Neoadjuvant systemic therapy for breast cancer: an overview and review of recent clinical trials

Hanrahan, Emer O.; Hennessy, Bryan T.; Valero, Vicente

doi:10.1517/14656566.6.9.1477

Cited by 34 publications

(18 citation statements)

References 54 publications

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“…(3) needs to be expressed solely in terms of quantities that are actually measured in an MRI experiment -the relaxation rate constants. Towards this end, the Kety pharmacokinetic rate law is frequently employed [16]: (4) where K trans is the CA extravasation rate constant and C p (t) is the concentration of CA in blood plasma, the so-called arterial input function (AIF). Substituting Eq.…”

Section: Discussionmentioning

confidence: 99%

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Integration of quantitative DCE-MRI and ADC mapping to monitor treatment response in human breast cancer: initial results

Yankeelov¹,

Lepage²,

Chakravarthy³

et al. 2007

Magnetic Resonance Imaging

284

266

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Purpose-The objective of this study was to assess changes in the water apparent diffusion coefficient (ADC) and in pharmacokinetic parameters obtained from the fast-exchange regime (FXR) modeling of dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) during neoadjuvant chemotherapy in breast cancer.Materials and Methods-Eleven patients with locally advanced breast cancer underwent MRI examination prior to and after chemotherapy but prior to surgery. A 1.5-T scanner was used to obtain T 1 , ADC and DCE-MRI data. DCE-MRI data were analyzed by the FXR model returning estimates of K trans (volume transfer constant), ν e (extravascular extracellular volume fraction) and τs i (average intracellular water lifetime). Histogram and correlation analyses assessed parameter changes posttreatment.Results-Significant ( P <.05) changes or trends towards significance ( P <.10) were seen in all parameters except τ i , although there was qualitative reduction in τ i values post-treatment. In particular, there was reduction ( P <.035) in voxels with K trans values in the range 0.2-0.5 min -1 and a decrease ( P <.05) in voxels with ADC values in the range 0.99×10 -3 to 1.35×10 -3 mm 2 /s. ADC and ν e were negatively correlated (r = -.60, P <.02). Parameters sensitive to water distribution and geometry (T 1 , ν e ,τs i and ADC) correlated with a multivariable linear regression model. Conclusion-The analysis presented here is sensitive to longitudinal changes in breast tumor status; K trans and ADC are most sensitive to these changes. Relationships between parameters provide information on water distribution and geometry in the tumor environment.

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Section: Discussionmentioning

confidence: 99%

“…Neoadjuvant chemotherapy is currently the standard of care for women with locally advanced breast cancer [1][2][3][4]. Neoadjuvant therapy reduces tumor burden, allowing a less extensive surgical procedure and early initiation of systemic therapy in patients at high risk for distant and local failure.…”

Section: Introductionmentioning

confidence: 99%

Integration of quantitative DCE-MRI and ADC mapping to monitor treatment response in human breast cancer: initial results

Yankeelov¹,

Lepage²,

Chakravarthy³

et al. 2007

Magnetic Resonance Imaging

284

266

View full text Add to dashboard Cite

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“…HER2-driven tumor cell growth is inhibited by trastuzumab (Herceptin, Genentech), a humanized anti-HER2 antibody that shows clinical efficacy as a single agent and more recently as adjuvant therapy (16)(17)(18). Some HER2-overexpressing tumors are resistant to trastuzumab (19) but might still be sensitive to anti-HER2-drug conjugate therapy.…”

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confidence: 99%

Oxidizing potential of endosomes and lysosomes limits intracellular cleavage of disulfide-based antibody–drug conjugates

Austin¹,

Wen²,

Gazzard³

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

215

174

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Antibody-drug conjugate therapy entails targeted killing of cancer cells with cytotoxic compounds covalently linked to tumor-specific antibodies and shows promise in the treatment of several human cancers. Current antibody-drug conjugate designs that incorporate a disulfide linker between the antibody and cytotoxic drug are inspired by indirect evidence suggesting that the redox potential within the endosomal system is reducing. It is presumed that antigen-dependent endocytosis leads to disulfide linker reduction and intracellular release of free drug, but direct demonstration of such a mechanism is lacking. To determine whether the disulfide N-succinimidyl 4-(2-pyridyldithio)pentanoate (SPP) linker would be reduced during endocytic recycling of the anti-HER2 antibody trastuzumab (Herceptin, Genentech), we synthesized a trastuzumab-SPP-Rhodamine red conjugate and developed a linker cleavage assay by using the self-quenching property of this fluorophore. In breast carcinoma SKBr3 cells, no SPP linker cleavage was observed, as detected by fluorescence dequenching upon internalization. By contrast, the conjugate did display fluorescence dequenching when diverted to the lysosomal pathway by geldanamycin, an effect partly due to proteolytic degradation rather than disulfide reduction. To understand why linker reduction was inefficient, we measured redox potentials of endocytic compartments by expressing a redox-sensitive variant of GFP fused to various endocytic proteins. Unexpectedly, we found that recycling endosomes, late endosomes, and lysosomes are not reducing, but oxidizing and comparable with conditions in the endoplasmic reticulum. These results suggest that intracellular reduction is unlikely to account for the potency of disulfide-linked antibodydrug conjugates.disulfide linker ͉ redox potential ͉ endocytosis ͉ HER2 ͉ Herceptin O ne approach to the treatment of cancer is to specifically target cytotoxic drugs to tumor cells by linking them via a cleavable linker to antibodies that recognize a tumor-restricted antigen. Such linkers include hydrazone linkers, designed to hydrolyze upon internalization into acidic endosomes and lysosomes (1-3); peptide linkers optimized for cleavage by certain lysosomal proteases (3-5); and disulfide linkers, thought to be cleaved by the reducing environment within the endocytic pathway (6-10). In the latter category, the monoclonal antibody C242 against CanAg (a glycotope on the mucin1 (MUC1) colorectal tumor antigen) has shown efficacy against colorectal xenograft models in vivo when disulfide-linked to the ribosomal inhibitor ricin A chain via a 4-succinimdyloxycarbonyl-methyl-␣-[2-pyridyldithio]-toluene (SMPT) linker (11) and to the maytansinoid-derived microtubule active drug DM1 via an N-succinimidyl 4-(2-pyridyldithio)pentanoate (SPP) linker (12). The latter conjugate is now humanized and in clinical trials as cantuzumab mertansine (9, 13). An ideal linker should be cleaved only upon internalization of the antibody-drug conjugate into the tumor cell, thereby specifical...

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“…Furthermore, tumor response to neoadjuvant treatment has been shown to be prognostically significant. Other less proven benefits of neoadjuvant chemotherapy include eradication of microscopic metastases and improved survivals (1)(2)(3). Postoperative adjuvant chemotherapy has been used successfully to improve survival rates in patients with early stage breast cancer (4).…”

Section: Introductionmentioning

confidence: 99%

Tumor proteomic profiling predicts the susceptibility of breast cancer to chemotherapy

Shen²,

Chung³

et al. 2009

Int J Oncol

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Abstract. Chemotherapy is often used for breast cancer treatment, but individual outcome varies widely. We hypothesized that tumor proteomic profiles obtained prior to chemotherapy may predict the individual tumor response to treatment. The goal of our study was to explore feasibility of using proteomic profiling to preselect patients for an effective chemotherapeutic regimen. Tumors from 52 patients with T2-T4 breast cancer were prospectively collected before neoadjuvant chemotherapy, and were analyzed using surface-enhanced laser desorption ionization/time of flight (SELDI) mass spectrometry. Mass spectral profiles were obtained from tumors with various sensitivities to chemotherapy. Both nonsupervised hierarchical clustering and supervised neural network-based classification approaches were employed to compare the profiles. The first two thirds of the enrolled cases (35) were allocated to a training set to select peaks characteristic of resistant tumors. The candidate peaks were used to develop a predicting rule to evaluate the remaining 17 specimens in the validation set. In the training set, the most prominent differences were found between drug resistant and drug susceptible tumors by non-supervised hierarchical clustering. In the validation set, the supervised classification with the K nearest neighbor (KNN) model correctly classified most tumor responses with an accuracy rate of 92.3% [100% of resistant tumors (4/4), and 84.6% of the tumors with favorable response (11/13)]. In the entire group, a single peak at m/z 16,906 correctly separated 88.9% of the tumors with pathologically complete response, and 91.7% of the resistant tumors. The data suggest that breast cancer protein biomarkers may be used to pre-select patients for optimal chemotherapeutic treatment. IntroductionPreoperative chemotherapy (neoadjuvant chemotherapy) has gained wide acceptance for treating patients with locally advanced breast cancer. In these patients the most acknowledged benefit is the reduction in tumor size allowing either a complete resection of an otherwise unresectable tumor or breast conservation surgery in some patients with large tumors. Furthermore, tumor response to neoadjuvant treatment has been shown to be prognostically significant. Other less proven benefits of neoadjuvant chemotherapy include eradication of microscopic metastases and improved survivals (1-3). Postoperative adjuvant chemotherapy has been used successfully to improve survival rates in patients with early stage breast cancer (4). Although many patients benefit from chemotherapy, some fail to respond. However, the success of chemotherapy, whether pre-or post-operative, in any given individual cannot be predicted. The uncertain benefit for a particular individual, as well as significant toxicity of chemotherapy in all patients, calls for development of methods to select the right patients for treatment and spare those who will not benefit. ); PAM, prediction analysis with microarrays; pCR, pathological complete response, no residual cancer found at ...

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Neoadjuvant systemic therapy for breast cancer: an overview and review of recent clinical trials

Cited by 34 publications

References 54 publications

Integration of quantitative DCE-MRI and ADC mapping to monitor treatment response in human breast cancer: initial results

Integration of quantitative DCE-MRI and ADC mapping to monitor treatment response in human breast cancer: initial results

Oxidizing potential of endosomes and lysosomes limits intracellular cleavage of disulfide-based antibody–drug conjugates

Tumor proteomic profiling predicts the susceptibility of breast cancer to chemotherapy

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