CASE STUDIES CLINICAL CASE SCENARIOS. Matthew J. Ellis, MD, PhD

Size: px

Start display at page:

Download "CASE STUDIES CLINICAL CASE SCENARIOS. Matthew J. Ellis, MD, PhD"

Roy Carter
5 years ago
Views:

1 CLINICAL CASE SCENARIOS Matthew J. Ellis, MD, PhD Clinicians face daily challenges in the management of individual patients with breast cancer who demonstrate different characteristics in terms of estrogen receptor (ER) and human epidermal growth factor receptor 2 (HER2) status. Two case studies are presented that compare and discuss valid therapeutic strategies in a patient with ER-positive, HER2-negative disease, and a patient with ER-negative, HER2-positive disease. CASE 1: ADJUVANT THERAPY IN ER-POSITIVE, HER2-NEGATIVE BREAST CANCER A 57-year-old African American mother of 3 presents with stage IIB breast cancer. She is found to have 2 positive nodes. The tumor is characterized as grade 2, ERpositive, progesterone receptor (PR)-negative, and HER2-negative. She has demonstrated osteopenia of the femoral neck, with an osteopenia T-score of -1.5, and her 25-hydroxyvitamin D level is 12 ng/ml. A course of chemotherapy and breast radiation therapy is completed, and the patient returns for the initiation of long-term hormonal therapy. The patient is prescribed a regimen of nonsteroidal aromatase inhibitor (AI) therapy, as well as calcium and vitamin D supplementation. However, the patient returns complaining of joint stiffness and muscle pain. After 3 months of vitamin D U weekly, her vitamin D level increases to 42 ng/ml, and her bone and joint symptoms have improved. How would you manage a patient with this disease profile? What are some of the important treatment issues in patients with ER-positive, HER2-negative breast cancer? DISCUSSION Dr Ellis: To begin our discussion, which kind of chemotherapy would you prescribe in this patient? Dr Stearns: Based on the presence of 2 positive nodes, I would prescribe an initial regimen of doxorubicin plus cyclophosphamide (AC) anthracycline therapy followed by dose-dense paclitaxel or docetaxel plus doxorubicin and cyclophosphamide (TAC). Dr Ellis: What about recent data suggesting that dose-dense regimens do not benefit ER-positive patients? Dr Stearns: The data suggest that there is not as much of a benefit with taxanes in ER-positive patients, but there is still some degree of benefit with dose-dense taxane therapy. Dr Isaacs: I tend to prescribe dose-dense regimens in high-risk patients, but there are plenty of regimens that can be considered in the high-risk population. The options of dose-dense paclitaxel or TAC regimens are available, for instance. As for the issue of describing a different high-risk regimen in those with ER-positive and ER-negative disease, the TAC data demonstrate a benefit in both patient groups. In general, I get the sense that chemotherapy is less effective in patients with ER-positive disease, and I am not convinced that a different taxane dosing strategy is going to make a substantial difference in ER-positive patients. Dr Ellis: Do you think there is value in conducting a trial that is confined to the subpopulation of ER-positive, HER2-negative patients? Dr Stearns: I think that additional trials in specific subpopulations will be needed. Otherwise we will be limited to retrospective analyses of existing data to make questionably valid treatment decisions. Dr Partridge: I think that it is important to note that the observed rates of amenorrhea were higher in patients receiving TAC versus fluorouracil plus doxorubicin and cyclophosphamide therapy. Therefore, it is possible that subset analyses of chemotherapy trials will reveal disease-related effects that are not a result of direct effects on the tumor, but may be through hormonal mechanisms. Dr Wolff: I am convinced that the choice of adjuvant chemotherapy in the average patient with ER-pos- Johns Hopkins Advanced Studies in Medicine 523

2 itive disease is not an issue. In our practice, we have tried to streamline chemotherapy management and avoid different regimens that confuse nurses and staff. We generally use an AC regimen followed by dosedense paclitaxel, with the addition of granulocytecolony stimulating factor, every 2 weeks for 8 weeks. Dr Partridge: The individual clinician dictates the choice of chemotherapy regimen at Dana-Farber Cancer Institute. In a high-risk patient, the use of AC followed by dose-dense paclitaxel would be reasonable. Based on available data, I like to offer dose-dense therapy with the option of discontinuing the taxane if dose-limiting neuropathy or another substantial adverse effect is encountered. Dr Blackwell: At Duke, we have the flexibility to make treatment choices based on the data and individual patient characteristics. However, I am concerned about the value of taxane therapy in patients with ERpositive disease. I have concerns about routinely adding taxane therapy in ER-positive patients based on retrospective subgroup analyses. I would probably discuss a TAC regimen in the patient. Dr Ellis: Do you ever consider Oncotype DX (Genomic Health, Inc; Redwood City, CA) analyses in a node-positive patient? Dr Blackwell: We are using these analyses, and the literature does show some value in N1 disease (1 3 lymph nodes involved). However, I would not order an oncotype analysis in this patient, as I would proceed with chemotherapy regardless of the findings. I am concerned about the lack of data comparing 8-cycle versus 4-cycle (dose-dense) regimens in ER-positive patients. Therefore, in the absence of data, I would probably prescribe the TAC regimen. I would also have concerns about long-term neuropathy in a patient who I assume is an otherwise healthy individual. Dr Ellis: Personally, I commonly prescribe a fluorouracil, epirubicin, and cyclophosphamide regimen followed by docetaxel, although this is a more common approach in Europe. I am also concerned about giving up on the fluorouracil because in the metastatic setting, as it is very active in ER-positive disease. The docetaxel schedule of every 3 weeks is convenient for my patients, many of whom live a long distance from the treatment center. Dr Isaacs: As Dr Wolff discussed, it is important to use a consistent regimen that the clinician and staff are comfortable with, especially when managing possible adverse effects. The comfort level in prescribing a specific regimen may be more important than which regimen is prescribed. Dr Partridge: I am generally comfortable prescribing taxanes in higher-risk ER-positive patients. The data from the Cancer and Leukemia Group B 9334 trial do show some benefit in ER-positive, HER2-positive patients, thus I think we need to look beyond ER status and consider other factors, including HER2 status. Dr Dickler: However, we should be careful in making treatment decisions based on subset analyses. Dr Ellis: In terms of the choice of hormonal therapy, would anyone choose sequential therapy in this high-risk patient, or begin with AI therapy? Dr Stearns: I would proceed with sequential therapy. Dr Dickler: Although data have not yet demonstrated a difference in overall survival between up front versus sequential use of AIs, my preference is to use up front AI therapy, especially in a high-risk population of patients. Dr Wolff: We also need to emphasize the role of nurse practitioners and other staff members in long-term follow-up as survivorship increases. It is now increasingly accepted that long-term follow-up can be managed by staff members other than the medical oncologist. Dr Griffith: Yes, nurse practitioners and other staff members are particularly critical in monitoring bone density, prescribing and monitoring exercise therapy, and providing services, such as nutritional support counseling. Dr Ellis: What about vitamin D screening and management? Dr Partridge: Vitamin D deficiency is surprisingly common in many women, and we have been increasingly checking vitamin D levels in patients. We are particularly careful to check vitamin D levels before the initiation of bisphosphonate therapy to avoid hypocalcemia. I generally recommend calcium, vitamin D, and exercise in daily practice. Dr Ellis: My view is that vitamin D status should be monitored and managed in all women on estrogen deprivation. Symptoms of adult osteomalacia are often dismissed as aches and pains associated with AI therapy, and vitamin D deficiency may be overlooked. Furthermore, clinicians should keep in mind that patients of African ancestry living in northern latitudes may be particularly susceptible to vitamin D deficiency. In general, clinicians should prescribe vitamin D therapy of U weekly until a vitamin D level of 524 Vol. 7, No. 16 December 2007

3 40 ng/ml is achieved. In patients with very low levels (below 10 ng/ml) 6 months of therapy or more may be required. Calcium levels also should be checked before and after replacement to rule out hyperparathyroidism. Dr Dickler: Vitamin D is easy for nurse practitioners and other staff members to manage once an algorithm is established. CASE 2: ADJUVANT THERAPY IN HER2-POSITIVE BREAST CANCER A patient with stage IIB breast cancer presents with 2 positive nodes and a tumor that is characterized as ERnegative and HER2-positive. She has a borderline left ventricular ejection fraction (LVEF) of 52%. Based on her disease state, she has a 10-year risk of relapse of approximately 60%, which could be reduced to approximately 30% with a third-generation regimen that includes hormonal therapy and trastuzumab, if possible. How would you address adjuvant therapy in a patient with ER-negative, HER2-positive breast cancer? Should trastuzumab be prescribed in this patient? If so, in the context of which chemotherapy combination, and which sequence? How would you address the potential for adverse effects with different regimens? DISCUSSION Dr Stearns: In this patient with a borderline ejection fraction, I would be reluctant to begin doxorubicin therapy because it may impact our ability to use trastuzumab later on. I would probably opt for carboplatin plus docetaxel and concurrent trastuzumab (TCH) in this patient. Dr Ellis: If I see an abnormally low LVEF, I personally order a stress test to determine the cause. Would you send this patient to a cardiologist? Dr Blackwell: I think it would depend on the patient s underlying cardiac risk factors. Trastuzumab is associated with a higher risk of cardiomyopathy in patients who have received previous antihypertensive drugs. The risk is also linearly related to age. Baseline LVEF is also an important predictor. We are now incorporating cardiac magnetic resonance imaging and other diagnostics to get a better picture of global cardiac function, and we do not necessarily send all of our patients with LVEF levels in this range to a cardiologist. I have seen an increasing number of patients with LVEFs in the 35% to 40% range, who were completely asymptomatic. I think we lack data in the adjuvant setting right now, but agree that TCH is an appropriate strategy in patients with a low baseline LVEF. In the metastatic setting, we are going to run into more of these issues as well. Dr Dickler: Unless someone is symptomatic, or if it is in the context of a clinical trial, I do not check LVEF in asymptomatic patients with metastatic breast cancer, as long as they continue to derive therapeutic benefit from trastuzumab. Dr Partridge: I do check LVEF in patients because it provides additional information in the event that a patient does become symptomatic. We can triage to some degree if we know the baseline LVEF. If the LVEF is falling and the patient is asymptomatic, I just monitor things more closely. Dr Wolff: I agree that trastuzumab can be continued, even if LVEF levels are falling, as long as the situation is closely monitored. Dr Blackwell: It is also important to note that we still do not know if trastuzumab should be continued forever in the metastatic setting. In metastatic disease, it may be important to continue therapy and monitor, discussing the risks and benefits of therapy with the patient. Dr Ellis: Another issue is the stopping and restarting of therapy in the adjuvant setting. If the patient s LVEF did drop to 40%, would you discontinue trastuzumab and then restart at a later time? Would you restart therapy at all? Dr Wolff: In my experience, approximately 50% of my patients discontinuing trastuzumab because of cardiotoxicity have demonstrated LVEF recovery and were able to restart therapy. Dr Blackwell: We also should recognize inconsistencies in imaging modalities to determine LVEF. Also, tachycardia should be recognized as one of the first signs of cardiomyopathy. If I do see reproducible tachycardia, I send the patient for cardiac imaging. Tachycardia is easy and inexpensive to monitor and could be an important measure in addition to LVEF to track cardiac function. Dr Ellis: We should also emphasize the LVEF data we do have, including the analysis from the National Surgical Adjuvant Breast and Bowel Project B31 trial that linked congestive heart failure risk with age and LVEF (Table). 1 Dr Stearns: Could you comment on how clinicians judge the relative reliability of the HER2 tests that they receive from diagnostic laboratories? How do you assess the quality and accuracy of the results? Dr Wolff: This is an important issue, especially because many patients have their laboratory work performed elsewhere. I am always reminding pathologists of Johns Hopkins Advanced Studies in Medicine 525

4 Table. Post-AC LVEF and Age Are Independent Predictors of Trastuzumab-Associated CHF: Data from NSABP B31 Age LVEF, % < /48 (6.3%) 9/47 (19.1%) /229 (2.2%) 10/194 (5.2%) 65+ 1/160 (0.6%) 2/159 (1.3%) AC = doxorubicin plus cyclophosphamide chemotherapy; CHF = congestive heart failure; LVEF = left ventricular ejection fraction; NSABP B31 = National Surgical Adjuvant Breast and Bowel Project trial B31. Data from Romond et al. 1 their responsibility in getting the results right and using consistent laboratory techniques, because these values are used to make long-term management decisions. Dr Ellis: I agree that we need to push pathologists hard on this issue. There is a huge difference between morphologic pathology and chemical pathology. Although chemical pathologists are used to testing the accuracy and robustness of their tests, morphologic pathologists are not used to being pressed on this point. In particular, we need to standardize the ways in which tumors are processed. Dr Wolff: Overall, we should encourage pathologists to adhere to a processing technique in which tumors remain in a solution of 10% formalyn for a minimum of 6 hours and no more than 48 hours prior to processing. Dr Isaacs: What do you do when there are discrepancies, such as cases in which immunohistochemistry (IHC) tests are positive for HER2 and fluorescence in situ hybridization (FISH) tests are negative? Dr Wolff: Some preliminary retrospective analyses, suggest that tumors with IHC results of less than 3+ and FISH positive may not respond to trastuzumab. In the case of discrepant findings, I usually use trastuzumab in the absence of data on this issue. REFERENCE 1. Romond EH, Perez EA, Bryant J, et al. Trastuzumab plus adjuvant chemotherapy for operable HER2-positive breast cancer. N Engl J Med. 2005;353: Vol. 7, No. 16 December 2007

5 NOTES Johns Hopkins Advanced Studies in Medicine 527

Non-Anthracycline Adjuvant Therapy: When to Use?

Northwestern University Feinberg School of Medicine Non-Anthracycline Adjuvant Therapy: When to Use? William J. Gradishar MD Betsy Bramsen Professor of Breast Oncology Director, Maggie Daley Center for