Methods for selecting active agents for cancer treatment

Abstract

The present invention provides methods for individualizing chemotherapy, and particularly methods for individualizing neoadjuvant chemotherapy. The present invention provides methods for predicting a cancer patient's response to neoadjuvant chemotherapy, including assessing the probability of a positive response upon treatment with candidate agents prior to surgery. In various aspects, the invention involves culturing a monolayer of malignant cells from an explant of a patient's biopsy specimen, such as a transcutaneous biopsy-sized specimen, and testing the malignant cells for resistance or sensitivity to one or a plurality of candidate agents for neoadjuvant therapy. In other aspects, the invention provides methods for accurately scoring and interpreting such assays, and discloses in vitro chemoresponse results that are predictive of a patient's pathological complete response (pCR) upon receiving the corresponding treatment regimen.

Description

[0001]This application claims priority to U.S. Provisional Application No. 60 / 980,098, filed Oct. 15, 2007, the entire disclosure of which is hereby incorporated by reference in its entirety.BACKGROUND[0002]Neoadjuvant chemotherapy refers to drug treatment administered to cancer patients prior to surgery. A goal of neoadjuvant chemotherapy is to reduce the size of the cancer before surgery, thus making surgery easier and more likely to be successful. Neoadjuvant chemotherapy is used commonly in cancers that are locally advanced and / or inoperable. The use of such chemotherapy can effectively reduce the difficulty and morbidity of a subsequent surgical procedure; for example in the case of breast cancer, allowing for breast-conserving surgery to be performed instead of mastectomy.[0003]Neoadjuvant chemotherapy has improved overall survival rates in breast cancer patients from 10-20% by local therapy alone to 30-60% with neoadjuvant chemotherapy followed by local therapy (3). However, ...

AI Technical Summary

Benefits of technology

[0005]The present invention provides methods for individualizing chemotherapy, and particularly methods for individualizing neoadjuvant chemotherapy. The present invention provides methods for predicting a cancer patient's response to neoadjuvant chemotherapy, including assessing the probability of a positive response (e.g., pathological complete response (pCR)) upon treatment with candidate agents prior to surgery. In various aspects, the invention involves culturing a monolayer of malignant cells from an explant of a patient's biopsy specimen, such as a transcutaneous biopsy-sized specimen, and testing the malignant cells for resistance or sensitivity to one or a plurality of candidate agents for neoadjuvant therapy. In other aspects, the invention provides methods for accurately scoring and interpreting such assays, and discloses in vitro chemoresponse results that are predictive of a patient's pathological complete response (pCR) upon receiving the corresponding treatment regimen.

[0006]In one aspect, the invention provides a method for culturing malignant cells from transcutaneouos biopsy-sized specimens, so that a tumor's sensitivity or resistance to candidate agent(s) can be evaluated without surgery. Such specimens, such as breast tissue specimens, may be obtained, for example, via core needle biopsy or MAMMOTOME® biopsy system, and may contain 50 mg of tissue or less. The present invention allows malignant cells from such specimens to be reproducibly cultured for chemosensitivity and resistance testing, so that neoadjuvant chemotherapy may be selected on an individualized basis.

[0007]In a second aspect, the invention provides methods, including algorithms, for assessing the sensitivity of cells to active agents. The method involves determining a cytotoxic index within a dose range, and calculating an adjusted area under the curve (aAUC) for the resulting dose-response curve. The aAUC for an active agent accurately reflects the sensitivity of cells to in vitro drug exposure, and takes into account differences in dose / response curve shapes. Thus, according to this aspect, the invention provides algorithms for scoring the sensitivity of cultured cells to drugs, thereby allowing accurate evaluations of chemosensitivity / resistance. Such algorithms improve the interpretation of chemosensitivity data, to individualize chemotherapy selection, including neoadjuvant chemotherapy selection.

[0008]In a third aspect, the invention provides a method for predicting the effectiveness, for a given breast cancer patient, of various neoadjuvant chemotherapy regimens that are currently employed for the treatment of breast cancer. For example, the invention provides a method for predicting a patient's response to a neoadjuvant chemotherapy regimen comprising docetaxel / fluorouracil (DF), or related agents. As disclosed herein, in vitro sensitivity to DF or related agents is an independent predictor of a positive outcome (e.g., pCR) to a neoadjuvant chemotherapy regimen comprising DF. The invention thereby supports individualized chemotherapy decisions, including decisions involving treatment with DF or related agents, prior to surgery.

Problems solved by technology

As a result, many patients are treated with unnecessary or ineffective chemotherapy, which can result in unnecessary toxicity and costs, may delay more effective treatment, and may cause the tumor to become cross-resistant to additional drugs (4).

Inadequate treatment choices for neoadjuvant therapy are partly due to the lack of accurate predictors of response in individual patients.

While numerous in vitro chemosensitivity and resistance assays (CSRAs) have emerged, the assays are often limited in their utility for assessing neoadjuvant treatment, due to, for example, technical difficulties, the need for large amounts of fresh tissue (1-2 g), limited consistency in producing results (often less than 50% of submitted specimens), and the lack of reproducibility and clinical utility in predicting patient outcomes (5,6).

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