Chemo+endocrine, endocrine + endocrine

[Rich66]

Clin Breast Cancer. 2010 Aug 1;10(4):313-7.
Exemestane and Chemotherapy as First-line Treatment of Metastatic Breast Cancer: Results of a Phase II Study.

de la Haba-Rodriguez J, Mancha RG, Manga GP, Aguilar EA, Baena Cañada JM, Rovira PS, Conejo EA.
Hospital Reina SofÃ*a, Córdoba, Spain.
Abstract

Background: Metastatic breast cancer remains largely incurable. Strategies involving the combination of the selective estrogen receptor modulator tamoxifen and chemotherapy have been abandoned in view of unacceptable toxicity because of thromboembolic events. The aim of this study was to investigate the safety and efficacy of the third-generation steroidal aromatase inhibitor exemestane plus chemotherapy. Patients and Methods: Postmenopausal women with advanced breast cancer received 6 cycles of intravenous chemotherapy (5-fluorouracil [5-FU], epirubicin, and cyclophosphamide) and exemestane 25 mg/day that was continued after chemotherapy was completed. The primary efficacy endpoint was time to progression (TTP), and response rates were also assessed. Safety was assessed from adverse events. Results: Twenty-three patients (median age, 62 years) were included in this study. Twenty patients completed 6 chemotherapy cycles. Median TTP was 13.7 months. Overall response was achieved by 20 patients (73.9%), and the clinical benefit rate was 87%. During the chemotherapy plus exemestane treatments, 50 adverse events were reported in 14 of the 23 patients (60.9%). As expected, the incidence of adverse events decreased during the phase of exemestane treatment alone (19 adverse events in 10 of 20 patients [50%]). There were 2 grade 4 events reported, pulmonary embolism and pneumonia, although pneumonia was not considered to be related. Conclusion: Although a small number of patients were included, the combination of exemestane and chemotherapy was well tolerated and only 1 thromboembolic event was reported. Response rates were similar to other comparable series and may encourage further studies to confirm the efficacy of chemotherapy in combination with an aromatase inhibitor.

PMID: 20705565 [PubMed - in process]

-----------------------------------------------

Endocrine+Endocrine

Fulvestrant (F) and letrozole (L) combination in second-line or more for estrogen receptor (ER)-positive (+) metastatic breast cancer (MBC): Efficacy and predictive factors of response. Sub-category: ER+ Category: Breast Cancer - HER2/ER Meeting: 2011 ASCO Annual Meeting Abstract No: e11137 Citation: J Clin Oncol 29: 2011 (suppl; abstr e11137)

Publication-only abstracts (abstract number preceded by an "e"), published in conjunction with the 2011 Annual Meeting but not presented at the Meeting, can be found online only. The publication-only abstracts are not included in the print or USB versions of the ASCO Annual Meeting Proceedings Part I, but they are citable to the Journal of Clinical Oncology as a supplement (see citation on left).

Author(s): A. M. Obermiller, M. S. Copur, M. Bolton, R. C. Ramaekers, R. Hays, D. Nelson, H. Benzel, M. Mickey, M. Norvell, J. Olsen, M. Tharnish, B. Luebbe, S. Schneider, S. Woodward, B. Keenportz, S. Frankforter, L. Mlinar; Saint Francis Cancer Treatment Center, Grand Island, NE; St. Francis Medical Center, Grand Island, NE; University of Nebraska Medical Center, Grand Island, NE; Grand Island Surgery Group, Grand Island, NE; Surgery Group of Grand Island, Grand Island, NE; Saint Francis Medical Center, Grand Island, NE

Abstract Disclosures

Abstract:
Background: Preclinical data show that complete estrogen blockade, by down regulating ER and inhibiting estrogen synthesis, has greater effect on tumor growth than either treatment alone. Combination of an aromatase inhibitor (AI) and F may be an optimal second-line therapy by preventing activation of growth factor pathways and possible cross talk with ER. One clinical study has shown no benefit of adding anastrozole (A) to F at first relapse. No clinical data on combination L and F in the second line or more MBC is available. Methods: ER+, progesterone receptor(PgR) + or negative (-) MBC patients (pts) with prior chemo and/or non-AI endocrine(E) therapy were treated with L and F. Pts with complete/partial response, or stable disease were considered to have clinical benefit (CR+PR+SD). The predictive effect of age, number of prior regimens, ER/PgR status, and lobular histology were examined using Chi-square test. Results: 32 pts received L (2.5 mg/d po) plus F (250 mg/month, im). Mean age was 70 (Range: 35-92), median number of prior treatments was 2 (range1-6). 25 pts had ER+/PgR+, 7 pts had ER+/PgR- tumors. 25 pts had prior non-AI E therapy. 8 pts had lobular histology. Overall clinical benefit rate was 71% (3 CR, 7 PR, 13 SD). Mean duration of the clinical benefit was 15 months (range 2-38). 8 pts progressed under therapy. Age > 65 vs younger (89% vs 46%, p=0.007), prior treatments< 4 vs more (87% vs 25%, p=0.0007) and ER+/PgR+ vs ER+/PgR- (84% vs 42%, p<0.05) were predictive of clinical benefit; lobular histology and prior E therapy did not have any effect on clinical benefit (p>0.05). Conclusions: In pretreated MBC, combination of L and F can be effective with mean clinical benefit duration of 15 months. Older age, < 4 prior lines of therapy, and expression of both ER/PgR are predictive of clinical benefit while lobular histology and prior E therapy are not. L and F combination can be a reasonable option in selected group of MBC pts and should be further evaluated in larger studies using high dose F schedule.


Gathered info:
Researchers note that efficacy may be even better with new higher dose Fulvestrant (500mg/mo) and that the combination of Fulvestrant and AIs is safe and worth trying. And since steroidal exemestane (Aromasin) is thought to often work after failed non-steroidal AIs (Arimidex, Femara), combining fulvestrant with Exemestane after other AIs may be especially worthwhile.


Breast Cancer Res Treat. 2011 Jul 27. [Epub ahead of print]
A phase II neoadjuvant trial of anastrozole, fulvestrant, and gefitinib in patients with newly diagnosed estrogen receptor positive breast cancer.

Massarweh S, Tham YL, Huang J, Sexton K, Weiss H, Tsimelzon A, Beyer A, Rimawi M, Cai WY, Hilsenbeck S, Fuqua S, Elledge R.
Source

The Department of Internal Medicine, University of Kentucky, Lexington, KY, 40536, USA, massarweh@uky.edu.


LINK


Abstract

Endocrine therapy in patients with breast cancer can be limited by the problem of resistance. Preclinical studies suggest that complete blockade of the estrogen receptor (ER) combined with inhibition of the epidermal growth factor receptor can overcome endocrine resistance. We tested this hypothesis in a phase II neoadjuvant trial of anastrozole and fulvestrant combined with gefitinib in postmenopausal women with newly diagnosed ER-positive breast cancer. After a baseline tumor core biopsy, patients were randomized to receive anastrozole and fulvestrant or anastrozole, fulvestrant, and gefitinib (AFG) for 3 weeks. After a second biopsy at 3 weeks, all patients received AFG for 4 months and surgery was done if the tumor was operable. The primary endpoint was best clinical response by RECIST criteria and secondary endpoints were toxicity and change in biomarkers. The study closed after 15 patients were enrolled because of slow accrual. Median patient age was 67 years and median clinical tumor size was 7 cm. Four patients had metastatic disease present. Three patients withdrew before response was assessed. In the remaining 12 patients, there were two complete clinical responses (17%), three partial responses (25%), five had stable disease (41%), and two (17%) had progressive disease. Most common adverse events were rash in four patients, diarrhea in four, joint symptoms in three, and abnormal liver function tests in three. There were no grade 4 toxicities and all toxicities were reversible. At 3 weeks, cell proliferation as measured by Ki-67 was significantly reduced in the AFG group (P value = 0.01), with a parallel reduction in the expression of the Cyclin D1 (P value = 0.02). RNA microarray data showed a corresponding decrease in the expression of cell cycle genes. These results suggest that AFG was an effective neoadjuvant therapy and consistently reduced proliferation in ER-positive tumors.

PMID:

21792626

[PubMed - as supplied by publisher]

Cancer Res. 2005 Jun 15;65(12):5439-44.
Additive antitumor effect of aromatase inhibitor letrozole and antiestrogen fulvestrant in a postmenopausal breast cancer model.

Jelovac D, Macedo L, Goloubeva OG, Handratta V, Brodie AM.
Department of Pharmacology and Experimental Therapeutics, School of Medicine, University of Maryland, Baltimore, Maryland, USA.



Blocking estrogen receptors with antiestrogens and blocking estrogen synthesis with aromatase inhibitors are two strategies currently being used for reducing the effect of estrogen in postmenopausal estrogen receptor-positive breast cancer patients. To optimize these treatment strategies, we have investigated whether tumor progression can be delayed by combining the pure antiestrogen fulvestrant with the nonsteroidal aromatase inhibitor letrozole. These studies were done in ovariectomized, athymic mice bearing tumors of estrogen receptor-positive human breast cancer cells stably transfected with the aromatase gene (MCF-7Ca). Groups of mice with equivalent tumor volumes were injected s.c. daily with vehicle (control; n = 6), fulvestrant (1 mg/d; n = 7), letrozole (10 microg/d; n = 18), or letrozole (10 microg/d) plus fulvestrant (1 mg/d; n = 5). All treatments were effective in suppressing tumor growth compared with controls (P < 0.001). Tumor volumes of the fulvestrant-treated group had doubled in 10 weeks. After 19 weeks of letrozole (10 microg/d) treatment when tumors had nearly doubled in volume, mice (n = 18) were assigned to second-line therapy with letrozole (100 microg/d; n = 6), tamoxifen (100 microg/d; n = 6), or remained on letrozole treatment (10 microg/d; n = 6). However, tumors continued to increase in volume in these groups. Tumors of animals treated with the combination of letrozole plus Faslodex regressed over 29 weeks of treatment by 45%. Thus, the combination of letrozole plus fulvestrant was more effective in suppressing tumor growth than either letrozole or fulvestrant alone or sequential therapies with tamoxifen or a higher dose of letrozole (100 microg/d).


11/09 researcher off the record:
"I think it is not clear from the current clinical tirals. There appears to be no difference between anatsrozole and anastrozole + fulvestrant in the trials so far. It may be that with more time there will be a difference."



http://clinicaltrials.gov/ct2/show/NCT00570323

Arimidex With or Without Faslodex In Postmenopausal Women With HR Positive Breast Cancer (PACT 001)
This study is currently recruiting participants.
Verified by Baylor Breast Care Center, August 2009
First Received: December 6, 2007 Last Updated: August 3, 2009 History of Changes

Sponsor:	Baylor Breast Care Center
Collaborator:	AstraZeneca
Information provided by:	Baylor Breast Care Center
ClinicalTrials.gov Identifier:	NCT00570323

Purpose Over the last 3 decades, a steady shift has occurred in the management of breast cancer. Because it was traditionally viewed as a local disease, many advocated the use of radical surgery to achieve maximum survival benefit. This view has been slowly replaced by a broader biologic view that recognizes the often systemic nature of breast cancer, even when it appears to be localized to the breast. Results from randomized clinical trials have demonstrated that less extensive surgery, or lumpectomy plus radiation therapy, are optimal for local management of early breast cancer. In addition to the less radical approach to surgical treatment of breast cancer, other randomized clinical trials have established the value of postoperative systemic therapy in improving overall survival by eradicating micrometastatic disease, the major cause of mortality from breast cancer. Despite the well-documented benefits of adjuvant systemic therapy, it is not effective in preventing death from breast cancer in all patients who are candidates for such treatment. The worth of such therapy can only be judged in retrospect upon disease relapse, a time when breast cancer is nearly always incurable. Currently, there are few reliable methods to predict the success or failure of a particular postoperative treatment modality, and better ways to predict and optimize outcome are needed.
Combination endocrine therapy: Using endocrine agents with different mechanisms of action together has the potential advantage of more effectively blocking ER signaling, thus improving the efficacy of such agents against breast cancer. In the past, attempts to combine endocrine agents for ER-positive breast cancer have had mixed results, depending on the setting and the patient population studied.
Endocrine agents without any agonist effect could potentially be used in combination with aromatase inhibitors, under the rationale that the combination would maximally blockade estrogen receptor signaling, thus potentially improving the antitumor effect. Fulvestrant (FASLODEX) is a pure estrogen antagonist with no known agonist effect; thus, it has the potential to provide additional benefit when combined with an aromatase inhibitor. This concept provides the rationale for using the combination of anastrazole and fulvestrant in this study.

Condition	Intervention	Phase
Breast Cancer	Drug: Arimidex with Faslodex Drug: Arimidex without Faslodex	Phase II

Tumori. 2009 Nov-Dec;95(6):804-7.
Inhibition of HER2/estrogen receptor cross-talk, probable relation to prolonged remission of stage IV breast cancer: a case report.

Tisman G.
Whittier Cancer Research Building, 13025 Bailey Street, Suite A, Whittier, CA 90601, USA. glennmd@gmail.com
Metastatic breast cancer to the liver is considered incurable. Though many patients with liver metastases may enjoy response to chemo-, immuno- and hormonal therapy, those so inflicted rarely remain disease-free from the time of diagnosis for longer than 6-11 months. New laboratory and clinical research identified that cross-talk between activation of the epidermal growth factor family of tyrosine kinase transduction pathways (EGF/HER2) and estrogen receptor (ER) activation plays a role in resistance to hormonal therapy. A 59-year-old woman with a 4.5-cm invasive ductal, ER-positive/PR-negative, grade III adenocarcinoma of the breast was treated with mastectomy. Staging revealed biopsy-proven liver metastases. Surgery was immediately followed with vinorelbine, trastuzumab, tamoxifen and exemestane. The patient underwent a bone scan and PET/CT documented complete remission. She has remained in complete remission for 7 years. It is proposed that a possible mechanism for prolonged remission of stage IV breast cancer in this patient may be related to suppression of EGF/HER2 by trastuzumab, thus inhibiting cross-talk-associated tamoxifen/estrogen withdrawal resistance.

PMID: 20210247 [PubMed - in process]

Tamoxifen and exemestane were started after discontinuation of vinorelbine after only 6 weeks of therapy due to a vinorelbine-induced rash. Complete clinical response was confirmed after 2 months from the start of therapy. The patient has remained free of disease for 7 years and receives trastuzumab 6 mg/kg every 6 weeks, tamoxifen 20 mg daily, and exemestane 25 mg daily.

The ATAC study reported less than optimal activity for the combination of tamoxifen and anastrozole when compared to the AI alone20. It was decided, however, to continue this patient on the combination of tamoxifen plus AI because of the early success of therapy.

It is conjectured that this patient’s prolonged complete remission of 7+ years may represent the result of inhibition of EGFR/HER2-ER cross-talk, thus prolonging benefit from hormonal therapy. However, it is also possible – though less likely – that the independent effects of trastuzumab, tamoxifen and exemestane inhibition of tumor growth is responsible as well.

Maybe the interaction is different between Tam+Anastrazole vs TAM+Exemestane:

Clin Cancer Res. 2005 Dec 15;11(24 Pt 1):8722-7.
Effect of exemestane on tamoxifen pharmacokinetics in postmenopausal women treated for breast cancer.

Hutson PR, Love RR, Havighurst TC, Rogers E, Cleary JF.
School of Pharmacy, University of Wisconsin, Madison, Wisconsin 53705-2222, USA. prhutson@pharmacy.wisc.edu
PURPOSE: Rodent models of human breast cancer suggest that the combination of the steroidal aromatase inhibitor exemestane with tamoxifen may have additive activity. Clinical trials combining tamoxifen with letrozole or anastrazole have shown minor pharmacokinetic drug interactions. We did an open-label crossover clinical trial of the effect of exemestane on tamoxifen pharmacokinetics. DESIGN: Thirty-two postmenopausal women who were clinically disease-free following primary treatments for breast cancer receiving tamoxifen for at least 3 months were studied. Blood was collected for pharmacokinetic analysis after at least 4 months of receiving 20 mg tamoxifen daily. Subjects then began 8 weeks of oral exemestane (25 mg daily), followed by another set of blood samples. RESULTS: There were no serious toxicities noted when the two drugs were combined. There was no significant effect of exemestane on the area under the plasma concentration versus time curve (AUC) of tamoxifen at steady state before [3.04 mg h/L; 90% confidence interval (90% CI), 2.71-3.44] and during exemestane treatment (3.05 mg h/L; 90% CI, 2.72-3.41). There were no significant changes in the formation of primary tamoxifen metabolites. Oral clearance of exemestane averaged 602 L/h based on an average plasma exemestane AUC of 41.5 microg h/L (90% CI, 36.7-62.6). Plasma concentrations of estradiol, estrone, and estrone sulfate decreased when exemestane was begun; estradiol concentrations consistently decreased below the limit of quantitation. CONCLUSIONS: There is no pharmacokinetic interaction between tamoxifen and exemestane. No modification in the standard regimen of either drug seems to be indicated if they are used in combination. The combination of the two drugs was well tolerated during the 8-week evaluation period.

PMID: 16361559 [PubMed - indexed for MEDLINE]

[gdpawel]

Existing genomic tests for breast cancer provide information about future risk in general, but not the likely benefit of each treatment option separate from a patient's overall prognosis if no treatment followed surgery.

It is important to independently assess each predictor - prognosis, of sensitivity to chemotherapy and sensitivity to hormone therapy. It is important to know the sensitivity of the cancer to chemo- or endocrine therapies independent of the risk of recurrence alone.

The Microarray (gene chips), a device that measures differences in gene sequence, gene expression or protein expression in biological samples. Microarrays may be used to compare gene or protein expression under different conditions, such as cells found in cancer.

Hence the headlong rush to develop tests to identify molecular predisposing mechansims whose presence still does not guarantee that a drug will be effective for an individual patient. Nor can they, for any patient or even large group of patients, discriminate the potential for clinical activity among different agents of the same class.

Genetic profiles are able to help doctors determine which patients will probably develop cancer, and those who will most likely relapse. However, it cannot be suitable for specific treatments for individual patients.

In the new paradigm of requiring a companion diagnostic as a condition for approval of new targeted therapies, the pressure is so great that the companion diagnostics they’ve approved often have been mostly or totally ineffective at identifying clinical responders (durable and otherwise) to the various therapies.

Cancer cells often have many mutations in many different pathways, so even if one route is shut down by a targeted treatment, the cancer cell may be able to use other routes. Targeting one pathway may not be as effective as targeting multiple pathways in a cancer cell.

Another challenge is to identify for which patients the targeted treatment will be effective. Tumors can become resistant to a targeted treatment, or the drug no longer works, even if it has previously been effective in shrinking a tumor. Drugs are combined with existing ones to target the tumor more effectively. Most cancers cannot be effectively treated with targeted drugs alone. Understanding “targeted� treatments begins with understanding the cancer cell.

If you find one or more implicated genes in a patient's tumor cells, how do you know if they are functional (is the encoded protein actually produced)? If the protein is produced, is it functional? If the protein is functional, how is it interacting with other functional proteins in the cell?

All cells exist in a state of dynamic tension in which several internal and external forces work with and against each other. Just detecting an amplified or deleted gene won't tell you anything about protein interactions. Are you sure that you've identified every single gene that might influence sensitivity or resistance to a certain class of drug?

Assuming you resolve all of the preceeding issues, you'll never be able to distinguish between susceptibility of the cell to different drugs in the same class. Nor can you tell anything about susceptibility to drug combinations. And what about external facts such as drug uptake into the cell?

Gene profiling tests, important in order to identify new therapeutic targets and thereby to develop useful drugs, are still years away from working successfully in predicting treatment response for individual patients. Perhaps this is because they are performed on dead, preserved cells that were never actually exposed to the drugs whose activity they are trying to assess.

It will never be as effective as the cell "function" method, which exists today and is not hampered by the problems associated with gene expression tests. That is because they measure the net effect of all processes within the cancer, acting with and against each other in real time, and it tests living cells actually exposed to drugs and drug combinations of interest.

It would be more advantageous to sort out what's the best "profile" in terms of which patients benefit from this drug or that drug. Can they be combined? What's the proper way to work with all the new drugs? If a drug works extremely well for a certain percentage of cancer patients, identify which ones and "personalize" their treatment. If one drug or another is working for some patients then obviously there are others who would also benefit. But, what's good for the group (population studies) may not be good for the individual.

Patients would certainly have a better chance of success had their cancer been chemo-sensitive rather than chemo-resistant, where it is more apparent that chemotherapy improves the survival of patients, and where identifying the most effective chemotherapy would be more likely to improve survival above that achieved with "best guess" empiric chemotherapy through clinical trials.

It may be very important to zero in on different genes and proteins. However, when actually taking the "targeted" drugs, do the drugs even enter the cancer cell? Once entered, does it immediately get metabolized or pumped out, or does it accumulate? In other words, will it work for every patient?

All the validations of this gene or that protein provides us with a variety of sophisticated techniques to provide new insights into the tumorigenic process, but if the "targeted" drug either won't "get in" in the first place or if it gets pumped out/extruded or if it gets immediately metabolized inside the cell, it just isn't going to work.

To overcome the problems of heterogeneity in cancer and prevent rapid cellular adaptation, oncologists are able to tailor chemotherapy in individual patients. This can be done by testing "live" tumor cells to see if they are susceptible to particular drugs, before giving them to the patient. DNA microarray work will prove to be highly complementary to the parellel breakthrough efforts in targeted therapy through cell function analysis.

As we enter the era of "personalized" medicine, it is time to take a fresh look at how we evaluate new medicines and treatments for cancer. More emphasis should be put on matching treatment to the patient, through the use of individualized pre-testing.

Upgrading clinical therapy by using drug sensitivity assays measuring "cell death" of three dimensional microclusters of "live" fresh tumor cell, can improve the situation by allowing more drugs to be considered. The more drug types there are in the selective arsenal, the more likely the system is to prove beneficial.

Literature Citation: Eur J Clin Invest 37 (suppl. 1):60, 2007