Ingredients for Success: A Familial Cancer Clinic in an Oncology Practice Setting

Genetic cancer risk assessment has become increasingly important in clinical cancer care; incorporation into the oncology practice setting can enhance the standard of care for the entire community.

Abstract

Purpose:

Genetic cancer risk assessment (GCRA) has become increasingly important in clinical cancer care. Almost all published information on genetic risk assessment has come from academic institutions. However, a majority of patients with cancer are seen in the community practice setting.

Methods:

We describe the evolution of a community oncology practice GCRA clinic.

Results:

Over a 10-year period, 445 patients were seen for a possible genetic cancer syndrome. This included 325 patients with family history of breast or ovarian cancer, 92 patients with family history of colorectal cancer or polyposis, and 28 families with another familial cancer predisposition. Fifty-three unique families with a genetic mutation were identified.

Conclusion:

A GCRA clinic can be incorporated into an oncology practice setting and can enhance the standard of care for the entire community. We present data reflecting a 10-year experience with such a clinic and provide recommendations for establishing a successful one.

Introduction

ASCO has issued three policy statements regarding genetic testing for cancer susceptibility.^1–3 In 1997, an ASCO task force developed the “Train the Trainer” curriculum to teach established medical oncologists how to offer familial cancer susceptibility consultations in their own practices as well as train other professionals in their home communities. One of the authors (P.R.D.) was a course participant. The other (J.T.L.) completed the City of Hope (Los Angeles, CA) “Intensive Course in Cancer Risk Assessment” in 2007.⁴ We describe the evolution of the Hematology Oncology Associates (HOA) Family Cancer Clinic (FCC; Albuquerque, NM) and its genetic cancer risk assessment (GCRA) program from 1998 to 2008 and make recommendations for setting up such a clinic.

Methods

HOA is a multiphysician community hematology/oncology practice. At the HOA FCC, the genetic oncologist is the genetic counselor.⁵ This person orders genetic testing, conveys the results, makes the appropriate treatment or risk reduction recommendations to the patient, and communicates with and educates the referring physician. Although we have no experience in doing so, certified genetic counselors, nurse practitioners, and physician assistants who have additional cancer genetics education can also be incorporated into a GCRA clinic, and utilization of these professionals has recently been reviewed in detail.⁵

At the current time, physicians are encouraged to refer patients to the HOA FCC according to the general guidelines presented in Table 1. Patients have been referred by primary care physicians and a broad group of specialists. The practice Web site is a valuable resource for patients and referring physicians regarding the HOA FCC program.⁶ At the first visit, the genetic oncologist determines whether the patient is likely to be part of a hereditary cancer–susceptible family.^5,7 Introducing the concepts of the uninformative negative test^8–10 and variant of unknown significance is an important part of the genetic consult.¹¹ Other medical, legal, and ethical issues involved in genetic testing are also covered, as recommended in the ASCO guidelines.^1–3

Table 1.

General Guidelines for Referral to the HOA FCC

Guideline
Early onset (age < 50 years) of any cancer (most common: breast, colon, endometrial cancers)
Cancer doublet in patient or family (eg, breast/ovarian, colon/endometrium)
Breast cancer associated with thyroid cancer, sarcoma, or adrenocortical cancer in family
Male breast cancer
Personal history of ovarian, fallopian tube, or primary peritoneal cancer
Relatives of patients with known BRCA mutation
Colon cancer and family members with other Lynch syndrome cancers (ie, colon, endometrial, ovarian, gastric, pancreatic, small bowel, ureter, renal pelvis cancers)
Patients with multiple colon polyps (> 10 cumulative) or family members with multiple colon polyps or colon cancer
Individuals clinically affected with FAP (> 100 colon adenomas)
Relatives of APC, MYH, and Lynch syndrome mutation carriers
Patients whose family history seems to include excessive cancer, although specific guideline is not met
Patients who have had genetic testing elsewhere and need more information about results and implications
Patients with colon or endometrial cancer who have shown lack of expression by immunohistochemistry for mismatch repair protein

Abbreviations: HOA, Hematology Oncology Associates; FCC, Family Cancer Clinic; FAP, familial adenomatous polyposis.

Each patient who undergoes testing is requested to return for discussion of the results. Many insurers are now recognizing the specialized nature of familial cancer evaluations and are asking for documentation of a genetic counseling visit that includes an appropriate genetic testing consent discussion and family pedigree. A copy of the GCRA consultation document is sent to the patient, the referring physician, and all physicians involved in the patient's care. This is an important teaching tool; references can be cited, or electronic reference files can be sent.

Results

The categories of patients seen at the HOA FCC are presented in Table 2. Disease-specific genetic tests ordered are presented in Tables 3 and 4.

Table 2.

Genetic Consultations

Year	No. of Patients	Type of Cancer			Physician
		Breast/Ovarian	Colon/Polyposis	Other
Before 1999	5	2	1	2	P.R.D.
1999-2003	104	83	17	4	P.R.D.
2004-2008	336	240	74	22	P.R.D., J.T.L. (from 2006)
Total	445	325	92	28

Table 3.

Breast/Ovarian Genetic Testing Results Through December 2008

BRCA Test Results (n = 172)	No. of Patients (n = 325)
Positive	46
Unique families	36
Family members of positive probands	10
Hispanic families	14
New Mexican colonial Hispanic families	11
BRCA1 187delAG (founder)	11
Other Hispanic families	3
BRCA1 3148delCT	2
BRCA2 5154delGA	1
Negative	118
Variants of uncertain significance	8

Table 4.

Colon/Endometrial/Polyposis Genetic Testing Results Through December 2008

Test Results	No. of Patients (n = 92)
Potential Lynch families	36
Unique mutations identified	9
Families with negative gene testing	6
Variants of uncertain significance	2
Appropriate for testing but no member consented	4
Familial colon cancer syndrome X	10
Microsatellite stable/extracolonic tumors	5
Polyposis syndromes	13
APC mutation identified	6
MYH mutation identified	0
Hyperplastic polyp syndrome	1
Polyposis phenotype, no mutation identified	6

Hereditary Breast/Ovarian Cancer

As listed in Table 3, 325 patients with a breast or ovarian cancer diagnosis or who had relatives with breast or ovarian cancer were evaluated. BRCA testing was recommended for 172 of these patients (53%). Deleterious BRCA mutations were found in 46 patients (27%), and variants of unknown significance in eight patients (5%). The majority of patients tested had negative genetic test results.¹² However, these women and their family members may still have an increased risk of developing breast cancer,¹³ and discussion of appropriate risk reduction strategies, such as the use of selective estrogen receptor modulators¹⁴ or screening with breast magnetic resonance imaging,¹⁵ is necessary. The 153 patients who were not tested included patients without cancer who were not the optimum family member to be tested or members of a family that on closer inspection did not represent a high-risk family. Some were patients with cancer who did not meet testing guidelines or patients who elected after consultation not to be tested.

Founder mutations are recognized to exist in certain populations, and this allows one to use a more directed genetic testing strategy.^9,12 In the HOA FCC population, women with hereditary breast or ovarian cancer who identified themselves as having colonial New Mexican Hispanic heritage seemed to carry the BRCA1 mutation 187delAG with high frequency (Table 3).¹⁶ Of the 14 Hispanic families with a positive BRCA mutation, 11 (79%) were carriers of the 187delAG BRCA1 founder mutation. Thus, in this population, single-site BRCA1 187delAG mutation testing is ordered initially, with reflex to full BRCA1 and BRCA2 testing if single-site testing is negative.

Women with newly diagnosed breast cancer who have already had a deleterious BRCA mutation identified have additional treatment and risk reduction decisions to make; they need the expertise of an oncologist familiar with all of the current recommendations. Recent publications deal with the literature in this important area.^{13,14,17–21} Although BRCA mutations are by far the most common cause of familial breast cancer, other familial syndromes such as Li-Fraumeni, Cowden's, and familial gastric cancer also involve an increased risk of breast cancer.¹² The HOA FCC has seen one case of familial breast cancer resulting from Li-Fraumeni syndrome.

Hereditary Colon Cancer and Polyposis Syndromes

As listed in Table 4, 92 patients were referred for questions regarding familial colon cancer. After microsatellite instability assay or mismatch repair protein (MMR) immunohistochemistry (IHC) as the initial tumor tissue study, 21 patients showed an abnormality in MMR, and 15 showed no abnormality. Lynch syndrome is the most common of the hereditary colon cancer syndromes, and demonstrating an abnormality in MMR is an essential part of the workup. BRAF mutation testing or assay of promoter region methylation in tumors with absent MLH1 IHC confirms the presence of sporadic colorectal cancer.²² Absent expression of MMR IHC narrows the choice of which MMR gene to submit for sequencing. Using these intermediate steps, a deleterious Lynch mutation was found in nine (53%) of 17 patients (Table 4).

Although the referral data suggest that Lynch syndrome is far less common than BRCA mutation (Table 3), this likely reflects the relative difficulty in the clinical recognition and underdiagnosis of Lynch syndrome rather than its true incidence. After publication of the Ohio State data on population screening for Lynch syndrome and subsequent editorial comments,^23,24 an Albuquerque community hospital task force reviewed the findings. It concluded that it was appropriate to test prospectively all patients with newly diagnosed colon cancer age 60 years or younger and patients with newly diagnosed endometrial cancer age 50 years or younger with the four–MMR protein (ie, MLH1, MSH2, MSH6, and PMS2) IHC.²⁵ This program was started in January 2008 and has already led to the timely identification of several new Lynch syndrome families. Preliminary results were presented at the 2010 ASCO Annual Meeting, with nearly 10% of screened patients being mutation positive.²⁶

Thirteen patients were evaluated for one of the familial polyposis syndromes (Table 4). Six patients with an APC mutation were identified, and one patient was found to have familial hyperplastic polyp syndrome.²⁷

Other Familial Cancer Predisposition Syndromes

Two families with p53 mutation–positive Li-Fraumeni syndrome were identified at the clinic. Patients with other familial cancers, such as gastric cancer, renal cell carcinoma, pancreatic adenocarcinoma, and papillary thyroid cancer, were also seen, although it was not determined whether these families carried an identifiable genetic mutation.

Discussion

Clinical Research

In the HOA FCC experience, patients with possible genetic cancer syndromes, whether or not they had an identifiable mutation, were interested in participating in clinical research. As of 2008, 54 patients and families had been enrolled onto cancer genetics clinical studies through an affiliation with the City of Hope.⁴ The Early Detection Research Network, of which the Creighton University Hereditary Cancer Institute (Omaha, NE) is a member, provides an avenue for clinical research collaboration and has an associate membership program. Henry Lynch, MD, director at Creighton, welcomes clinical collaboration, and the HOA FCC has collaborated with Creighton for many years with a large Native American Lynch kindred. The Cleveland Clinic (Cleveland, OH) Cowden's protocol is open for physician collaboration and is an example of disease-specific collaboration under Charis Eng, MD, PhD.

How It Was Done—Lessons Learned

Designate an oncologist in the practice willing to lead this effort as the genetic oncologist. There are cancer genetics education programs that provide continuing medical education–qualified genetics education for clinicians. Attending one of these programs is highly recommended.^4,5

Establish in the practice a GCRA clinical structure with a business plan.^5,28 An efficient single-visit genetic consult requires 1 to 2 hours to cover all the issues involved.^1–3

Establish a relationship with an National Cancer Institute–designated comprehensive center that offers expertise in GCRA.^4,5 This facilitates continuing education in this rapidly developing field and allows community patients to participate in clinical research.

Use a genetics software program that allows data sharing and facilitates drawing cancer family pedigrees.⁴ Pedigrees can be incorporated directly into the office electronic medical record. At the HOA FCC, Progeny (Progeny Software, Delray Beach, FL) is used, but there are a number of other programs available, such as Cyrillic (Cyrillic Software, Wallingford, United Kingdom) and Pedigree-Draw (Jurek Software, Cottage Grove, WI).²⁹

Establish a community-wide education program. Consultations are an opportunity to educate individual providers. Community tumor boards are excellent forums for the presentation of case-based treatment and risk-reducing options. Grand rounds presentations enhance community awareness of genetic syndromes. Research carried out in the practice upgrades GCRA appreciation and awareness throughout the physician and patient community.^4,16,26

Conclusion

Recognition and identification of patients and members of their families with familial cancer syndromes can lead to changes in management that have been shown to improve survival.^30,31 The incorporation of GCRA programs into oncology practices will benefit a significant subset of patients and allow oncology practices to truly participate in cancer prevention strategies. Collaboration with academic GCRA programs facilitates the participation of community patients in clinical research in this rapidly evolving field.

Authors' Disclosures of Potential Conflicts of Interest

The authors indicated no potential conflicts of interest.

Author Contributions

Conception and design: Paul R. Duncan

Financial support: Paul R. Duncan

Administrative support: Paul R. Duncan

Collection and assembly of data: Paul R. Duncan, James T. Lin

Data analysis and interpretation: Paul R. Duncan, James T. Lin

Manuscript writing: Paul R. Duncan, James T. Lin

Final approval of manuscript: Paul R. Duncan, James T. Lin