ ability to make appropriately informed medical decisions. On an individual level, we should be mindful of the words we use, particularly in the setting of a new diagnosis, and consider how they may affect how patients perceive options and interactions they have with doctors. We need to encourage and explain the purpose of obtaining multiple opinions where possible, and when patients seem to have their mind made up quickly, we should take the time to understand why this may be the case.

But to enable more targeted improvements, the medical field needs a better understanding for how anchoring and status quo biases may impact patients’ treatment decisions, and how physicians can guard against undue influence of these biases. More research is needed on how much a subsequent opinion has the ability to change patient treatment, and under what circumstances. And when and why do patients skip second opinions in cases where multiple treatment modalities are available? To my knowledge, little or no studies meaningfully answer these questions directly. Future work—such as through patient satisfaction and questionnaire-based studies&mdash;should seek to clarify how the timing, source, and context of medical information influence how patients come to conclusions, and identify optimal strategies for avoiding undue anchoring and the status quo bias.

We ultimately may find that the best responses to any decision-making biases are more systemic in nature. As with the prostate cancer examples above, multidisciplinary teams that recommend consensus-based treatment opinions and produce balanced educational materials may offer a key solution to overcoming biases that unduly influence patient decisions. Studies should consider whether and when such approaches lead to better outcomes and efficiencies in specific disease areas. Researchers also should seek to determine whether multidisciplinary teams are able to instill more confidence in their patients who, like my father, want to feel sure that they made the best choice possible under difficult circumstances.

: Harvard University Radiation Oncology Program, Harvard Medical School, Boston, MA.

: The author has no conflicts of interest to disclose.

 Ravi A. Chandra, MD, PhD, 75 Francis St. L2, Boston, MA 02115. (617)732-6310. rachandra@partners.org.

			D’Amico AV, Whittington R, Malkowicz SB, Schultz D, Blank K, Broderick GA, et al. Biochemical outcome after radical prostatectomy, external beam radiation therapy, or interstitial radiation therapy for clinically localized prostate cancer. JAMA. 1998;280(11):969-974.

			Kupelian PA, Elshaikh M, Reddy CA, Zippe C, Klein EA. Comparison of the efficacy of local therapies for localized prostate cancer in the prostate-specific antigen era: A large single-institution experience with radical prostatectomy and external-beam radiotherapy. J Clin Oncol 2002;20:3376-3385.

			Anchoring Effect (Accessed May 30, 2014, at http://www.pon.harvard .edu/tag/anchoring-effect).

			Malhotra D, Bazerman MH. Psychological influence in negotiation: an introduction long overdue. J Manag 2008;34:509-531.

			Jang TL, Bekelman JE, Liu Y, Bach PB, Basch EM, Elkin EB, et al. Physician visits prior to treatment for clinically localized prostate cancer. Arch Intern Med 2010;170:440-450.

			Hoffman KE, Niu J, Shen Y, Jiang J, Davis JW, Kim J, et al. Physician variation in management of low-risk prostate cancer. JAMA Intern Med. 2014; 174(9):1450-1459.

			Aizer AA, Paly JJ, Zietman AL, Nguyen PL, Beard CJ, Rao SK, et al. Multidisciplinary care and pursuit of active surveillance in low-risk prostate cancer. J Clin Oncol. 2012;30(25):3071-3076.

			Cooperberg MR, Ramakrishna NR, Duff SB, Hughes KE, Sadownik S, Smith JA, et al. Primary treatments for clinically localized prostate cancer: a comprehensive lifetime cost-utility analysis. BJU Int. 2013;111(3):437-450.

Doctors are taught to think through medical decisions by listing a series of options, weighing the risks and benefits of each, and ultimately concluding on the superior option. This comparative maximization approach is drilled into us as medical students and residents.

November 2014 | Contemporary Oncology®

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