Combining Molecular-Driven Approach and Immunotherapy to Improve Treatment for Patients With Inflammatory Breast Cancer

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Massimo Cristofanilli, MD, FACP

These patients do not survive as long as they should because chemotherapy is very ineffective. There are a number of reasons for that, but chemoresistance is one of the hallmarks of this disease, so we need to find a way to combine biologic therapy with immunotherapy.

—Massimo Cristofanilli, MD, FACP

We have a responsibility to develop better treatment for inflammatory breast cancer,”
Massimo Cristofanilli, MD, FACP, told participants at the 17th Annual Lynn Sage Breast Cancer Symposium in Chicago. As recently appointed Associate Director of Translational Research and Precision Medicine at the Robert H. Lurie Comprehensive Cancer Center, Northwestern University, Chicago, Dr. Cristofanilli is overseeing efforts there to develop a molecular pattern–driven therapeutic approach to improve treatment for patients with inflammatory breast cancer and other malignancies.

Inflammatory breast cancer is “the most aggressive and lethal form of the disease,” Dr. Cristofanilli said, with a large proportion of patients experiencing early recurrence and surviving less than 5 years. “These patients do not survive as long as they should because chemotherapy is very ineffective. There are a number of reasons for that, but chemoresistance is one of the hallmarks of this disease, so we need to find a way to combine biologic therapy with immunotherapy,” Dr. Cristofanilli elaborated in an interview with The ASCO Post.

Distinct but Not Rare Disease

It is a misconception that inflammatory breast cancer is a rare disease. “It is distinct but not a rare type of breast cancer,” Dr. Cristofanilli said. This misconception about inflammatory breast cancer is “related to the fact that it is frequently misdiagnosed and underdiagnosed,” Dr. Cristofanilli said, “and that is a major problem.”

As a clinicopathologic entity, inflammatory breast cancer is “defined by rapid onset of diffuse erythema” and “edema of the breast without underlying mass.” According to Dr. Cristofanilli, 95% of women presenting with erythema first receive antibiotics, sometimes for up to 6 months. “These are not women who go to a tertiary center or see a specialist right away. They may go to the family physician, then to their obstetrician/gynecologist. So they go through a number of steps,” he said.

Some women who have a delayed diagnosis have been breastfeeding. “If you are breastfeeding and have swollen and red breasts, your first impression is it must be an infection. But if after a week your infection has not improved, there must be a reason for that.” Other women who present with swollen breasts report that it happened over a very short period of time and that a mammogram was negative just months ago.

No Conservative Surgery

Treatment for inflammatory breast cancer requires multimodality therapy, with chemotherapy, mastectomy, and radiation therapy. “There is no conservative surgery, no skin-sparing mastectomy, no lumpectomy” for patients with inflammatory breast cancer, Dr. Cristofanilli noted.

Even with this treatment, a large proportion of patients experience early recurrence (within the first 2 years). Many patients do not reach 5-year survival. “Even in the latest statistics,” Dr. Cristofanilli said, “overall survival is only around 36 months.” Prognosis is worse than for other types of breast cancer, even when matched for standard biomarkers—estrogen receptor, progesterone receptor, and HER2.

“So what can we do to improve on this modality of treatment, and what can we add? First of all, we can certainly look at the possibility of improving the neoadjuvant systemic therapy,” Dr. Cristofanilli said. That could involve combining chemotherapy and radiation therapy upfront “in patients who are refractory and not able to achieve tumor response with chemotherapy before mastectomy,” he said.

“Another question that remains open is: What type of adjuvant chemotherapy can we use in patients for whom chemotherapy has failed, who have extensive disease, and who have a high chance of recurrence, where standard endocrine therapy may not be enough?” he added.

A Role for Immunity

“It is well established that the molecular subtypes are represented in both inflammatory and noninflammatory disease, but there is an immune signature that appears in inflammatory patients,” Dr. Cristofanilli said.

“In the search for a multigene predictor of pathologic complete response in [inflammatory breast cancer] using DNA microarrays, a 107-gene signature was found that distinguished between responders and nonresponders.1 This signature was enriched for immunity-related genes, showing that in [inflammatory breast cancer], as in [other types of breast cancer], response to neoadjuvant chemotherapy is associated with immunity-related processes,” Dr. Cristofanilli reported, “clearly suggesting there is a role for immunity in this particular disease.”

The same group of researchers also looked at the expression of programmed cell death protein ligand 1 (PD-L1) “to see if checkpoint inhibition would be important for predicting and eventually reducing the chance of recurrence in these patients,” Dr. ­Cristofanilli said. “They found that PD-L1 expression was actually associated with recurrence, although the small numbers do not lead to evidence of any disease survival difference. These results were just published this year.”2

Genomic Profiling Study

Genomic analysis has identified novel drivers and targetable pathways in inflammatory breast cancer. In a genomic profiling study reported just this November by Dr. Cristofanilli and colleagues,3 “the most important information is that mutations were detected pretty much in every patient,” Dr. Cristofanilli said.

Comprehensive genetic profiling was done on 53 formalin-fixed paraffin-embedded specimens of inflammatory breast cancer. The median number of mutations was five. Clinically relevant genomic alterations, defined as genomic alterations “associated with on-label targeted therapies and targeted therapies in mechanism-driven clinical trials” were present in 96% of the cases.

The most frequently altered genes were TP53 (62%), MYC (32%), ­PIK3CA (28%), ERBB2 (26%), FGFR1 (17%), BRCA2 (15%), and PTEN (15%). In the triple-negative breast cancer subset (39% of the patients), 8 (42%) of 19 showed MYC amplification vs 9 (28%) of 32 in non–triple-negative inflammatory breast cancer.

“There are clearly three major pathways: the cell cycle and apoptosis pathway, the PI3K pathway, and the RTK/RAS pathway,” Dr. Cristofanilli reported. “These are now guides for us to look at what type of specific treatment—either standard or investigational treatments in clinical trials—we can use for selected patients with inflammatory breast cancer.” He noted the high proportions of mutations in the cell cycle and apoptosis pathway, “suggesting that underlying genomic instability will be important to target and consider in the selection of treatment.”

Pathways Talk to Each Other

An unpublished study of 20 pair-matched cases of inflammatory breast cancer revealed variations within and across tumors. Intratumor heterogeneity analysis found that the majority of genetic variants occurred at low frequencies in individual tumors, and intertumor heterogeneity analysis found that the majority of genes showed low levels of variation across tumor samples.

Looking at genomic variation in core pathways and processes shared across inflammatory breast cancer cases, PI3K “seems to be extremely important for survival and proliferation,” whereas APC/WNT and NOTCH are more involved with cell fate. “This is very important for developing therapies to reduce the chance of recurrence,” Dr. Cristofanilli noted.

Inflammatory breast cancers harbor frequent genomic alterations in ERBB (HER) and PI3K pathways and many variants detected in the PI3K/ERBB pathway are predicted to functionally activate the pathway. “The ERBB pathway and the PI3 kinase pathway talk to each other,” Dr. Cristofanilli said, “and this is very important to targeted therapy.”

Summarizing recent studies, Dr. Cristofanilli noted that next-generation sequencing analysis can identify multiple potentially targetable lesions in inflammatory breast cancer based on current therapies and drugs in development. The higher mutation rates in ERBB3 for inflammatory breast cancer than for other cancers may mean it is a new target in inflammatory breast cancer.

“ERBB-targeted therapies for [inflammatory breast cancer] may be associated with resistance due to a high level of PI3K pathway variants. Combination therapy is important,” Dr. Cristofanilli reported. “Preliminary data,” he added, “suggest that [next-generation sequencing] can be used to predict the level of immune infiltrates in [inflammatory breast cancer] tumors.”

Ongoing Trial for Patients With Metastases

Inflammatory breast cancer is characterized by cell aggregates defined as “tumor emboli” that metastasize into the chest wall and skin and express e-cadherin. About 25% of patients with inflammatory breast cancer develop brain metastases because of this disease.

A phase I/II study at Northwestern is testing romidepsin (Istodax) in combination with nab-paclitaxel ­(Abraxane) in patients with metastatic inflammatory breast cancer. “Phase I has been completed,” Dr. Cristofanilli said, and the 10-mg dose is safe. “We have already seen evidence of a response very early on, suggesting that even in patients who are less heavily pretreated, there is a possibility that we can affect the metastatic process of this disease.”

Continuing inflammatory breast cancer–directed research, including the use of preclinical models, is needed to better understand the disease and the patient, Dr. Cristofanilli advised. Future steps will involve “looking very deeply into germline analysis,” he said, as well as “investigating checkpoint inhibitors in immunotherapy, first in an advanced setting and maybe later in neoadjuvant therapy.” ■

Disclosure: Dr. Cristofanilli reported no potential conflicts of interest.


1. Bertucci F, Ueno NT, Finetti P, et al: Gene expression profiles of inflammatory breast cancer: Correlation with response to neoadjuvant chemotherapy and metastasis-free survival. Ann Oncol 25:358-365, 2014.

2. Bertucci F, Finetti P, Colpaert C, et al: PDL1 expression in inflammatory breast cancer is frequent and predicts for the pathological response to chemotherapy. Oncotarget 6:13506-13519, 2015.

3. Ross JS, Ali SM, Wang K, et al: Comprehensive genomic profiling of inflammatory breast cancer cases reveals a high frequency of clinically relevant genomic alterations. Breast Cancer Res Treat 154:155-162, 2015.