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Neoadjuvant Chemotherapy Breast Cancer Guidelines

Targeted Chemotherapy In Early

Dr. King on Neoadjuvant Chemotherapy in Breast Cancer

Research has been performed on targeted chemotherapy agents, including the following:

  • Cyclin-dependent kinase inhibitors
  • Small-molecule epidermal growth factor receptor tyrosine kinase inhibitors
  • Blockade by antiangiogenic agents
  • PI3K/Akt/mammalian target of rapamycin inhibitors
  • Poly polymerase inhibitors]

The CDK4/6 inhibitor abemaciclib has been approved for use in early breast cancer for use in hormone receptor positve, HER2-negative early breast cancer, for patients who have high-risk, node-positive disease and whose tumors have a Ki-67 score of 20%, as determined by a US Food and Drug Administration approved test.

Asco Guideline Covers Patient Selection Treatment Options Follow

byCharles Bankhead, Senior Editor, MedPage Today February 2, 2021

Neoadjuvant chemotherapy is the treatment of choice for newly diagnosed inflammatory or unresectable breast cancer, as well as locally advanced disease that might be rendered operable with neoadjuvant therapy, according to a new guideline from the American Society of Clinical Oncology .

A limited number of factors have sufficient evidence to support routine use of clinical decision-making: tumor histology, grade, stage, and hormone receptor status . Data remain insufficient to support use of other markers or genomic profiling to inform decisions about neoadjuvant chemotherapy, stated guideline panel co-chairs Larissa A. Korde, MD, of the National Cancer Institute in Bethesda, Maryland, and Dawn L. Hershman, MD, of Columbia University in New York City, and co-authors in the Journal of Clinical Oncology.

Outlining decades of research and progress in neoadjuvant chemotherapy, the panel emphasized the need to optimize patient selection and treatment choices.

“As our understanding of the biology of breast cancer has evolved in recent decades, it has become clear that optimal therapy for breast cancer is driven by subtype,” they wrote. “Thus, older neoadjuvant trials that used a one-size-fits-all approach to therapy selection are less relevant in the current era of biologically driven treatment selection.”

Disclosures

Local Recurrence Following Neoadjuvant Chemotherapy

The local recurrence rate reported in the randomized trials varies between 3 and 27 per cent, and depends on duration of follow-up and the local treatment used. In the study by Scholl et al., the rate of local recurrence in the NAC group was 27 per cent, which may be related to the fact that the primary locoregional treatment following NAC was radiotherapy. In the NSABP B-18 trial, the rate of ipsilateral breast tumour recurrence in patients who had breast-conserving surgery after preoperative chemotherapy instead of the proposed mastectomy was 11 of 69 compared with 43 of 434 in patients who received breast-conserving surgery as planned. Overall, there was a non-significant increase in local recurrence between those receiving NAC and those receiving postoperative chemotherapy .

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For Metastatic Breast Cancer

Chemo can be used as the main treatment for women whose cancer has spread outside the breast and underarm area to distant organs like the liver or lungs. Chemo can be given either when breast cancer is diagnosed or after initial treatments. The length of treatment depends on how well the chemo is working and how well you tolerate it.

Gene Expression Profiling And Proteomics As Biological Markers

General NCCN Guidelines

Recently, gene expression profiling and proteomics have been used as molecular markers to predict tumour response, sensitivity to chemotherapeutic agents or patient prognosis. DNA microarrays allow tumours to be defined by the expression patterns of thousands of genes simultaneously. These so-called genetic signatures of tumours can then be used to identify a group of patients who are more likely to benefit from chemotherapy, thereby avoiding potentially toxic treatment in patients who are unlikely to benefit. Proteomics is the study of the complete set of proteins expressed in a cell, usually using mass spectrometry. One can study protein profiles before and after a specific treatment to determine profiles that may predict response to treatment or clinical outcome.

A recent study reported gene expression profiling to predict response to docetaxel NAC in 24 patients with locally advanced breast cancer. Differential patterns of expression of 92 genes that correlated with response were identified with an accuracy of 88 per cent. These new technologies have great potential, especially in the neoadjuvant setting, but they remain at an early stage of development. If gene profiles or specific proteins that determine either response to treatment or predict outcome can be identified, it would be possible to tailor treatment based on the expression profile of tumours.

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Chemotherapy And Antiangiogenic Agents

Chemotherapy, given with anti-HER2-targeted drugs in the case of HER2-positive disease, is the standard neoadjuvant approach. Commonly used regimens for patients with HER2-negative disease, especially in the higher-risk category, include anthracycline-based regimens such as doxorubicin and cyclophosphamide followed or proceeded by a taxane . For those in whom the potential cardiotoxic effects of anthracyclines are a primary concern, non-anthracycline regimens are a reasonable alternative .

Patients With Contraindications For Surgery

Neoadjuvant chemotherapy or endocrine therapy may be a suitable option for patients who have contraindications to undergo surgery at the time of diagnosis or in situations in which delays in elective surgeries are encountered or necessitated, such as during a pandemic, during pregnancy or after a recent venous thromboembolism.

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To Put That Into Context

Triple-negative breast cancer

Although there are no approved drugs specifically indicated for TNBC, this subtype is associated with relatively high pCR rates following chemotherapy, with many novel agents under investigation. The addition of the antivascular endothelial growth factor receptor monoclonal antibody bevacizumab to chemotherapy has been studied extensively in the setting of neoadjuvant treatment for breast cancer. The German Breast Group 44 study and the Avastin Randomized Trial With Neoadjuvant Chemotherapy for Patients With Early Breast Cancer found that in TNBC cohorts, the addition of bevacizumab improved the rates of ypT0N0 pCR by 11.4% and 14% , respectively. The recently presented Austrian Breast and Colorectal Cancer Study Group 32 study and the Southwestern Oncology Group S0800 study have also reported improvements in pCR rates, especially in patients with TNBC. The NSABP B-40 and CALGB 40603 studies found statistically significant improvements in ypT0Nx pCR in the breast with the addition of bevacizumab, but differences in ypT0N0 rates were not statistically significant . While these neoadjuvant studies demonstrated improvements in pCR, three large randomized studies in multiple breast cancer subtypes in the adjuvant setting have failed to demonstrate a survival advantage. These data demonstrate no role for bevacizumab at this time in unselected populations with early-stage breast cancer.

Residual disease

What Is Neoadjuvant Chemotherapy

Refining Neoadjuvant Chemotherapy for HER2 Breast Cancer

In most cases of breast cancers, the primary, definitive treatment is surgery to remove the cancer. Additional systemic treatment, such as chemotherapy or hormone therapy, is used either before or after the primary therapy. Extra treatment in addition to surgery, given after primary therapy is referred to as adjuvant therapy whereas extra treatment given before primary therapy is referred to as neoadjuvant therapy .

Systemic therapy given for non-metastatic invasive breast cancer whether administered pre or post op, is intended primarily to reduce the risk of distant recurrence. The purpose of administering it prior to surgery, is also for the treatment of locoregional disease.

Neoadjuvant chemotherapy was originally employed in breast cancer patients who presented with inoperable disease in order to render them operable candidates. More recently however, potential benefits of NAC have been increasingly appreciated in early operable breast cancer.

While surgery remains the first treatment recommended for the majority of patients with early breast cancer, neoadjuvant chemotherapy is being used with increasing frequency in the multidisciplinary treatment of patients with operable breast cancer.

Neoadjuvant therapy also allows to monitor response to therapy at an early stage potentially allowing time and flexibility to switch therapies if patients do not respond.

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How Is Chemotherapy For Breast Cancer Given

Chemo drugs for breast cancer are typically given into a vein , either as an injection over a few minutes or as an infusion over a longer period of time. This can be done in a doctors office, infusion center, or in a hospital setting.

Often, a slightly larger and sturdier IV is required in the vein system to administer chemo. These are known as central venous catheters , central venous access devices , or central lines. They are used to put medicines, blood products, nutrients, or fluids right into your blood. They can also be used to take out blood for testing.

There are many different kinds of CVCs. The most common types are the port and the PICC line. For breast cancer patients, the central line is typically placed on the side opposite of the breast cancer. If a woman has breast cancer in both breasts, the central line will most likely be placed on the side that had fewer lymph nodes removed or involved with cancer.

Chemo is given in cycles, followed by a rest period to give you time to recover from the effects of the drugs. Chemo cycles are most often 2 or 3 weeks long. The schedule varies depending on the drugs used. For example, with some drugs, chemo is given only on the first day of the cycle. With others, it is given one day a week for a few weeks or every other week. Then, at the end of the cycle, the chemo schedule repeats to start the next cycle.

Clinical And Radiological Assessment In The Neoadjuvant Approach

Neoadjuvant chemotherapy allows for visualization of a marked reduction in tumor size, thus it is critical to accurately mark the primary tumor at the time of diagnosis. Prior to undergoing NACT, the following is required: physical examination, breast imaging including ultrasound, mammogram, and core biopsy, and a biopsy of the lymph node with clip/marker placement. Prior to each cycle of chemotherapy, a physical examination should be performed to monitor response to therapy. There are rare occasions where the tumor has little response or grows despite NACT, necessitating a change in therapy or proceeding to earlier surgery. Therefore, periodic physical examinations are crucial. At the conclusion of therapy, repeat breast imaging including a mammogram and ultrasound are performed. The following will discuss the key indications for neoadjuvant therapy .

Table 1 Indications for Consideration of Neoadjuvant Chemotherapy

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Interpreting Pathologic Complete Response

For patients who achieve a pCR, numerous data demonstrate that they are more likely to experience a survival benefit when pCR is defined as ypT0/is ypN0. Naturally, pCR achieved in a single patient may not correlate to the pCR rate in a population of patients as a function of a therapy. To date, only our experience with trastuzumab has demonstrated that improvements in pCR are linked to improved survival investigations of lapatinib and bevacizumab have failed to show this, and we await results from the APHINITY trial to see if pertuzumab will demonstrate a correlation between pCR and survival endpoints. Similarly, studies are ongoing in the neoadjuvant and adjuvant settings to investigate the role of carboplatin in early TNBC. Certainly the anticancer potency of the drug under investigation matters, and perhaps the degree of change in pCR rate may also matter. When considering neoadjuvant therapy, a clinician must weigh the potential benefits of agents with no proven survival benefit against their potential toxicity. The impact of toxicity on the ability of patients to complete standard-of-care therapy should also be considered. Furthermore, clinicians should be cautious in extrapolating neoadjuvant data to the adjuvant setting in the absence of survival data.

Rationale For Neoadjuvant Systemic Therapy Compared To Adjuvant Therapy

Improving Neoadjuvant Breast Cancer Therapy Rates Uptake with Education ...

Early initiation of systemic therapy was thought to improve overall survival in high-risk patients receiving NACT. However, in the Early Breast Cancer Trialists Collaborative Group meta-analysis, no difference was observed in distant recurrence rate or breast cancer mortality in patients treated with NACT compared to adjuvant chemotherapy at 15-year follow-up.2 Furthermore, despite NACT leading to a higher frequency of breast-conserving therapy compared to adjuvant chemotherapy, there was also an associated increased risk of local recurrence in patients . Similarly, the NSABP B-18 study showed equivalent disease-free survival , distant disease-free survival, and OS in patients receiving pre-operative and post-operative chemotherapy , however with more women able to achieve BCT in the pre-operative chemotherapy group.3 One group that did experience a superior DFS and OS in those receiving NACT was patients who had a pathologic complete response . Altogether, the aforementioned studies suggest NACT provides therapy that is equivalent to adjuvant therapy and notably demonstrates a survival advantage in those who have a complete response.4

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Locally Advanced Breast Cancer Or Clinically Node

Patients with T3 or T4 breast lesions or with multiple axillary lymph nodes involved are candidates for NACT as they are often not amenable to upfront resection and they would not be candidates for breast conservation. Additionally, patients with limited clinically node-positive disease are also eligible for NACT, as it often converts cN1 patients to pN0,especially in patients with aggressive subtypes.

More importantly, several studies haveperformed secondary analyseswhich demonstrated that patients who were not candidatesfor breast-conserving surgeryat diagnosiswere able to become candidates forBCS after neoadjuvant therapy.In the CALGB40,601 study, breast-conserving surgery candidacy was assessed of patients with stage IIIII HER2+ breast cancer before and after neoadjuvant therapy.68 43% of the patients who were not initially candidates for BCS converted to candidates for BCS after neoadjuvant therapy. In the more recentBrighTNessRCT,604 patients with stage IIIII TNBC were assessed for BCS candidacy before and after neoadjuvant therapy.69 Ofthe 141 patients who were deemed BCS ineligible at baseline, 53.2% then converted to BCS eligible after neoadjuvant therapy with ACT ± carboplatin and/or veliparib.

Pathological Complete Response And Survival

A pCR implies the absence of residual invasive or in situ disease following NAC and surgery. However, longer follow-up within the randomized trials is needed to determine whether higher pCR rates translate into improved survival. The largest study of NAC, the NSABP B-18 trial,, did not show any significant difference in overall or disease-free survival between the two groups at 9 years. However, there was a statistically significant correlation between primary tumour response and outcome . This statistically significant association between clinical response and survival persisted after adjustment for tumour size, node status and age at randomization. Furthermore, at 9 years the overall survival rate for patients achieving a pCR was 85 per cent compared with 73 per cent in patients in whom residual cancer was detected on histopathological examination. For disease-free survival the respective rates were 75 and 58 per cent. After adjustment for other prognostic factors, patients with a pCR had a 50 per cent reduction in risk of death compared with the group as a whole.

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Recommendations From An International Consensus Conference On The Current Status And Future Of Neoadjuvant Systemic Therapy In Primary Breast Cancer

Kaufmann M, von Minckwitz G, Mamounas EP, et alAnn Surg Oncol. 2011 Dec 23.

Study Summary

This article summarizes the recommendations from a panel of experts that met in Biedenkopf, Germany, in September 2010. This was the fourth meeting of this group, which comprised experts in medical oncology, breast surgery, diagnostics, radiology, radiation oncology, pathology, and genomics — 6 of whom were from the United States and 13 from Europe. Panel members were charged with reviewing all available data from published prospective clinical trials of neoadjuvant therapy as well as unpublished presentations made at major scientific meetings.

The major recommendations concerned 5 management issues.

Goals and indications of neoadjuvant therapy. The most important clinical goals remain to improve disease-free and overall survival and enable more limited surgery. Neoadjuvant therapy increases the rates of conservation for patients with locally advanced disease. There is still controversy about proper management in patients whose response to neoadjuvant therapy is suboptimal, as well as the extent of axillary surgery in patients who had involved nodes at presentation. Any patient who is a candidate for adjuvant systemic therapy can be considered for neoadjuvant treatment. However, neoadjuvant therapy should not be recommended if there is any uncertainty about the appropriateness of or need for systemic therapy.

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Menstrual Changes And Fertility Issues

Neoadjuvant And Adjuvant Chemotherapy: Which Is Better?

For younger women, changes in menstrual periods are a common side effect of chemo. Premature menopause and infertility may occur and could be permanent. If this happens, there is an increased risk of heart disease, bone loss, and osteoporosis. There are medicines that can treat or help prevent bone loss.

Even if your periods stop while you are on chemo, you may still be able to get pregnant. Getting pregnant while on chemo could lead to birth defects and interfere with treatment. If you have not gone through menopause before treatment and are sexually active, its important to discuss using birth control with your doctor. It is not a good idea for women with hormone receptor-positive breast cancer to take hormonal birth control , so its important to talk with both your oncologist and your gynecologist about what options would be best for you. When women have finished treatment , they can safely go on to have children, but it’s not safe to get pregnant while being treated.

If you think you might want to have children after being treated for breast cancer, talk with your doctor soon after being diagnosed and before you start treatment. For some women, adding medicines, like monthly injections with a luteinizing hormone-releasing hormone analog, along with chemo, can help them have a successful pregnancy after cancer treatment. To learn more, see Female Fertility and Cancer.

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Adjuvant And Neoadjuvant Breast Cancer Treatments: A Systematic Review Of Their Effects On Mortality

Clinical guidelines recommend > 20 adjuvant or neoadjuvant breast cancer options.

Randomised data on 100010,000 women are available for most options.

Breast cancer mortality or recurrence was reduced by 1025% for most options.

Anthracycline chemotherapy and radiotherapy increased non-breast-cancer mortality.

Radiotherapy-related risks increased with increasing organ dose.

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