WO2010014249A1

WO2010014249A1 - Cancer therapy comprising estrogen inhibitors

Info

Publication number: WO2010014249A1
Application number: PCT/US2009/004423
Authority: WO
Inventors: Jack Singer
Original assignee: Cell Therapeutics, Inc.
Priority date: 2008-08-01
Filing date: 2009-07-31
Publication date: 2010-02-04

Abstract

Disclosed are methods for treating various types of cancers in males and females, comprising the determination of plasma or serum levels of estrogen prior to selecting the cancer therapy, followed by the administration of estrogen inhibitors.

Description

CANCER THERAPY COMPRISING ESTROGEN INHIBITORS CROSS-REFERENCE TO RELATED APPLICATION

This application claims the benefit of the filing date of United States Provisional Patent Application No. 61/137,675 filed 08/01/08, the disclosure of which is hereby incorporated herein by reference. BACKGROUND OF THE INVENTION

[0001] Hormones can have an impact on cancer development and growth. Certain cancers are sensitive to hormones and hormone therapy may prove beneficial to overall cancer treatment . Other cancers may display hormone receptors and their growth may be exacerbated by the presence of specific hormones. Therefore, it is not surprising that the hormone sensitivities of certain cancers are taken into account when planning a cancer therapy regimen. SUMMARY OF THE INVENTION

[0002] A first aspect of the present invention is directed to a method of treating a patient, diagnosed with a cancer, comprising determining the serum or plasma level of endogenous estrogen, and selecting a cancer regimen based on that endogenous estrogen level. When the serum or plasma endogenous estrogen level is about 25 pg/ml or greater, the patient is treated with a cancer regimen comprising the administration of a paclitaxel drug, followed by the administration of an estrogen inhibitor.

[0003] Some cancer patients do not have serum or plasma endogenous estrogen levels of about 25 pg/ml or greater, nor are they on a hormone replacement therapy at the time of the cancer diagnosis. Thus, a second aspect of the invention is directed to a method of treating a patient, diagnosed with a cancer, comprising determining the serum or plasma level of endogenous estrogen, and selecting a cancer regimen based on that endogenous estrogen level . When the serum or plasma endogenous estrogen level is less than 25 pg/ml, the patient is provided with a cancer regimen comprising the administration of a paclitaxel drug and hormone replacement therapy, followed by the cessation of the hormone replacement therapy and the administration of an estrogen inhibitor. [0004] Likewise, some cancer patients do not have serum or plasma endogenous estrogen levels of about 25 pg/ml or greater, but do have such levels due to any number of hormone replacement therapies. Thus, a third aspect of the present invention is directed to a method of treating a patient, diagnosed with a cancer and taking hormone replacement therapy, comprising determining the serum or plasma level of estrogen, and selecting a cancer regimen based on that estrogen level. When the serum or plasma estrogen level is about 25 pg/ml or greater, the patient is provided with a cancer regimen comprising the administration of a paclitaxel drug, followed by the administration of an estrogen inhibitor. [0005] While not intending to be bound by any particular theory of operation, Applicant believes that the presence of estrogen (i.e., endogenous or exogenously supplied estrogen therapy) enhances the efficacy of conjugated paclitaxel by increasing the amount of paclitaxel delivered to the cancerous tissue (e.g., tumor). On the other hand, presence of estrogen after treatment with conjugated paclitaxel might exacerbate the cancer growth, thereby negating the initial positive effect of conjugated paclitaxel. DETAILED DESCRIPTION

[0006] The present invention is directed to a method of treating a patient, diagnosed with a cancer, comprising determining the serum or plasma level of endogenous estrogen, and selecting a cancer regimen based on that endogenous estrogen level. It is envisioned that the invention will encompass at least three patient populations: (1) patients diagnosed with cancer and possessing a serum or plasma endogenous estrogen level of about 25 pg/ml or greater (2) patient, diagnosed with cancer and possessing a serum or plasma endogenous estrogen level less than 25 pg/ml,- and

(3) patient, diagnosed with cancer, and who are on hormone replacement therapy resulting in a serum or plasma estrogen level of about 25 pg/ml or greater.

[0007] Thus, a first aspect of the present invention encompasses selecting a cancer treatment regimen based on a serum or plasma endogenous estrogen level of about 25 pg/ml or greater, wherein the regimen comprises the administration of a paclitaxel conjugate, followed by treatment with an estrogen inhibitor.

[0008] Although it is envisioned that the invention will be useful for all types of cancer, it is especially useful for estrogen receptor-bearing cancers. As used herein, the term "estrogen receptor-bearing cancer" refers to any cancer, tumor-forming or otherwise, (e.g., hematopoietic cancers such as leukemia) characterized by the presence of cancer cells bearing estrogen receptors, or a cancer that originates in an organ or tissue containing normal (non-diseased) cells that bear estrogen receptors . The estrogen receptor may be transiently expressed and/or the estrogen receptor-bearing cells may represent a fraction of the total population of cells (cancer cells or non-diseased cells). Thus, not all the cells associated with a particular cancer, or in the originating tissue, will necessarily have estrogen receptors nor will the cancer cells always express estrogen receptors over the course of disease progression (nor will the normal cells in the originating tissue express estrogen receptors over their entire lifetime) . There are two forms of estrogen receptors, namely α- and β-receptors. The prevalence of either receptor on cancer cells may be related to the particular type of cancer and/or a particular stage of progression of the cancer. Thus, the cancer cells may express each form at different times during progression of the disease. See, Leav, et al . , Am. J. Path. 159:79-92 (2001). Estrogen receptor β bearing cancers include, but are not limited to, non-small cell lung cancer, breast cancer, ovarian cancer, uterine epithelial cancer and sarcomas, colon cancer, glioma, prostate cancer, testicular cancers, and melanoma. For this application, estrogen β receptors are of particular interest as they are the only functional receptors expressed in lung tissues and in non-small cell lung cancer and in prostate and colorectal cancers. See Patrone et al . , MoI. Cell. Bio. 23:8542-8552 (2003).

[0009] As used herein, the term "endogenous estrogen level" refers to the naturally occurring estrogen level, as measured in serum or plasma, i.e., the patient's estrogen level is not predicated on or influenced by additional treatments such as hormone replacement therapy. Thus, the endogenous estrogen level as defined herein, is in contrast to estrogen levels based on a hormone replacement therapy. Endogenous estrogen levels of about 25 pg/ml or greater are typically found, for example in premenopausal women. In such women, the vast majority of estrogen is produced by the ovaries. [0010] In postmenopausal women and men, estrogen is produced predominantly by the conversion of androgens by the enzyme known as aromatase. This enzyme may be highly expressed and active in many epithelial cancers and result in high estradiol levels in post menopausal women and in men. [0011] In general, estrogen levels can be measured, either directly or indirectly, in blood serum or plasma utilizing a variety of assays such as an enzyme linked immunosorbent assay (ELISA) or a Western blot analysis . In an exemplary embodiment, estrogen levels are calculated by measuring 17β estradiol levels in serum utilizing an ELISA kit such as the Estradiol ELISA Kit (RDI Division of Fitzgerald Industries

Intl., Concord, MA). [0012] As used herein, the term "serum or plasma level of estrogen" refers to estrogen levels, measured in blood serum or plasma, wherein the levels are measured either directly or indirectly as previously described.

[0013] The invention contemplates using blood serum or plasma that is obtained from whole blood, and may contain additional components such as anticoagulants and preservatives, that are added prior to, at the time of, or after blood collection. Whole blood may be obtained by any medically approved method including, but not limited to venipuncture. Methods for obtaining serum or plasma from whole blood are well known in the art and will not be further discussed herein.

[0014] As stated, the invention provides that patients diagnosed with cancer and presenting with a serum or plasma estrogen level of about 25 pg/ml or greater are administered cancer therapy comprising or including a conjugated paclitaxel. As used herein, the terms "paclitaxel drug conjugate," "conjugated paclitaxel" and "paclitaxel conjugate" refer to any of the taxol drugs, conjugated to a polymer backbone. In an exemplary embodiment, the polymer backbone is polyglutamate .

[0015] Paclitaxel conjugates are well known in the art. Methods for conjugating paclitaxel to polymer backbones are described in Li et al . , U.S. Patent 6,441,025. Polymer backbones may be synthesized in accordance with several types of standard techniques, including chemical and recombinant processes. For example, a homopolymer of glutamic acid may be prepared in a two-step process, in which (i) glutamic acid is treated with phosgene or an equivalent reagent, e.g., diphosgene, at a temperature of from 15°C to 70⁰C to form an N-carboxyanhydride (NCA) , and (ii) ring-opening polymerization of the N-carboxyanhydride is effected with a base to yield poly- (glutamic acid) . Suitable bases include alkoxides, e.g., alkali metal alkoxides such as sodium methoxide, organometallic compounds and primary, secondary or tertiary amines, for example butylamine or triethylamine . See, U.S. Patent 5,470,510. Additional methods for chemically synthesizing poly(amino acids) are well-known in the art and will not be further described herein.

[0016] The paclitaxel conjugated drugs of the present invention are multiple taxane skeleton molecules while traditional paclitaxel (i.e., unconjugated paclitaxel) is a single taxane skeleton molecule. The amount of drug conjugated to the polymer is variable. At the lower end, the drug polymer conjugate may comprise from about 1%, about 2%, about 3%, about 4%, about 5%, about 6%, about 7%, about 8%, about 9%, about 10%, about 11%, about 12%, about 13%, about 14%, about 15%, about 16%, about 17%, about 18%, about 19%, about 20%, about 21% about 22%, about 23%, about 24%, to about 25% (w/w) of drug relative to the mass of the conjugate. At the high end, the drug-polymer conjugate may comprise from about 26%, about 27%, about 28%, about 29%, about 25%, about 31% about 32%, about 33%, about 34%, about 35%, about 36%, about 37%, about 38%, about 39%, about 40%, to about 50% or more (w/w) of drug relative to the mass of the conjugate.

[0017] Similarly, the number of molecules of drug conjugated per molecule of polymer can vary. At the lower end, the drug-polymer conjugate may comprise from about 1, about 2, about 3, about 4, about 5, about 6, about 7, about 8, about 9, about 10, about 11, about 12, about 13, about 14, about 15, about 16, about 17, about 18, about 19, to about 20 or more molecules of the drug per molecule of polymer. At the higher end, the drug-polymer conjugate may comprise from about 21, about 22, about 23, about 24, about 25, about 26, about 27, about 28, about 29, about 25, about 31, about 32, about 33, about 34, about 35, about 36, about 37, about 38, about 39 , about 40 , about 41 , about 42 , about 43 , about 44 , about 45 , about 46 , about 47 , about 48 , about 49 , about 50 , about 51, about 52 , about 53, about 54, about 55, about 56 , about 57, about 58 , about 59, about 60 about 61, about 62 , about 63, about 64, about 65, about 66, about 67, about 68, about 69, about 70, about 71, about 72, about 73, about 74, to about 75 or more molecules or more of drug per molecule of polymer.

[0018] To provide at least one meaningful comparison between the conjugated and unconjugated paclitaxel drugs, each taxane skeleton molecule in the conjugated drug is calculated as one paclitaxel (i.e., unconjugated paclitaxel) equivalent. [0019] An exemplary paclitaxel conjugate, suitable for use in the present invention is paclitaxel poliglumex (PPX) , which is fully described in U.S. Patent Application Publication No. : 2007/0167349 Al. PPX is paclitaxel conjugated to poly- (1-glutaτnic acid). PPX has an average MW in the range of about 35,000 to about 40,000 Da, but does not exceed 75,000 Da, with about 35% to about 37% weight to weight (w/w) paclitaxel loading.

[0020] In addition to treating with a paclitaxel conjugate, the invention also contemplates the use of two or more drugs, each conjugated to the same type of polymer, as well as mixtures of two or more drugs, each conjugated to a different polymer. In certain embodiments, two or more different drug moieties may be conjugated to a single polymer. The invention also contemplates administration of other cancer drugs (e.g., carboplatin) in addition to the drug conjugate and/or hormone therapy.

[0021] Paclitaxel drug conjugates, including PPX may be delivered or administered by any therapeutically suitable means. For example, administration may be parenteral or oral. In preferred embodiments administration is intravenous. [0022] Compositions include the conjugate and a pharmaceutically acceptable carrier. As used herein, pharmaceutically acceptable carriers include solvents (e.g., buffered aqueous medium), dispersion media, coatings, antibacterial and antifungal agents, isotonicity agents (e.g., glucose) and the like. Pharmaceutical compositions containing the conjugates suitable for intravenous use include sterile aqueous solutions or dispersions, as well as sterile powders that can then be reconstituted in an aqueous solution. The carrier may be a solvent or dispersion medium containing, for example, water, ethanol, a polyol, suitable mixtures thereof, and vegetable oils. Suitable injectable solutions may be prepared by incorporating an appropriate amount of the conjugate into an appropriate solvent, optionally with various other ingredients as listed above. Solutions may be sterilized by filtration. Dispersions may be prepared by incorporating the conjugate into a sterile vehicle containing the dispersion medium and any other ingredients from those listed above. Sterile powders may be prepared by vacuum drying and freeze-drying techniques, yielding a powder of the conjugate and any additional desired ingredients from a previously sterile- filtered solution thereof.

[0023] Pharmaceutical compositions may be delivered or administered in an appropriate dosage and for a suitable duration and frequency. Dose and duration of administration are typically determined by such factors as the condition of the patient, the type and severity of the patient's disease, the particular form of the active ingredient and the method of administration. The appropriate dosage and treatment regimens are designed to achieve a therapeutic benefit (e.g., an improved clinical outcome, such as more frequent complete or partial remissions, or longer disease-free and/or overall survival) . Examples of different ranges of dosage and administration schedules are provided in U.S. Patent 5,670,537 (disclosing dosages and administration schedules for taxol) . [0024] In some embodiments of the invention, patients in need of such treatment receive a drug conjugate such as PPX, on a triweekly, every 4 weeks, or other clinically useful schedule, at dose levels typically used for the particular conjugate involved. To provide a meaningful comparison between multiple taxane skeleton molecule therapies and other single taxane skeleton molecule therapies, the dosing of taxane conjugates can be expressed as "paclitaxel equivalents" . For example, for dosing purposes, each taxane skeleton in a taxane conjugate molecule is calculated as one paclitaxel equivalent. The dose level generally ranges from about 175 to about 250 mg/m² paclitaxel equivalents. In preferred embodiments, patients are treated with PPX in an amount of about 200 to about 250 mg/m² paclitaxel equivalents every 21 days or about once every 3 weeks. In the most preferred embodiment patients are treated with PPX in an amount of about 175 mg/m² paclitaxel equivalent every 21 days or about once every 3 weeks .

[0025] Intravenous infusion may be for any appropriate time period, which is readily determinable by one of ordinary skill in the art. For example, infusions may last for about one to about 24 hours, although shorter or longer infusion times also fall within the scope of the invention.

[0026] The invention also encompasses the administration of an estrogen inhibitor at a point in time after treatment with the paclitaxel conjugate. In general, an estrogen inhibitor is any substance or agent that suppresses, prevents or opposes the action of estrogen. Thus, estrogen inhibitors may act to prevent the production and/or activity of estrogen. Substances that prevent the production of estrogen are well known in the art and include aromatase inhibitors. Likewise, substances that inhibit estrogen activity are well known in the art and include substances such as estrogen receptor antagonists .

[0027] In one exemplary embodiment, administration of the estrogen inhibitor occurs about 7 days to 28 days after cessation of treatment with the paclitaxel conjugate. In another exemplary embodiment, administration of the estrogen inhibitor occurs about 28 days to 90 days after cessation of the paclitaxel conjugate.

[0028] As used herein, the term "estrogen inhibitor" more-specifically refers to any physiological and medically appropriate substance that serves to either decrease serum or plasma estrogen to a level less than 25 pg/ml or to block the effect of estradiol at the estrogen receptor. In an exemplary embodiment, the levels are reduced to about 5 to about 15 pg/ml of serum or plasma. In another exemplary embodiment, the levels are reduced to about 0 to about 5 pg/ml of serum or plasma .

[0029] Estrogen inhibitors suitable for use in the current invention are well known in the art. Examples include inhibitors or inactivators of aromatase such as anastrozole, exemestane and letrozole. These chemicals are often formulated into tablets or pills and are taken orally. In exemplary embodiment, anastrozole is taken as a 1 mg tablet, once a day, beginning about 7 days to about 28 days after cessation of a paclitaxel conjugate, and is continued indefinitely. In another exemplary embodiment, exemestane is taken as a 25 mg tablet, once a day, beginning about 7 days to about 28 days after cessation of a paclitaxel conjugate, and is continued indefinitely. In yet another exemplary embodiment, letrozole is taken as a 2.5 mg tablet, once a day, beginning about 7 days to about 28 days after cessation of a paclitaxel conjugate, and is continued indefinitely. [0030] In another aspect of the invention, the methods are practiced on patients diagnosed with cancer who have endogenous estrogen levels less than 25 pg/ml . In this aspect, the patient is treated with a combination therapy comprising the administration of a paclitaxel as described and the administration of a hormone replacement therapy. [0031] As used herein, the term "hormone replacement therapy" refers to the administration of any physiological or medically appropriate substance that serves to increase serum or plasma estrogen levels to at least about 25 pg/ml. In one exemplary embodiment, the estrogen level is increased to about 25 to about 30, 35, 40, 45 or even 50 pg/ml. In another exemplary embodiment, the estrogen level is increased to about 50 pg/ml, 75, 100, 125, 150, 175 or to about 200 pg/ml. [0032] Substances suitable for elevating serum or plasma estrogen levels are well known in the art and include, but are not limited to, any of the naturally occurring mammalian estrogens and congeners thereof, e.g., estradiol and its organic esters (e.g., estradiol benzoate, estradiol cypionate and estradiol valerate), estrone, diethylstilbestrol, piperazine estrone sulfate, ethinyl estradiol, mestranol, polyestradiol phosphate, estriol, estriol hemisuccinate, quinestrol, estropipate, pinestrol, estrone potassium sulfate, and tibolone, estrogen metabolites, e.g., 17-β-estradiol, estrogen analogs, natural compounds with estrogenic activity, e.g., phytoestrogens, such as genestein or isoflavone, estrogen agonists, e.g., selective estrogen receptor modulators with some agonistic activity (e.g., tamoxifen), and other substances capable of interaction with cell surface estrogen receptors. These estrogens and estrogenic substances may be natural or synthetic .

[0033] Estrogen or estrogenic substances can be formulated by any means compatible with mammalian physiology and the selected route of delivery. These methods are well known in the art. See U.S. Pharmacopeia National Formulary, United States Pharmacopeal Convention, Inc., pp. 525-541 (1990). [0034] Estrogen therapy can be administered by any suitable route such as locally, orally, systemically, intravenously, intramuscularly, tnucosally, or transdermally (e.g., a patch). The estrogen therapy may be administered on a regular (e.g., a daily/weekly) basis, and may be intermittent or substantially continuous with respect to the drug-conjugate therapy. Typical dose ranges depend on the compound and the characteristics of the patient . The daily dose of the estrogen is typically based on the amount of a given preparation necessary to maintain serum or plasma

17-β-estradiol levels greater than 25 pg/tnl when estrogen or its metabolites are used.

[0035] Treatment regimens include, but are not limited to, hormone replacement therapy, such as estrogen/progesterone therapy at 0.3mg/l.5mg, 0.45mg/l.5mg, 0.625mg/2.5mg, or 0.625mg/5. Omg daily. In another embodiment, therapy may comprise estrogen therapy at 0.15mg, 0.3mg, 0.625mg or 1.25π\g once or twice daily. In a preferred embodiment, therapy comprises lOmg estrogen three times daily. An example of estrogen is Premarin^® (Wyeth Pharmaceuticals, Inc., PA) and an example of estrogen/progesterone combination is Prempro^® (Wyeth Pharmaceuticals, Inc., PA). Alternate therapies include tamoxifen administered at 20 to 40mg per day in 10 mg doses multiple times per day or 20 mg daily in a single dose. [0036] The methods of the invention do not require that each component of the combination therapy (i.e., drug conjugate and estrogen therapy) be delivered by the same route or even at the same time. In some embodiments of the invention, however, the drug conjugate and estrogen therapy are given at the same time by the same route of administration. In a more preferred embodiment, the estrogen therapy is administered transdermally (e.g., by a patch) or orally (e.g., daily tablet, capsule or pill) so as to be substantially continuous over the duration of the drug conjugate treatment course.

[0037] Following the combination therapy, the patient is then optionally administered an estrogen inhibitor as previously described. In one exemplary embodiment, a patient diagnosed with cancer and possessing a serum or plasma estrogen level less than 25 pg/ml is administered a combination therapy comprising about 135 to about 175 paclitaxel equivalents of PPX together with sufficient 17β estradiol to achieve plasma levels >25 pg/ml, both administered at the same time. In the preferred embodiment, estradiol is administered transcutaneously by skin patch or gel at approximately twice the dose recommended for post-menopausal replacement therapy although higher doses may be required to achieve the desired blood levels. Following said combination therapy, the patient is then provided with anastrozole, taken once a day, beginning about 7 days to about 28 days after cessation of the combination therapy, and is continued indefinitely.

[0038] In yet another aspect of the invention, a patient diagnosed with cancer, who is on a hormone replacement therapy and presents with serum or plasma estrogen levels of about 25 pg/ml or higher, is administered a paclitaxel conjugate, followed by the cessation of the hormone replacement therapy and optionally, the administration of an estrogen inhibitor. [0039] INDUSTRIAL APPLICABILITY

[0040] The present invention has industrial applicability in the field of cancer therapy.

[0041] All publications cited in the specification, both patent publications and non-patent publications, are indicative of the level of skill of those skilled in the art to which this invention pertains. All these publications are herein incorporated by reference to the same extent as if each individual publication were specifically and individually indicated as being incorporated by reference.

[0042] Although the invention herein has been described with reference to particular embodiments, it is to be understood that these embodiments are merely illustrative of the principles and applications of the present invention. It is therefore to be understood that numerous modifications may be made to the illustrative embodiments and that other arrangements may be devised without departing from the spirit and scope of the present invention as defined by the appended claims .

Claims

1. A method for treating a patient, diagnosed with a cancer, comprising: determining the serum or plasma level of endogenous estrogen of said patient, and selecting a cancer regimen based on the estrogen level, wherein said patient with an estrogen level of about 25 pg/ml or higher, is treated with a paclitaxel conjugate, followed by treatment with an estrogen inhibitor.

2. The method of claim 1, wherein the cancer is characterized by the presence of estrogen receptor-bearing cancer cells, or wherein the cancer originated in a tissue or organ containing estrogen receptor-bearing cells .

3. The method of claim 2, wherein the cancer is lung cancer.

4. The method of claim 3₍ wherein the lung cancer is non-small cell lung cancer.

5. The method of claim 2, wherein the cancer is prostate cancer.

6. The method of claim 2, wherein the cancer is colon cancer.

7. The method of claim 2, wherein the cancer is ovarian cancer.

8. The method of claim 2, wherein the cancer is a glioma .

9. The method of claim 1, wherein said paclitaxel conjugate is administered in an amount of about 135-175 to mg/m² paclitaxel equivalents .

10. The method of claim 9, wherein said paclitaxel conjugate is delivered intravenously.

11. The method of claim 10, wherein said paclitaxel conjugate is paclitaxel poliglumex.

12. The method of claim 1, wherein administration of the estrogen inhibitor begins 7-28 days after the last dose of the combination.

13. The method of claim 12, wherein the estrogen inhibitor is an aromatase inhibitor or inactivator.

14. The method of claim 13, wherein the aromatase inhibitor or inactivator is administered in standard dose.

15. The method of claim 14, wherein the aromatase inhibitor or inactivator is delivered intravenously.

16. A method for treating a patient, diagnosed with a cancer, comprising: determining the serum or plasma level of endogenous estrogen of said patient, and selecting a cancer regimen based on the estrogen level, wherein said patient with an estrogen level less than 25 pg/ml, is treated with a combination therapy comprising hormone replacement therapy and paclitaxel conjugate, optionally followed by treatment with an estrogen inhibitor.

17. The method of claim 16, wherein the cancer is characterized by the presence of estrogen receptor-bearing cancer cells, or wherein the cancer originated in a tissue or organ containing estrogen receptor-bearing cells .

18. The method of claim 17, wherein the cancer is lung cancer.

19. The method of claim 18, wherein the lung cancer is non-small cell lung cancer.

20. The method of claim 16, wherein said combination therapy comprises a paclitaxel conjugate, administered in an amount of about 175 to about 250 mg/m² paclitaxel equivalents, and hormone replacement therapy.

21. The method of claim 20, wherein the hormone replacement therapy comprises 17β estradiol.

22. The method of claim 20, wherein said combination therapy is delivered intravenously.

23. The method of claim 22, wherein said paclitaxel conjugate is paclitaxel poliglumex.

24. The method of claim 16, wherein administration of the estrogen inhibitor begins 7 to 28 days after last dose of paclitaxel conjugate.

25. The method of claim 24, wherein the estrogen inhibitor is an aromatase inhibitor or inactivator.

26. The method of claim 25, wherein the aromatase inhibitor or inactivator is administered in an amount of about standard dose per label .

27. The method of claim 26, wherein the aromatase inhibitor or inactivator is delivered intravenously.

28. A method for treating a patient, diagnosed with a cancer, wherein said patient is on hormone replacement therapy, comprising: determining the serum or plasma level of estrogen of said patient, and selecting a cancer regimen based on the estrogen level, wherein said patient with an estrogen level of about 25 pg/ml or higher is treated with a paclitaxel conjugate, followed by cessation of said hormone replacement therapy and optionally, administration of an estrogen inhibitor.

29. The method of claim 28, wherein the patient is a postmenopausal female .

30. The method of claim 28, wherein the patient is a male .

31. The method of claim 28, wherein the cancer is characterized by the presence of estrogen receptor-bearing cancer cells, or wherein the cancer originated in a tissue or organ containing estrogen receptor-bearing cells.

32. The method of claim 31, wherein the cancer is lung cancer .

33. The method of claim 32, wherein the lung cancer is non- small cell lung cancer.

34. The method of claim 28, wherein said paclitaxel conjugate is administered in an amount of about 175 to about 250 mg/m² paclitaxel equivalents.

35. The method of claim 34, wherein said paclitaxel conjugate is delivered intravenously.

36. The method of claim 35, wherein said paclitaxel conjugate is paclitaxel poliglumex.

37. The method of claim 28, wherein the cessation of hormone replacement therapy and the administration of the estrogen inhibitor begins 7-28 days after last dose of paclitaxel conjugate.

38. The method of claim 37, wherein the estrogen inhibitor is an aromatase inhibitor or inactivator.

39. The method of claim 38, wherein the aromatase inhibitor or inactivator is administered in an amount of about standard dose per label.

40. The method of claim 39, wherein the aromatase inhibitor or inactivator is delivered intravenously.