Free Essay Example on Breast Cancer

Introduction

In 2016, an estimation of around 3.5 million women was identified to be living with a history of breast cancer (BC) in the United States (Mariotto et al., p.810). The number includes newly diagnosed women with breast cancer undergoing surgery and adjuvant treatment, women who may have experienced a relapse after the illness-free interval and long term survivors of the illness. Distant metastatic cancers such as metastases found at diagnosis (de novo) and those that happen later in the infection provide a majority representation of an advanced form. Around 6 percent of women have metastatic breast cancer when an initial diagnosis is carried out on them. Hence breast cancer is considered the second most common cause of mortality in women due to cancer (Mariotto et al., p.810).

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Recently, various molecular pathways liable for tumorigenesis have been identified. Due to that knowledge, there has been the probability of effective anti-cancer treatments whose aim is on novel targets with toxicities linked with conventional cytotoxic therapies (Harries and Smith, p.76). The development and the use of Herceptin (trastuzumab), which is a monoclonal antibody that has been explicitly humanized for HER-2, a growth factor that is found to be overexpressed in 20-30% of the breast cancer occurring in humans, has been significant (Harries and Smith, p.76). Therefore, Herceptin has been shown to treat patients that have metastatic breast cancer whose tumors overexpress HER2.

Discovery and Development of Herceptin

Many threads of oncogene which converge on tyrosine kinase usually signal the exciting prospect of oncogene-directed therapy. At first glance, the ATP present in kinases was exploited by small molecule kinase inhibitors' possible findings. But across all the kinases, there is high conservation of its family members, which raises an obvious concern about selectivity thus toxicity without even mentioning the effectiveness needed when overcoming the high (micro-molar) concentration of ATP in cells. Indeed, the field for kinase-inhibitors continued to be quite large for another 10-15 years up to the dramatic concept proofs given by imatinib (Gleevec) i9n chronic myeloid leukemia (Sawyers, p. 10). The finding of HER2, a diverse strategy because of its cell-surface nature, resulted in a monoclonal antibody's theoretical target.

However, the antibodies against neu-containing transfectants of NIH 3T3 cell, which was already raised by the Weinberg Group, demonstrated the gratitude of the extracellular domain of the p185 neu protein. In partnership with Jeff Drebin and Mark Greene at Harvard, they showed these antibodies to reverting NIH 3T3 neu transfectants' transformation appearance in mice growth and culture. Significantly, the Ras transfectants were not used when observing these effects, thereby providing evidence for selectivity (Cortés et al., p.1207). Ulrich also confirmed human HER2 playing a functional role in transformation based on the overexpressed tumorigenicity in NIH 3T3 cells. This, together with the Cambridge data on the anti-neu antibody, caused the search at Genentech for human HER2 targeting antibodies that ultimately generated Herceptin. With Ullrich now in partnership with Mike Shepard, they immunized mice which had NIH 3T3 cells expressing high levels of human HER2 by boosting them with purified HER2 proteins, having them undergo immunoreactivity screen sera and hybridomas prepared from the spleens of high titter mice (Slamon et al., p.1280).

Previous experiences had proved the potent immunogenicity of rodent-derived antibodies in humans, making it impossible to test 4D5 in patients. Recently, the new altering mouse antibody techniques had been described as grafting molecular in variable region order of the binding mouse antibody onto a human antibody (Harries and Smith, p.77). Shepard steered he humanized the 4D5 effort at Genentech by using a new approach; significant technical modifications were made along the way that resulted in improved speed and efficiency. Clinical Herceptin was the outcome of the modification. Shepard and colleagues importantly showed Herceptin's activity to be selective at killing cells expressing high levels of HER2, an outcome with critical implications for patients with potential toxicity against normal cells expressing HER2 as well as selection.

In 1992 Herceptin entered clinical development, and in 1998 it was approved, at first, for treatment of HER2-positive metastatic breast cancer. Phase 2 studies revealed 15% of objective response of patients treated with Herceptin alone, thus giving clear evidence of clinical activity (Slamon et al., p.1275). While the studies from phase 3 that was convincing showed a 20% decrease in risk of death when administering it with standard chemotherapy (Cortés et al., p.1204). Undoubtedly, its approval in the history of targeted cancer therapy eight years later is the main way. It involved the expansion use of Herceptin to include post-surgical (adjuvant) treatment of HER2 positive breast cancer, which was based on a remarkable 33% and 50% decrease in death and relapse risk, respectively (Sawyers, p. 10). These milestone studies changed the lives of women with HER2-positive breast cancer forever. In 2006, the trial began recruiting patients about eight years after the Herceptin was approved by the Federal and Drug Administration (FDA) in the HER2 positive breast cancer metastatic setting and five years after it was published indicating the superiority of trastuzumab over anti-HER2 treatment in the setting.

Ethical Issues

The trial was carried in countries whereby the public health system does not compensate Herceptin. The sponsors and investigators based the trial and the entire team on the outdated fourth edition of the Helsinki Declaration from 1996 that lacked a clear definition of the standard of care (Ades, para.4). Therefore, the medical study never assured the patients and control group the best proven diagnostic and therapeutic method in the trastuzumab discovery and development process. The fifth (2000) and sixth (2008) editions of the Helsinki Declaration gives a clear roadmap in defining ethical issues of carrying out clinical trials on populations that could not benefit from the study and in the use of the placebo (Ades, para.6). However, this process was conducted on populations that were not compensated for and using outdated declaration principles.

Current Use and Future Direction

More than 250 000 women in America are diagnosed with invasive breast cancer every year, of which 20 percent have a probability of developing tumors with amplification of the HER2 gene (Sawyers, p. 8). However, with the discovery of Herceptin today, a monoclonal antibody, it will increase the survival rate of breast cancer women to around 85 percent of women for at least ten years, which will be a significant outcome for cancer women. Moreover, Herceptin has proved to be effective in 20% of gastric cancer patients whose tumors are HER2-positive (Sawyers, p. 8). Besides, two next-generation versions of Herceptin, which has been modified to kill tumor growth, indicate that clinical benefit in patients that have advanced after treatment with the parent antibody. Therefore, Herceptin is a single monoclonal antibody that has greatly impacted the lives of many cancer patients. Moreover, it has provided innovative inspiration to the whole monoclonal-antibody-engineering field by credibly indicating the additional advantage of conjugation to toxic drug payloads.

Currently, Herceptin is approved by the United States Food and Drug Administration for treating metastatic HER2-positive breast cancer to inhibit cancer from growing (Viani et al., p.153). Moreover, Herceptin is used in treating the early stages of HER2 positive breast cancer, either a portion of regimen with chemotherapy or alone after a chemotherapy regimen that encompasses an anthracycline for reducing breast cancer risk relapse (Viani et al., p.153)

Ethical Issues

In his recent publication in the Clinical Oncology journal, Guan et al. indicated results of a randomized, placebo-controlled phase III pharma sponsored trial that investigated lapatinib's addition to paclitaxel first-line treatment of HER2-positive cancer (Ades, para.2). The trial demonstrated that the addition of lapatinib was linked with improvement in progression-free (median PFFS: 6.5 6.5 versus 9.7 months; HR, 0.52; 95% CI, 0.42 to 0.64; P < .001) and overall survival (median OS: 27.8 versus 20.5 months; HR, 0.74; 95% CI, 0.58 to 0.94; P = .0124) (Ades, para.2).

Conclusion

There should mandatory testing for all women with breast cancer for overexpression of HER-2. Early breast cancer patients with high expression tumors should be considered for entry into an adjuvant Herceptin in combination with taxane if a person was initially treated with a taxane. Single-agent Herceptin must be available as first-line treatment for metastatic illness in patients that do not desire to have immediate chemotherapy.

Works Cited

Ades, Felipe. "Clinical Research in HER2 Positive Metastatic Breast Cancer – Ethical Issues of Trials Conducted in Low Resource Environments." ESMO, ESMO, 6 May 2013,
http://www.esmo.org/career-development/young-oncologists-corner/journal-club/Clinical-Research-in-HER2-Positive-Metastatic-Breast-Cancer-Ethical-Issues-of-Trials-Conducted-in-Low-Resource-Environments.

Cortés, Javier, et al. "Efficacy and safety of trastuzumab emtansine plus capecitabine vs. trastuzumab emtansine alone in patients with previously treated ERBB2 (HER2)-positive metastatic breast cancer: a phase 1 and randomized phase 2 trial." JAMA oncology 6.8 (2020): 1203-1209.

Harries, M., and I. Smith. "The development and clinical use of trastuzumab (Herceptin)." Endocrine-related cancer 9.2 (2002): 75-85.

Mariotto, Angela B., et al. "Estimation of the number of women living with metastatic breast cancer in the United States." Cancer Epidemiology and Prevention Biomarkers 26.6 (2017): 809-815.

Slamon, Dennis, et al. "Adjuvant trastuzumab in HER2-positive breast cancer." New England Journal of Medicine 365.14 (2011): 1273-1283.

Sawyers, Charles L. "Herceptin: A First Assault on Oncogenes that Launched a Revolution." Cell 179.1 (2019): 8-12.

Viani, Gustavo A., et al. "Adjuvant trastuzumab in the treatment of her-2-positive early breast cancer: a meta-analysis of published randomized trials." BMC Cancer 7.1 (2007): 153.