Molecular Oncology

Personalized context of the cancer cell

For decades, prognostic markers and therapeutics have been focused largely on the cancer cell’s growth patterns in tissue culture or in animal models.

In parallel, studies of metastases inspired by the seed-soil hypothesis — first articulated by Stephen Paget in 1889 — deepened the understanding of the contribution of other tissues and cells to cancer initiation and progression. This hypothesis is a precursor of the current research landscape focused on cells and tissues that surround and infiltrate cancer lesions, as well as on developing predictive and prognostic biomarkers such as systemic circulating protein and metabolic factors, cell-free tumor DNA, and circulating tumor cells (CTCs) and immune cells.

So, how will we, as cancer-focused health care providers, introduce the totality of an individual’s personalized factors in the design of prevention and therapeutic strategies in the next 5 to 10 years?

Sofia D. Merajver, MD, PhD
Sofia D. Merajver

This is an extensive topic I am sure will be covered in many installments of this column; I will try to touch upon some salient discoveries that are not often discussed, but that are likely to affect how we design patient-centered therapies in the next decade. Eventually, it is hoped that personalized oncology will consider all aspects of a person’s ecosystem inside and outside the body to formulate successful prevention and treatments for everyone.

Germline factors

Beyond high-penetrance cancer susceptibility genes, thousands of individuals are undergoing genetic testing for large panels of medium- and low-penetrance genes associated with multiple cancer syndromes.

This transition to panel testing has been further accelerated by the inexorable march toward testing all patients affected with breast, ovarian, prostate and pancreatic cancers, regardless of family history, due to the availability of mutation-based therapeutics.

In this context, we, as health care providers, have had to face our enormous ignorance about the clinical significance of thousands of gene variants that we ascertain in our patients routinely, yet cannot interpret.

This has spurred research into the functional significance of variants by various methods. The expectation is that in the next 2 to 5 years, the genetic testing reports will be much more specific as to the functional significance of variants of uncertain significance (VUS).

However, researchers’ ability to know about variants that are ascertained broadly in the community depends on them being entered into databases — such as www.clinvar.com and promptstudy.info — which I encourage community health providers to utilize every time they encounter a VUS.

Beyond known cancer genes, research is seeking to understand whether there are hereditary factors that influence the observed differential risks for certain tumor subtypes, such as the increased proportion of triple-negative breast cancer in Africans and African-Americans.

The germline context matters for many reasons; it may suggest strategies for prevention and, further, the integrated germline variants are being connected to pathways dysregulated in cancer. Thus, it may provide a personalized context to predict drug sensitivity.

A pioneer in this area of research, Lajos Pusztai, MD, DPhil, of Yale University, said: “In the field of defining risk [for] breast cancer development, important new trends are emerging, including better understanding that some germline mutations in low-penetrance risk genes can confer risk for late-onset breast cancers, and that the totality of common germline polymorphisms that affect the function of regulatory proteins may function as a ‘cancer gene integrity’ risk score.”

Environmental factors

In a classic and paradigm-shifting study, Cerhan and colleagues showed increased exposure to estrogens in utero increases breast cancer risk in offspring, as exemplified by studies in twins. A corollary of this work was the formal realization that cancer risk is influenced by lifetime exposures.

However, modifiable conditions during pregnancy, such as obesity, also affect the cancer risk of the offspring. Studies have been focused on discerning the potential mechanisms to manage these risks.

Overall, a chronic inflammatory state has been shown to be present in adipocytes, which appears to modify cancer risk much later in life for mother and offspring. The details of the mechanism and strategies to avoid this excess risk are being investigated in animal models and epidemiological studies.

According to Leena Hilakivi-Clarke, PhD, of Georgetown University, “Maternal high fat-containing diet during pregnancy not only increases breast cancer risk in several generations of female offspring, but it appears that it can also preprogram a daughter’s breast cancer to exhibit resistance to antiestrogen therapy.”

Health care providers can contribute to curbing obesity by enhancing their own and society’s education about risks to the offspring. This can occur in multiple ways beyond the clinic, such as through educational sessions in support groups, schools, places of worship and on social media. Mobile e-health interventions during pregnancy are also promising tools.

Tumor microenvironment

Following on the seed-soil hypothesis, there has been increasing recognition that patient outcomes are influenced by the tumor microenvironment, through the initial pioneering work of giants of the field such as Mina Bissell, PhD, Lisa Coussens, PhD, and many others.

Further, the microenvironment — especially the immune component of the cancer niche — tends to differ between the primary and metastatic lesions. Thus, understanding how to search and find biomarkers that will help guide the use of microenvironment-based therapies as adjuncts to anticancer cell therapies is an essential component of current efforts in novel therapeutics.

According to Pusztai, “In studying the immune microenvironment of breast cancer, it is increasingly clear that primary tumors and metastatic lesions have different immune milieu; metastatic sites have an overall immune attenuated microenvironment with greater M2 macrophage presence.”

Macrophages influence tumor growth and progression at the primary and metastatic sites, and several novel trials are coupling macrophage modulation therapy with chemotherapy or targeted signaling therapies.

Because of the role of the niche in modulating resistance to chemotherapeutic agents, immune therapy and signaling-based therapies, the characterization of the stromal component is predicted to contribute to the design of novel therapeutics and clinical trials in the next decade.

In addition, analyses of circulating stromal cells is gaining importance.

“Given the well-established cancer-associated fibroblast (CAF)-mediated mechanisms of chemo- and hormone therapy resistance, the finding of circulating CAFs in heterotypic clusters with CTCs suggests additional applications where CAF-induced drug resistance mechanisms are in play and should not be ignored,” Dorraya El-Ashry, PhD, of University of Minnesota, said. “This role for CAFs in the circulation may indeed be necessary for CTC survival in circulation, whether from the primary tumor or reseeding from metastasis. Thus, CTC/cCAF co-clusters may be circulating drug-resistant sources of metastatic seeding and should be included in drug testing.”

Indeed, novel therapeutics based on this work are emerging.

“I believe the most significant advances we have made in recent years are related to our evidence that the stromal compartment — specifically cancer-associated fibroblasts and extracellular matrix — represents a critical vulnerability in solid tumors that can be exploited for potential therapeutic benefit,” Ellen Puré, PhD, of University of Pennsylvania, said. “Specifically we have identified a subpopulation of cancer-associated fibroblasts that promote tumor growth and progression in multiple types of carcinomas and demonstrated that the activity of a cell surface protease referred to fibroblast activation protein is an important factor that contributes to the pro-metastatic function of this subpopulation of CAFs.”

Novel cell detection bioinformatic technologies based on next-generation RNA sequencing — such as CIBERSORT and xCell — can determine the extent of immune infiltrates present in bulk cancer tissues; similarly, Immunoscore (HalioDx) employs immunohistochemistry and gene expression of the whole cancer tissue data to potentially stratify patients for eligibility into novel combination trials that address the influence of the cancer stroma.

Although these technologies are still experimental, it is expected they will be part of the armamentarium for clinical trial design in the next few years to enable the stratification of patients based on the cancer microenvironment.

Health behavior management

Outcomes disparities across ethnicities have been increasingly documented.

Especially relevant are studies that reveal greater mortality in disadvantaged socioeconomic groups or in certain ethnic minorities after controlling for stage at diagnosis.

These stage-controlled survival disparities allude to inadequate access to best care practices and to biological factors that arise in these populations through the structural adverse or undermining conditions globally affecting health, such as poor safety, dysnutrition, compromised access to education, stress and poverty. Important studies revealed strongly significant disparities of outcomes in patients living in structurally violent environments.

Effective personalized cancer care depends on multiple factors, many of which can be directly influenced by the health system and providers through interventions and counseling.

References:

Agarwal D, et al. Breast Cancer. 2017;doi: 10.1038/s41523-017-0051-5.

Cerhan JR, et al. J Natl Cancer Inst. 2000;2:261-265.

Halbert CH, et al. Prev Med. 2006;doi:10.1016/j.ypmed.2006.06.003.

Hart SN, et al. Genet Med. 2019;doi:10.1038/s41436-018-0018-4.

Heng YJ, et al. Breast Cancer Res Treat. 2018;doi:10.1007/s10549-018-5034-1.

Hilakivi-Clarke L, et al. J Natl Cancer Inst. 2017;doi:10.1093/jnci/djw188.

Jiagge E, et al. Ann Surg Oncol. 2016;doi:10.1245/s10434-016-5420-z.

Jiagge E, et al. J Glob Oncol. 2016;doi:10.1200/JGO.2015.002881.

Lo A, et al. JCI Insight. 2017;doi:10.1172/jci.insight.92232.

Mavaddat N, et al. Am J Hum Genet. 2019;doi:10.1016/j.ajhg.2018.11.002.

Moss JL, et al. Prev Med. 2017;doi:10.1016/j.ypmed.2017.09.006.

Ruffell B and Coussens LM. Cancer Cell. 2015;doi:10.1016/j.ccell.2015.02.015.

Swartz MA, et al. Cancer Res. 2012;doi:10.1158/0008-5472.CAN-12-0122.

For more information:

Sofia D. Merajver, MD, PhD, is professor of internal medicine and epidemiology at Rogel Cancer Center of University of Michigan. She can be reached at smerajve@umich.edu.

To contribute to this column or suggest topics, email Wafik S. El-Deiry, MD, PhD, FACP, at wafik.eldeiry@gmail.com.

Disclosure: Merajver reports no relevant financial disclosures.

For decades, prognostic markers and therapeutics have been focused largely on the cancer cell’s growth patterns in tissue culture or in animal models.

In parallel, studies of metastases inspired by the seed-soil hypothesis — first articulated by Stephen Paget in 1889 — deepened the understanding of the contribution of other tissues and cells to cancer initiation and progression. This hypothesis is a precursor of the current research landscape focused on cells and tissues that surround and infiltrate cancer lesions, as well as on developing predictive and prognostic biomarkers such as systemic circulating protein and metabolic factors, cell-free tumor DNA, and circulating tumor cells (CTCs) and immune cells.

So, how will we, as cancer-focused health care providers, introduce the totality of an individual’s personalized factors in the design of prevention and therapeutic strategies in the next 5 to 10 years?

Sofia D. Merajver, MD, PhD
Sofia D. Merajver

This is an extensive topic I am sure will be covered in many installments of this column; I will try to touch upon some salient discoveries that are not often discussed, but that are likely to affect how we design patient-centered therapies in the next decade. Eventually, it is hoped that personalized oncology will consider all aspects of a person’s ecosystem inside and outside the body to formulate successful prevention and treatments for everyone.

Germline factors

Beyond high-penetrance cancer susceptibility genes, thousands of individuals are undergoing genetic testing for large panels of medium- and low-penetrance genes associated with multiple cancer syndromes.

This transition to panel testing has been further accelerated by the inexorable march toward testing all patients affected with breast, ovarian, prostate and pancreatic cancers, regardless of family history, due to the availability of mutation-based therapeutics.

In this context, we, as health care providers, have had to face our enormous ignorance about the clinical significance of thousands of gene variants that we ascertain in our patients routinely, yet cannot interpret.

This has spurred research into the functional significance of variants by various methods. The expectation is that in the next 2 to 5 years, the genetic testing reports will be much more specific as to the functional significance of variants of uncertain significance (VUS).

However, researchers’ ability to know about variants that are ascertained broadly in the community depends on them being entered into databases — such as www.clinvar.com and promptstudy.info — which I encourage community health providers to utilize every time they encounter a VUS.

Beyond known cancer genes, research is seeking to understand whether there are hereditary factors that influence the observed differential risks for certain tumor subtypes, such as the increased proportion of triple-negative breast cancer in Africans and African-Americans.

PAGE BREAK

The germline context matters for many reasons; it may suggest strategies for prevention and, further, the integrated germline variants are being connected to pathways dysregulated in cancer. Thus, it may provide a personalized context to predict drug sensitivity.

A pioneer in this area of research, Lajos Pusztai, MD, DPhil, of Yale University, said: “In the field of defining risk [for] breast cancer development, important new trends are emerging, including better understanding that some germline mutations in low-penetrance risk genes can confer risk for late-onset breast cancers, and that the totality of common germline polymorphisms that affect the function of regulatory proteins may function as a ‘cancer gene integrity’ risk score.”

Environmental factors

In a classic and paradigm-shifting study, Cerhan and colleagues showed increased exposure to estrogens in utero increases breast cancer risk in offspring, as exemplified by studies in twins. A corollary of this work was the formal realization that cancer risk is influenced by lifetime exposures.

However, modifiable conditions during pregnancy, such as obesity, also affect the cancer risk of the offspring. Studies have been focused on discerning the potential mechanisms to manage these risks.

Overall, a chronic inflammatory state has been shown to be present in adipocytes, which appears to modify cancer risk much later in life for mother and offspring. The details of the mechanism and strategies to avoid this excess risk are being investigated in animal models and epidemiological studies.

According to Leena Hilakivi-Clarke, PhD, of Georgetown University, “Maternal high fat-containing diet during pregnancy not only increases breast cancer risk in several generations of female offspring, but it appears that it can also preprogram a daughter’s breast cancer to exhibit resistance to antiestrogen therapy.”

Health care providers can contribute to curbing obesity by enhancing their own and society’s education about risks to the offspring. This can occur in multiple ways beyond the clinic, such as through educational sessions in support groups, schools, places of worship and on social media. Mobile e-health interventions during pregnancy are also promising tools.

Tumor microenvironment

Following on the seed-soil hypothesis, there has been increasing recognition that patient outcomes are influenced by the tumor microenvironment, through the initial pioneering work of giants of the field such as Mina Bissell, PhD, Lisa Coussens, PhD, and many others.

Further, the microenvironment — especially the immune component of the cancer niche — tends to differ between the primary and metastatic lesions. Thus, understanding how to search and find biomarkers that will help guide the use of microenvironment-based therapies as adjuncts to anticancer cell therapies is an essential component of current efforts in novel therapeutics.

PAGE BREAK

According to Pusztai, “In studying the immune microenvironment of breast cancer, it is increasingly clear that primary tumors and metastatic lesions have different immune milieu; metastatic sites have an overall immune attenuated microenvironment with greater M2 macrophage presence.”

Macrophages influence tumor growth and progression at the primary and metastatic sites, and several novel trials are coupling macrophage modulation therapy with chemotherapy or targeted signaling therapies.

Because of the role of the niche in modulating resistance to chemotherapeutic agents, immune therapy and signaling-based therapies, the characterization of the stromal component is predicted to contribute to the design of novel therapeutics and clinical trials in the next decade.

In addition, analyses of circulating stromal cells is gaining importance.

“Given the well-established cancer-associated fibroblast (CAF)-mediated mechanisms of chemo- and hormone therapy resistance, the finding of circulating CAFs in heterotypic clusters with CTCs suggests additional applications where CAF-induced drug resistance mechanisms are in play and should not be ignored,” Dorraya El-Ashry, PhD, of University of Minnesota, said. “This role for CAFs in the circulation may indeed be necessary for CTC survival in circulation, whether from the primary tumor or reseeding from metastasis. Thus, CTC/cCAF co-clusters may be circulating drug-resistant sources of metastatic seeding and should be included in drug testing.”

Indeed, novel therapeutics based on this work are emerging.

“I believe the most significant advances we have made in recent years are related to our evidence that the stromal compartment — specifically cancer-associated fibroblasts and extracellular matrix — represents a critical vulnerability in solid tumors that can be exploited for potential therapeutic benefit,” Ellen Puré, PhD, of University of Pennsylvania, said. “Specifically we have identified a subpopulation of cancer-associated fibroblasts that promote tumor growth and progression in multiple types of carcinomas and demonstrated that the activity of a cell surface protease referred to fibroblast activation protein is an important factor that contributes to the pro-metastatic function of this subpopulation of CAFs.”

Novel cell detection bioinformatic technologies based on next-generation RNA sequencing — such as CIBERSORT and xCell — can determine the extent of immune infiltrates present in bulk cancer tissues; similarly, Immunoscore (HalioDx) employs immunohistochemistry and gene expression of the whole cancer tissue data to potentially stratify patients for eligibility into novel combination trials that address the influence of the cancer stroma.

Although these technologies are still experimental, it is expected they will be part of the armamentarium for clinical trial design in the next few years to enable the stratification of patients based on the cancer microenvironment.

PAGE BREAK

Health behavior management

Outcomes disparities across ethnicities have been increasingly documented.

Especially relevant are studies that reveal greater mortality in disadvantaged socioeconomic groups or in certain ethnic minorities after controlling for stage at diagnosis.

These stage-controlled survival disparities allude to inadequate access to best care practices and to biological factors that arise in these populations through the structural adverse or undermining conditions globally affecting health, such as poor safety, dysnutrition, compromised access to education, stress and poverty. Important studies revealed strongly significant disparities of outcomes in patients living in structurally violent environments.

Effective personalized cancer care depends on multiple factors, many of which can be directly influenced by the health system and providers through interventions and counseling.

References:

Agarwal D, et al. Breast Cancer. 2017;doi: 10.1038/s41523-017-0051-5.

Cerhan JR, et al. J Natl Cancer Inst. 2000;2:261-265.

Halbert CH, et al. Prev Med. 2006;doi:10.1016/j.ypmed.2006.06.003.

Hart SN, et al. Genet Med. 2019;doi:10.1038/s41436-018-0018-4.

Heng YJ, et al. Breast Cancer Res Treat. 2018;doi:10.1007/s10549-018-5034-1.

Hilakivi-Clarke L, et al. J Natl Cancer Inst. 2017;doi:10.1093/jnci/djw188.

Jiagge E, et al. Ann Surg Oncol. 2016;doi:10.1245/s10434-016-5420-z.

Jiagge E, et al. J Glob Oncol. 2016;doi:10.1200/JGO.2015.002881.

Lo A, et al. JCI Insight. 2017;doi:10.1172/jci.insight.92232.

Mavaddat N, et al. Am J Hum Genet. 2019;doi:10.1016/j.ajhg.2018.11.002.

Moss JL, et al. Prev Med. 2017;doi:10.1016/j.ypmed.2017.09.006.

Ruffell B and Coussens LM. Cancer Cell. 2015;doi:10.1016/j.ccell.2015.02.015.

Swartz MA, et al. Cancer Res. 2012;doi:10.1158/0008-5472.CAN-12-0122.

For more information:

Sofia D. Merajver, MD, PhD, is professor of internal medicine and epidemiology at Rogel Cancer Center of University of Michigan. She can be reached at smerajve@umich.edu.

To contribute to this column or suggest topics, email Wafik S. El-Deiry, MD, PhD, FACP, at wafik.eldeiry@gmail.com.

Disclosure: Merajver reports no relevant financial disclosures.

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