Triple Negative Breast Cancer Not Responding to Chemo

Triple-negative breast cancer (TNBC) is difficult to treat due to its aggressive nature. It often responds initially to chemotherapy but is the most common breast cancer to recur; when it recurs, it is more resistant to chemotherapy, making it less responsive and more challenging to treat.

This article discusses current research for new TNBC medications, options for unresponsive TNBC, alternative and complementary therapies to help with treatments' side effects, and where to find support.

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The Missing Link in TNBC and Chemo Research

Cytotoxic (cancer-cell-killing) chemotherapy has been the primary treatment therapy for triple-negative breast cancer. Doses are often high, given triple-negative breast cancer’s aggressive nature.

In the past decade, scientists have searched for alternative treatment options that require lower doses and minimize chemotherapy's side effects.

Combination therapy (chemotherapy with a non-chemotherapy medication) is one potential option scientists are exploring. With this treatment, the chemotherapeutic medications will kill the cancer cells, while non-chemotherapy medicines, such as a drug-inhibited tumor-associated macrophage, will block the body’s immune response against the tumor; together, they will effectively destroy the cancer cells.

Research indicates the two-step approach may effectively treat highly aggressive triple-negative breast cancer tumors and prevent metastasis (cancer spread).

Some of the alternative options that still need further evaluation include the following:

  • Use of third-generation chemotherapy medications (a newer class of agents)
  • Use of metronomic polychemotherapy (continuous, daily, or weekly low-dose drugs administered for a longer time)
  • Platinum chemotherapy medications interfere with the deoxyribonucleic acid (DNA) responsible for cellular activity, preventing cancer cell growth

Treatment Options for Unresponsive TNBC After Chemo

TNBC is an aggressive form of breast cancer with limited treatment options. Because triple-negative breast cancer does not respond to hormonal therapy or other medicines that target the HER2 gene, chemotherapy is the most frequent treatment option.

However, given TNBC's aggressiveness and resistance to treatment options, finding additional treatment options to target the cancer is critical to long-term treatment success. There are two relatively recent treatment options now available:

  • Trodelvy (sacituzumab govitecan-hziy): Trodelvy received accelerated U.S. Food and Drug Administration (FDA) approval as a targeted therapy specifically for triple-negative breast cancer. Trodelvy targets a specific cancer cell receptor that prevents cancer growth and spread.
  • Keytruda (pembrolizumab): Keytruda received FDA approval to treat triple-negative breast cancer that cannot be surgically removed or has grown beyond the initial site of the cancer tumor.


If triple-negative breast cancer has been successfully treated but comes back, it is considered recurrent. Treatment options for recurrent TNBC include:

  • Surgical removal of the breast cancer
  • Chemotherapy in combination with an antibody-drug conjugate, such as sacituzumab govitecan-hziy
  • Participation in various clinical trials for newer TNBC therapies


Metastatic cancer has spread elsewhere from the initial breast cancer site. Treatment for triple-negative breast cancer is more complex when the cancer metastasizes. In addition to standard chemotherapy medications, treatment considerations for metastatic TNBC include:

  • Adding platinum chemotherapy medications, such as Platinol, Platinol-AQ (cisplatin), or Paraplatin (carboplatin)
  • Poly (ADP-ribose) polymerase inhibitors, such as Lynparza (olaparib) or Talzenna (talazoparib), which prevent cancer cells damaged by chemotherapy from repairing themselves. The tumors of people with triple-negative breast cancer may carry BRCA1 or BRCA2 mutations and Lyparza or Talzenna are particularly useful in this situation.
  • An immunotherapy, like pembrolizumab, if the TNBC cells have a specific type of protein that’s susceptible to it

CAM Therapies

Complementary and alternative medicine (CAM) do not cure triple-negative breast cancer. Still, they can help people affected by TNBC find relief from treatment side effects, such as nausea, pain, or fatigue.

Discussing CAM therapies with your healthcare provider to ensure their inclusion won't adversely affect your current treatment plan is essential. CAM therapies include:

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  • Mind-body therapies: These therapies combine internal focus, breathing, and body movements to relax the body and mind. Some examples include meditation, biofeedback, hypnosis, yoga, tai chi, and visual imagery.
  • Biologically based practices: Biologically based practices use elements of nature. This includes vitamins, dietary supplements, botanicals, spices (like turmeric), plants (like cannabis), and special foods or diets.
  • Manipulative and body-based practices: This includes massage therapy or reflexology.
  • Energy healing: This type of healing focuses on balancing your internal energy flow. Examples of energy healing include reiki and therapeutic touch.
  • Whole medical systems: Whole medical systems are based on healing beliefs from other cultures and parts of the world and are not typically found within traditional Western medicine. These include Ayurvedic medicine, traditional Chinese medicine, and naturopathic medicine.

Emotional and Physical Burden of Unresponsive TNBC

Triple-negative breast cancer treatment can cause a multitude of physical symptoms, including:

  • Nausea
  • Hair loss
  • Fatigue
  • Swollen lymph nodes

Cancer can also affect your emotional health in various ways. Feelings might change from moment to moment and get intense at times. It is entirely normal to have a wide range of emotions, including:

  • Feeling overwhelmed
  • Anger
  • Fear and worry
  • Hope
  • Gratitude
  • Stress and anxiety
  • Sadness or depression
  • Guilt
  • Loneliness

Some suggested ways to cope with these emotions include the following:

  • Express your feelings
  • Don't blame yourself for your cancer
  • Don't pretend to be happy or positive when you are not
  • Find support to work through your emotions
  • Identify what you can control, such as activity level or diet choices

Where to Find TNBC Support

There are several organizations dedicated to supporting people diagnosed with breast cancer. The following organizations offer support, access to prevention and screening, recommendations to find appropriate healthcare professionals, and much more:


Triple-negative breast cancer (TNBC) accounts for 15–20% of all breast cancers and is considered the most aggressive form of breast cancer. Triple-negative breast cancer lacks certain receptors (estrogen, progesterone, and HER2), meaning treatment is usually limited to chemotherapy.

Although triple-negative breast cancer initially responds well to chemotherapy, it is more likely to recur and come back more resistant to treatment. Researchers continue to study new medication options, including combination therapy. Side effects from chemotherapy are often present, but complementary and alternative therapy options may help address symptoms.

TNBC can cause many physical and emotional challenges, so understanding where to find support and resources is essential to your overall health and recovery.

A Word From Verywell

A breast cancer diagnosis can generate many emotions, from feeling overwhelmed and scared to angry and sad. Speak to your healthcare providers about resources to help you cope and find support through treatment.

— Update: 06-01-2023 — found an additional article Breast cancer resistance to chemotherapy: When should we suspect it and how can we prevent it? from the website for the keyword triple-negative breast cancer not responding to chemo.

4. Measurement of chemotherapy response

Neoadjuvant chemotherapy has traditionally been used to treat locally advanced and initially inoperable breast cancer. One of the main reasons for applying a systemic therapy before rather than after curative surgery is the potential size reduction of a malignant tumor, which is thought to permit less-invasive curative surgery. In addition, clinical and pathological remission can be achieved before surgery, which can improve outcomes. Unfortunately, although in many cases a clinically meaningful remission can be achieved, not all patients benefit equally. Some tumors even increase in size despite ongoing chemotherapy, suggesting resistance. Nevertheless, neoadjuvant and adjuvant chemotherapy are still applied empirically, since no clinical tests currently exist that would allow reliably predicting the response to and benefit from a particular chemotherapy. Therefore, the effectiveness of the chemotherapy response must be assessed.

Surgical planning may be affected by tumor response patterns. Concentric shrinkage or a scattergun or honeycomb response may occur (Fig. 4); in the latter, the remaining carcinoma appears as many scattered foci over an ill-defined tumor bed [21]. This pattern of reaction is especially challenging when planning surgical treatments since clear margins are more difficult to attain [22].

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The effectiveness of chemotherapy can be assessed clinically or pathologically. Clinical changes from chemotherapy are measured, such as tumor shrinking, which is an indicator of a good response [24,25]. This could be evaluated after chemotherapy by physical examination, mammography, ultrasonography, computed tomography (CT) scan, or magnetic resonance imaging (MRI) [26] after at least 2–3 administrations of chemotherapy [25,27]. The accuracy for determining pCR in locally advanced breast cancer after neoadjuvant chemotherapy is 57% for physical exam, 74% for mammography, 79% for ultrasonography, and 93% for MRI [28].

Each measurement method has its advantages and disadvantages. Clinical measurement with a caliper is very easy to do but has drawbacks. Sometimes discrepancy exists between the chemotherapy response assessed by clinical examination and pathological study of the surgical specimen.

The presence of solid fibroglandular tissue and posttherapy fibrosis can cause the amount of residual illness to be overestimated during physical examination. Mammography and ultrasound had 74% and 79% accuracy for detecting postneoadjuvant pathologic tumor response, respectively, in a report of six investigations [28]. Mammography has been demonstrated to be more sensitive than physical examination in detecting the presence of residual tumor following treatment, although it is less specific and may underestimate the degree of treatment response [29,30]. After neoadjuvant therapy, ultrasound has proven a better predictor of pathologic tumor size than mammography [28,31]. In addition, when compared to mammography and physical examination, ultrasound is the most accurate predictor of axillary lymph node response [32]. When both modalities are negative, the combination of mammography and ultrasound appears to be the best technique for predicting complete pathologic response (80% chance) [31,33].

Breast MRI is the most sensitive imaging modality for detecting breast cancer [30,34] and the most reliable imaging modality for assessing tumor response to neoadjuvant therapy [28,35,36]. The positive predictive value (ability to accurately identify the presence of residual disease at the final pathologic examination) was high in a combined analysis of six investigations, at 93 [28]. The negative predictive value (ability to accurately identify the absence of disease at the final pathologic examination) was only moderate (65%), lowering the overall diagnostic accuracy to 84% [28,30].

The residual tumor size measured on MRI and the pathologic tumor size determined following surgical excision are generally in good agreement. A systematic review by Lobbes et al. discovered that MRI can overestimate or underestimate the residual tumor size, with a median correlation coefficient of 0.70 (range, 0.21–0.98) [35].

No criteria currently exist for reporting the tumor response to neoadjuvant therapy based on imaging. The current edition of the American College of Radiology Breast Imaging Reporting and Data System lacks clear guidelines on how to submit follow-up imaging for assessing the response to therapy. Typically, the biggest dimension measurement is used to compare tumor size before and after treatment. Descriptive patterns of tumor response, such as mammographic lesion density decrease, change in internal echotexture, and concentric versus fragmented lesion shrinking with intervening normal-appearing tissue, may also be beneficial [30].

In clinical practice, fluorodeoxyglucose positron emission tomography (FDG PET) imaging is the most commonly used molecular imaging agent for imaging tumor glycolytic metabolism with PET. FDG PET imaging can be used for optional systemic staging and restaging of patients with stage III illness, locally progressed and inflammatory breast cancer, and recurrent and/or metastatic breast cancer, according to the most recent National Comprehensive Cancer Network guidelines. It is especially useful when the results of standard staging investigations (CT or MRI with bone scan) are inconclusive [25].

FDG PET has been evaluated in many studies for predicting the pathologic response to neoadjuvant treatment [[38], [39], [40], [41], [42]]. The largest prospective multicenter analysis included 272 examinations of 104 patients with newly diagnosed large or locally advanced non-inflammatory primary breast cancer who were also enrolled in a trial comparing two preparatory chemotherapy regimens [43]. A threshold of a 45% drop in standardized uptake value accurately identified 11 of 15 histopathologic responders following the first cycle of chemotherapy. Nonresponders had a negative predictive value of approximately 90% (34 of 38). FDG PET imaging thus appears to help predict neoadjuvant chemotherapy response and detect early nonresponders [30].

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The effectiveness of chemotherapy on cancer cells is measured in terms of response. In 1981, the World Health Organization (WHO) developed a method for assessing tumor response bi-dimensionally, measuring the longest size of a tumor and its size perpendicular to that length [24]. In 1999, a new tumor response assessment method known as the Response Evaluation Criteria in Solid Tumors (RECIST) was introduced to measure uni-dimensional tumors. It was updated in 2009 (RECIST 1.1). The RECIST and WHO criteria each have advantages and disadvantages. Currently, RECIST is most used because the criteria are simpler [26,44,45].

Currently, in addition to RECIST 1.1, the Positron Emission Tomography Response Criteria in Solid Tumors (PERCIST) is available [30,46]. The response to therapy is measured as a continuous variable and expressed as a percentage difference in the SUL peak (or sum of lesion SULs) between pre- and posttreatment scans. In simple terms, a full metabolic response is the visible removal of all metabolically active tumor cells. A partial response is defined as a decrease in SUL peak of more than 30% and 0.8 units between the most intense lesion before therapy and the most intense lesion after treatment, which does not have to be the same lesion. Progressive illness is defined as an increase in SUL peak of more than 30% and new lesions of more than 0.8 units, if verified. Another indicator of advancement is a 75% rise in total lesion glycolysis [46].

Based on RECIST, responses are classified as a complete response, partial response, stable disease, or progressive disease. Complete response is the loss of all tumor masses. Partial response is a tumor that becomes at least 30% smaller than the longest diameter of the tumor. Stable disease is where the tumor size decrease is not enough for a partial response, but the tumor does not increase in size and become a progressive disease. Progressive disease is where a tumor increases by at least 20% of the longest diameter [24,45].

Pathological responses are more meaningful and reliable markers of life expectancy than clinical responses. However, pathological evaluation is more difficult because histopathological tissue assessment is conducted using core biopsy or during surgery. Pathological responses after chemotherapy induction in breast cancer are predictors of DFS and overall survival. Several classifications have been recommended, such as the Miller and Payne classification (Table 4), which is based on cell loss after more reliable therapy [[47], [48], [49]]. Based on this classification, pathological responses are divided into five levels based on the degree of death and cell damage [49].

In the Miller–Payne system, pathologic response is divided into five grades based on comparison of tumor cellularity between pre–neoadjuvant therapy core biopsy specimens and definitive surgical specimens. A grade of 1 indicates no change or some alteration in individual malignant cells but no reduction in overall cellularity (pathologic nonresponse); a grade of 2, minor loss of tumor cells but still high overall cellularity of up to 30% (pathologic partial response); a grade of 3, an estimated reduction in tumor cells of between 30% and 90% (pathologic partial response); a grade of 4, a marked disappearance of tumor cells such that only small clusters or widely dispersed individual cells remain, with more than 90% loss of tumor cells (almost pathologic complete response); and a grade of 5, no malignant cells identifiable in slices from the site of the tumor and only vascular fibroelastic stroma remaining, often containing macrophages, but ductal carcinoma in situ may be present (pathologic complete response) [49].

Clinical responses are often inconsistent with pathological responses, especially since the first stage of DNA fragmentation is difficult to evaluate with certainty. Therefore, the evaluation of specimens obtained from mastectomy is the gold standard for determining response to therapy [50].


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About the Author: Tung Chi