Minetta Liu

Minetta C. Liu, MD, received her B.A. in molecular biology from Princeton University and her M.D. from Jefferson Medical College before completing her training in Internal Medicine and Hematology/Oncology at Georgetown University Hospital. She joined the faculty of the Breast Cancer Program at the Lombardi Comprehensive Cancer Center in July 2001. An Assistant Professor of Medicine and Oncology and the Biomarker Section Chief for the Clinical Molecular Diagnostics Laboratory, she serves as the principal investigator for several institutional, industry-sponsored, and cooperative group clinical trials in breast cancer.

Dr. Liu is also involved in translational research with a particular focus on the development of new methods by which to increase our understanding of the molecular mechanisms underlying drug responsiveness. This research is currently supported by grants from the National Cancer Institute, the Department of Defense, the Susan G. Komen Breast Cancer Foundation, and industry sponsors. In recognition of her work, Dr. Liu has been appointed Chair of the MedStar Health Network's Breast Cancer Clinical Research Group, a Cadre Member of the CALGB's Breast Committee and Audit Committee, and a Member of the Medical Advisory Board for the Young Survival Coalition.

Questions & Responses:

Question Four:

Hi, I am 43, diagnosed with DCIS in one breast (10 cm) at 41. I had bilateral mastectomies and a sentinel node biopsy (the frozen section was negative, but the final pathology showed 8-10 ductal cells). I am currently on tamoxifen. My question is, I had genetic testing as my mother was diagnosed with invasive breast cancer—the screen was negative. This medical practice was "pushing" the idea of elective removal of ovaries, or hysterectomy, or both. My oncologist does not feel I should pursue this. I am a nurse, and a bit confused. I still get a period, not I'm too crazy about the idea of the surgery. What are your thoughts?

Six years ago when I was 31 I had Stage I, estrogen positive breast cancer. I did four rounds of AC and chose to have a bilateral mastectomy with reconstructive surgery. Last year, I chose to have a hysterectomy because my grandma beat ovarian cancer and I used to have abnormal PAP smears in my twenties. It's been six years since my diagnosis and I appear to be free of cancer. I never did tamoxifen or any other hormone therapy and the only way my oncologist monitors me is through blood work. I think my oncologist should be doing more, but she says there isn't anything to do. Can't I get checkups using an ultrasound to look for anything suspicious? Should I be on any hormone therapy or do the risks outweigh the benefits? I'm nervous because my mom had a recurrence of breast cancer after 17 years of supposedly being cancer free. She had a mastectomy at the age of 45, but never did chemo. Now she is Stage IV and I worry that I will someday have a recurrence.

I have been on tamoxifen for almost a year now, but declined the Zoladex injections. Every so often I start to think that maybe I should be doing the injections for extra insurance since my periods have been back for about seven months now. Are the injections typically recommended for stage 1?

Dr. Liu's Response:

The current standard of care for premenopausal women with hormone receptor positive, early stage (i.e., stage I or II) breast cancer is tamoxifen. Ovarian functional suppression uses medications such as goserelin (i.e., Zoladex) to temporarily induce menopause, or surgery (i.e., bilateral oophorectomy) to permanently induce menopause. Both maneuvers decrease estrogen production and represent unique treatment options for young premenopausal women with hormone receptor positive invasive breast cancer. The true efficacy of ovarian functional suppression, however, is still under investigation. Small studies examining the role of ovarian functional suppression in premenopausal patients with hormone receptor positive, early stage breast cancer suggest the potential for improved survival when combined with tamoxifen – particularly for women who do not receive adjuvant chemotherapy, or who do not experience treatment related amenorrhea after completing adjuvant chemotherapy. Nonetheless, definitive data are lacking in terms of the correct positioning of these interventions to achieve maximum benefit.

Appropriate premenopausal patients are therefore encouraged to consider participation in one of two international adjuvant clinical trials that were designed to address the following questions:

1. Will the addition of ovarian functional suppression be more efficacious that tamoxifen alone?
2. Are the benefits of ovarian functional suppression greatest when used in conjunction with an aromatase inhibitor as opposed to tamoxifen?
3. Does the timing of ovarian functional suppression relative to chemotherapy have an impact on efficacy?

SOFT ("Suppression of Ovarian Function Trial") is a randomized study comparing tamoxifen alone versus ovarian functional suppression plus tamoxifen versus ovarian functional suppression plus exemestane in patients for whom tamoxifen alone is adequate therapy, and in patients whose menstrual cycles continue despite chemotherapy. TEXT ("Tamoxifen and Exemestane Trial"), on the other hand, is a randomized study comparing ovarian functional suppression plus tamoxifen versus ovarian functional suppression plus exemestane in patients who may or may not receive adjuvant chemotherapy; if chemotherapy is indicated, ovarian functional suppression begins with chemotherapy, and tamoxifen or exemestane is added upon completion of the chemotherapy course. Together, these two large clinical trials will randomize over 4500 patients and help to more definitively determine the efficacy of ovarian functional suppression as a treatment option for premenopausal women. Importantly, they will also prospectively evaluate the long term effects of early menopause on quality of life and issues of health maintenance (e.g., bone mineral density) for this patient population.

In terms of the pros and cons of medically induced versus surgically induced ovarian functional suppression, there are data to demonstrate equivalence in terms of the potential impact on breast cancer related survival. The choice is often a personal one for the individual patient. The most obvious example regards premenopausal women with a personal history of hormone receptor positive, early stage breast cancer and a strong family history of breast and/or ovarian cancer; these women may opt for a bilateral oophorectomy after child bearing, as this serves the dual purpose as a risk reducing strategy against ovarian cancer and as a potential adjunct to standard endocrine therapy for her history of breast cancer. This decision requires careful consideration of the potential long terms risks of premature menopause, which may include osteoporosis, cardiovascular disease, and hypercholesterolemia. Discussion with a medical oncologist, primary care physician, and genetic counselor are therefore warranted before proceeding with this intervention.

Question Three:

I am 39 years-old and was diagnosed with breast cancer (ductal, ER/PR+, HER-2/NEU-) in October of 2002. My oncologist has been screening me with the CA 15.3 tumor marker test. My number was 31 for about a year until about 6 months ago and most recently it has risen to 63. My oncologist feels I should have a hysterectomy and oophorectomy to potentially stop feeding the "possible" recurrent cancer. What is your opinion on having the hysterectomy and oophorectomy in my situation?

Dr. Liu's Response:

The tumor markers used in breast cancer include CEA, CA 15.3, and CA 27.29, all of which are assessed through blood sampling. Typically CEA is monitored in conjunction with CA 15.3 or CA 27.29, although there are no absolute guidelines. There are several potential roles for these markers in managing patients with malignancies, which are summarized as follows:

1. screening: early detection for cancer
2. diagnosis: confirmation of malignant versus benign disease
3. surveillance: monitoring for disease recurrence after completing treatment for early stage disease
4. prediction: determination of treatment benefit in metastatic disease

For a patient who completed her planned course of therapy for early stage breast cancer, the primary focus is on surveillance. The theory is that identifying a recurrence earlier and starting treatment as soon as possible should improve patient outcomes. However, none of the available markers are recommended for routine use in monitoring for a breast cancer recurrence because there is no clear evidence that initiating treatment on the basis of tumor markers alone has a positive effect on survival or quality of life. In addition, tumor markers can be elevated in patients without active breast cancer, and not elevated in patients with active breast cancer. Therefore, tumor markers should not be used as a "stand alone test", meaning that data from radiographic studies (e.g., CT scans, bone scans, PET scans, etc.) and clinical evaluations must be the ultimate source of information when making treatment decisions for patients with breast cancer.

Despite the lack of definitive supportive data, tumor markers are often used to prompt an evaluation in the otherwise asymptomatic patient with a history of early stage breast cancer. If there is an increasing trend in the tumor markers, and if that trend is confirmed on repeat testing, a radiographic study is typically in order. Treatment is started if there are radiographic findings consistent with recurrent breast cancer, although the benefits of starting treatment in this setting are unclear (as opposed to starting it when a recurrence is diagnosed on the basis of clinical factors alone). It is not standard practice to begin or change therapy in the absence of these confirmatory radiographic findings, but the desire to do so in an attempt to maximize treatment efficacy is certainly understandable.

With respect to the case presented in the question above, there is no mention of adjuvant therapy with tamoxifen, which is a standard component of treatment for premenopausal women with early stage, hormone receptor positive, invasive breast cancer. If recent CT scans, bone scans, PET scans, etc. were unremarkable; I would continue tamoxifen and maintain close clinical, laboratory, and clinical follow-up. There is no indication for an oophorectomy to treat the breast cancer, but it could be considered as a preventive strategy against ovarian cancer if there is an increased risk based on the family history or genetic testing.

Question Two:

It seems that a high percentage of young women diagnosed with breast cancer are considered triple negatives. I know it's been depressing for me and other triple negs to see so many new drug therapies coming out for hormone+ cancers or Her2+ cancers. Is there anything in the works for us triple negs? Something that we could do after chemo? Is there anything that might be coming out soon?

Dr. Liu's Response:

Gene expression analysis of breast cancers has led to the recent identification of the following subclasses of invasive breast cancer:

- the normal breast-like group,
- the estrogen receptor positive luminal A group,
- the estrogen receptor positive luminal B group,
- the basal-like group, and
- the Her-2/neu positive group.

The basal-like subtype accounts for about 15% of all breast cancers, and particular interest has been generated because of its association with a poorer prognosis. Unfortunately, there is no clinically valid means by which to identify patients with true basal-like invasive breast cancer because gene expression analysis is not used routinely as a diagnostic tool; the current technology is such that it requires specialized tissue processing and analysis that are not feasible outside of major academic centers. Because these tumors are characterized as estrogen receptor negative, progesterone receptor negative, and Her-2/neu negative, this "triple negative" classification is currently being used as a surrogate marker for basal-like breast cancer. It is important to note, however, that approximately 25% of hormone receptor negative, Her-2/neu negative breast tumors have gene expression profiles that are not consistent with the true basal-like subtype. The significance of this distinction is unclear, but it suggests that the prognostic implications and treatment considerations associated with the basal-like subtype may not apply to all patients with triple negative disease.

Neither endocrine therapy (e.g., tamoxifen, fulvestrant, anastrozole, letrozole, exemestane) nor Her-2/neu directed therapy (e.g., trastuzumab, lapatinib) can be used in the treatment of triple negative breast tumors. Chemotherapy is therefore the mainstay of therapy, and the need for new effective agents in this setting is crucial. Further characterization of basal-like cancers has revealed an unusually high proportion of tumors that over express EGFR (i.e., the epidermal growth factor receptor), and laboratory studies indicate that basal-like breast cancer cells depend heavily on the EGFR pathway for growth. These observations have led to great interest in the use of EGFR inhibitors for triple negative patients. The EGFR inhibitors include such agents as cetuximab, gefinitib, and erlotinib. None of them proved to be effective single agents in previous phase II trials of unselected patients with metastatic breast cancer, but it is very possible that a treatment benefit will be demonstrated in studies targeting patients with EGFR dependent tumors. For example, one ongoing clinical trial is investigating the potential efficacy of cetuximab with or without the chemotherapy drug carboplatin in patients with estrogen receptor negative, progesterone receptor negative, Her-2/neu negative, metastatic breast cancer. This study is the first one specifically designed to target a breast cancer subtype identified by gene expression analysis, with the hope of identifying a class of agents that could offer triple negative patients a survival benefit that is comparable to that achieved with the use of trastuzumab in the setting of Her-2/neu positive disease.

Question One:

Please tell me what are the benefits of having chemo before a mastectomy or having it after. I was recently diagnosed at age 36, with one tumor 1.5 cm, 1 DCIS, 1 lymph node—all positive for cancer per core biopsy (ER/PR low positive, HER2 positive). I did not have sentinel node dissection since one node already positive. The tumor and DCIS are too far apart for lumpectomy so mastectomy recommended along with axillary node dissection.

Dr. Liu's Response:

Preoperative or neoadjuvant chemotherapy is the standard of care for patients with large tumors in the breast (5cm or more), and data from large clinical trials indicate that it increases breast conservation rates in the setting of early stage, operable breast cancer. There does not appear to be a difference in survival when the same chemotherapy agents are administered before or after surgery. However, many women experience a significant decrease in tumor size with preoperative chemotherapy, such that more women are able to undergo a wide local excision ("lumpectomy") as opposed to a mastectomy. In addition, the ability to measure the degree of tumor shrinkage during the course of treatment provides information about the effectiveness of the prescribed therapy – a measure that is not available in the adjuvant setting, where all disease in the breast and/or lymph nodes is surgically removed after the initial diagnosis.

Depending on the patient and the agents prescribed, the likelihood of a pathologic complete response (typically defined as the absence of invasive carcinoma in the breast at surgery) with preoperative chemotherapy is about 20%. These rates are expected to improve with the addition of biologic agents (e.g., bevacizumab and trastuzumab) and the use of new combinations of chemotherapeutics. In the case of minimal disease response, the medical oncologist can change the treatment regimen in an effort to improve the response. This is important because the documentation of disease responsiveness to preoperative therapy is a reliable marker of improved survival, particularly in the case of a pathologic complete response.

To be clear, patients who receive preoperative chemotherapy still require surgery. In addition, not all patients are good candidates for this treatment approach. For example, systemic therapy has no substantial effect on ductal carcinoma in situ (DCIS), and patients with extensive in situ disease may not achieve as high response rates as those with minimal in situ disease; these patients are often best served by proceeding with their surgery so that pathology and ER/PR/HER2 results are available on the invasive disease versus the in situ disease to appropriately guide systemic treatment recommendations. Consideration must also be given to instances in which a mastectomy is indicated irrespective of tumor response, as in the case of multicentric disease (i.e., the presence of carcinoma in more than one quadrant of the breast). In these cases, one could argue that there is no benefit to the individual patient.

In summary, the primary advantages of preoperative chemotherapy are to increase the likelihood of successful breast conserving surgery and to provide potentially useful, immediately available information on long term outcomes. Although the pursuit of preoperative therapy is rarely inappropriate, there are situations in which it is more preferred than others. It must therefore be administered under the guidance of the patient's surgeon and medical oncologist.