•	1989: 5-cm ER/PR-negative, right breast cancer, treated with mastectomy, axillary node dissection (negative nodes); received FAC x 8 chemotherapy and regional radiation therapy
•	2000: Patient is now in her 60s and asymptomatic; pleural effusion detected on clinical examination, confirmed by CT of the chest
•	Bone scan, CBC, liver function studies normal
•	CT of the abdomen and pelvis showed ascites, enlarged uterus and retroperitonial lymph nodes; ovaries not visible
•	CA.125 = 20,728 U/mL; CA 27.29 = 355 U/mL; CEA = 0.8 ng/mL
•	Thoracentesis showed poorly differentiated carcinoma, most likely an adenocarcinoma but unable to determine whether the primary tumor was breast or ovarian
Key discussion points:
	The utility of tumor markers in breast cancer management
	Differential diagnosis: Metastatic breast cancer versus advanced ovarian cancer
	Treating a patient with advanced disease and an unknown site of origin
	Discordance between primary and metastatic hormone receptors
	Treatment of the postmenopausal patient with ER/PR-positive metastatic disease

Dr Pillai: I don’t usually follow tumor markers in my practice because they may become elevated three or four months before a clinical diagnosis is made and, in a stage IV situation, I don’t think that makes a big difference in the treatment outcome. But in this patient, since I thought that she might have an ovarian primary, I decided to do markers.

Dr Argawal: A CA.125 of 20,000 U/mL screams ovarian cancer.

Dr Love: Nick, what do we know about CA.125 in breast cancer?

Dr Robert: CA.125 can be elevated in all the epithelial cancers, but tumor markers are selected based on a particular tumor. For example, an elevated CA 27.29 is more typical of breast cancer. I would agree that this patient’s tumor marker profile is certainly consistent with ovarian cancer.

Dr Love: Edith, have you ever heard of a CA.125 as high as 20,000 U/mL in breast cancer? Dr Perez: No, I haven’t.

Dr Brooks: I do markers on all my breast cancer patients, specifically CA 27.29, but inadvertently some patients are also tested for CA.125. I don’t think I’ve ever seen results in the range of 20,000 U/mL, but I have seen results in the thousands. I know it’s anecdotal and totally random, but I’ve ended up with these high numbers in my metastatic breast cancer patients, ordered sonograms of ovaries and everything else, but it turns out to be breast cancer.

Dr Aks: The lack of fidelity of these tumor markers is a genuine issue. I certainly see markedly elevated levels of CA.125 in patients with non-small cell lung carcinoma. This particular patient could have colon cancer with carcinomatosis. You definitely have to go after some tissue and do a full characterization.

Dr Pillai: I’m old fashioned in that I still try to make the diagnosis at the bedside. My clinical impression was that this patient had ovarian cancer because of the pleural effusion, negative disease in the liver, and the fact that 11 years had passed since her breast cancer diagnosis. However, I did not want to treat her without a tissue diagnosis, and I felt the easiest way to obtain tissue was a thoracentesis. The results showed a poorly differentiated carcinoma, probably an adenocarcinoma, but the pathologists couldn’t say whether it was from the breast or ovary.

Dr Perez: In a case like this, I would take the CT scans to the radiologist and request a pleural biopsy. To make a diagnosis by cytology alone is very difficult. It may be easier with a core biopsy.

Dr Robert: There’s a breast cystic protein stain that could be performed on the primary tumor and then the fluid to see if it’s positive, but I don’t know if I’d hang my hat on it. I think the biggest mistake we can make in a case like this is to assume the patient has recurrent breast cancer because of her history, and miss a diagnosis. Where I was trained, we were instructed “if there’s an issue, get some tissue.” My initial impression is that this woman has ovarian carcinoma, but we have to establish a tissue diagnosis. She could have pseudo-Meig’s syndrome, which is malignant pleural effusion associated with ovarian carcinoma. The bottom line is you need to get some tissue.

Dr Aks: If the retroperitonial lymphadenopathy is accessible by CT scan, a fine needle aspiration may be possible for diagnosis.

Dr Harth: The strong suspicion is that this patient has ovarian cancer. The next approach would be to enter her abdomen in some manner to establish a tissue diagnosis, but I don’t know whether a laparoscopy would be realistic with such ascites. Therefore, I think we would have to treat her assuming she has ovarian cancer.

Dr Brooks: This patient has a large uterus, and they can’t see the ovaries. I think if she has a gynecologic malignancy, it’s more likely to be endometrial cancer.

Dr Cohen: I’d do a PET scan to see if you can identify the ovaries. That would help you decide whether you needed to perform a laparotomy.

Dr Wilson: I, too, am in favor of obtaining more tissue. I would recommend approaching a gynecologic oncologist with this case and discussing the idea of doing a laparoscopic procedure with the intent of obtaining more tissue. Then, if ovarian cancer is confirmed, debulking could take place as well.

Dr Pillai: My differential diagnoses for this patient included ovarian cancer and metastatic breast cancer. If it was ovarian cancer, it was Stage IV and she was quite symptomatic. I didn’t think she would be able to go through a laparotomy. I decided to treat her with a regimen that would work for both breast and ovarian cancer and then consider interval debulking. I gave her three cycles of paclitaxel, 175 mg/m2 over three hours, and carboplatin at an AUC of six — standard doses for ovarian cancer.

The patient had an excellent clinical response. The pleural effusion and ascites disappeared; the CA.125 dropped to the 500 to 600 U/mL range; the CA 27.29 dropped about 50 percent; and the CT of the abdomen and pelvis were normal, except for a smaller but still bulky uterus. At that point, the gynecologic oncologist consult recommended continuing chemotherapy. The patient received three more courses and developed some neuropathy. At the completion of treatment, the only evidence of disease was a CA.125 of 197 U/mL.

Dr Argawal: This is the kind of response you see in ovarian cancer.

Dr Perez: This is the kind of response we see with paclitaxel and carboplatin in breast cancer as well (Table 9), and while it’s great for the patient, it doesn’t help us in our differential diagnosis. If she’s tolerating the treatment, I would continue therapy.

Dr Robert: If you assume this is a metastatic adenocarcinoma, you can give her carboplatin and a taxane to “cover the waterfront.” But if she really has an ovarian cancer, the procedure that most gynecologic oncologists recommend is to debulk the patient. That means not only a laparoscopy but a laparotomy. You can’t just treat her broadly with chemotherapy. You still need to know with what you are dealing. When patients are too sick for surgery, the gynecological oncologists will recommend starting chemotherapy and will want to see the patients later. If she has a great response, a laparotomy and debulking procedure can be done after treatment.

Dr Aks: If you obtain additional tissue and it shows a poorly differentiated carcinoma or adenocarcinoma, then the primary site is still unknown. If she has good organ function and performance status, you could fall back on the so-called Vanderbilt regimen, which incorporates paclitaxel, carboplatin and etoposide and covers all the bases.

Dr Firstenberg: I would be interested in seeing whether she has either ovarian cancer or an extraovarian papillary carcinomatosis. I am a principal investigator for a CA.125 antibody trial for which she would be eligible after she goes into remission.

Dr Pillai: After the chemotherapy, a hysterectomy and bilateral salpingo-oophorectomy revealed microscopic residual breast cancer in the uterus, ovaries and fallopian tubes. The hormone receptors were positive. I believe it’s the same breast cancer, but I think the methodology for testing has changed.

Dr Perez: The problem of discordance in hormone receptors between a primary and metastatic site is not uncommon. A presentation at ASCO addressed this and reported a discordance rate of almost 25 percent. In our practice, it’s becoming increasingly common to obtain biopsies when patients develop metastatic disease and re-test the hormone status. We do this not only because we’re interested in hormone receptors, but also to test the tumors for HER2.

Just this week I saw a similar case of a 47-year-old patient who had breast cancer nine years ago. Originally the tumor was ER/PR-negative. When it recurred in the pleural fluid, it was ER-positive. She was then treated with an aromatase inhibitor and the disease was controlled for one year. Now she has progressive disease, and we’ll perform another biopsy in order to help us decide how best to treat her today.

Dr Robert: When Dr Pillai’s patient was diagnosed 14 years ago, she might have had a charcoal ligand method used to assess her hormone receptor status. This older method was associated with a false-negative rate, especially in premenopausal women, because they were only looking at unoccupied receptors. The tip-off was that sometimes you would get ER-negative, PR-positive phenotypes. If an immunohistochemistry had been done on the original blocks, it might have been positive rather than negative. Dr Perez’s example, on the other hand, is a bit more recent, and it might have been tested by immunohistochemistry the first time around.

Dr Perez: At this point, I would treat this patient with an aromatase inhibitor rather than tamoxifen in view of the improved response rate and, in at least one trial, survival, when compared in the metastatic setting. She has already experienced toxicity from chemotherapy. It would be easier to maintain her quality of life with a hormonal therapy than further chemotherapy.

Dr Robert: I would do the same, and I would use either letrozole or anastrozole. This is a great case in which the physician treated the patient wisely, and he continued to ask questions that led to better outcomes for the patient. Now we have the opportunity to stop chemotherapy because we know she’s receptor-positive. I agree that the aromatase inhibitors would be a better choice than tamoxifen, but if she progresses, a number of hormonal alternatives can be tried. When necessary, she can be switched from a nonsteroidal aromatase inhibitor to a steroidal aromatase inhibitor, tamoxifen, fulvestrant, high-dose estrogens, or androgens.

Dr Pillai: At the time of surgery, the patient was 60 years old, her performance status was excellent and she had good family support. I gave her only six courses of chemotherapy preoperatively and was able to do so within a period of about four months. She still had an elevated CA.125 of 197 U/mL, so I felt that I should give her more chemotherapy. I did not want to use a taxane because of the peripheral neuropathy. I had previously given her doxorubicin, up to 400 mg/m2, so I was concerned about cardiac toxicity.

I elected to treat her with a protocol first published by Dr Hainsworth from Vanderbilt called the NFL regimen, which is a combination of mitoxantrone, 5-FU and leucovorin. It’s an easy protocol to use, and it doesn’t cause alopecia or peripheral neuropathy. Myelosuppression is a little more than what you see with a paclitaxel-based combination. After I gave her six courses, her CA.125 was normal. I then started her on tamoxifen.

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