We are facing difficult decisions and choices as we await the tsunami of COVID-19 cases. Despite the experience of our Chinese colleagues and their government through January, we did not anticipate the surge of infection and institute appropriate contagion policies at entry points and ramp up our medical supplies and capacity. As shown by recent graphs, we are about to hit the exponential phase of the outbreak, on track with China, Italy, and the rest of Europe. Britain may prove the unfortunate exception as they eschewed social distancing for the concept of “herd immunity” until just recently. The British National Health Service has less capacity than other systems; therefore, it is less able to react to this policy. Conversely, the countries that have “flattened the curve,” including Taiwan, South Korea, and Singapore, were the ones who developed effective strategies during the prior 

SARS) epidemic. They instituted aggressive screening at entry points and quarantining of suspected infected individuals.

As I walk through the streets of Manhattan today, I am reminded of walking through a ghostly Times Square on 9/11. All aspects of communal life have ground to a halt for the foreseeable future. Cultural institutions have shut down. We are sheltering in place. We, at Rutgers, have delayed elective surgeries, exchanged in-person routine follow-ups for phone or telemedicine interactions, and reduced staff gatherings or conferences in favor of video conferencing. Walking through the quiet hospital today seems like a slow weekend day, yet we know that soon we will be overwhelmed. We must learn the appropriate lessons for the next inevitable pandemic.

As Governor Andrew Cuomo of New York stated last week, if you do the math, you will break out in a sweat, hives, and palpitations. Nine million people live in New York City (NYC). If one-third of the population are infected, there will be 3 million cases, and if 10% require hospital-level care, 300,000 hospital beds will be needed. If 1% require intensive care unit (ICU)-level care and ventilators, that means 30,000 intensive beds will be needed. NYC has about 27,000 hospital beds and 5000 ICU beds, not to mention an inadequate number of medical professionals, including respiratory care therapists. I spent 30 years training and attending at Bellevue Hospital and New York University, and was on the frontline of the AIDS epidemic. I know there is no excess capacity. There is no excess capacity in NYC hospitals and our facilities are on the edge of being overwhelmed.

The federal government has failed to prepare in advance for this crisis, lead during the crisis, or plan for its aftermath. Blame has been shifted to prior administrations and current efforts have been shifted to state and city governments. Federal responsibility has been absent even though we are dealing with an infectious agent that does not recognize geographic or political boundaries, race, ethnicity, or political affiliation. We need a surge capacity of 5 to 10 times the current capacity. Healthcare workers are on the frontline, yet we do not have the basic equipment to fight this war. The federal government should nationalize medical supply production and acquisition to ensure supply and prevent crippling price gouging. A coordinated federal response is necessary to prevent our tightly stretched medical network from breaking.

What are we facing and what are we doing:

1.     Lack of testing is a critical problem. We are quarantining our staff who have had fevers despite minimal or no exposure. We need tremendous access to nucleic acid testing to screen those who are symptomatic and those who are asymptomatic, yet are potentially exposed. We are forcing desperately needed medical personnel to shelter in place since we cannot tell who is infected with COVID-19. We also need increased access to enzyme-linked immunosorbent assay testing for immunoglobulin (Ig) M and IgG antibodies to determine who is immune and safe from further infection. This problem has yet to be discussed in detail.

2.     No meetings except online. I still miss seeing my colleagues, but safety first.

3.     Lack of personal protective equipment. N95 respirator masks and other protective gear are already being rationed and the peak is coming in the next 2 to 3 weeks when demand will explode. Our first responders and healthcare providers are incredibly vulnerable to infection. In China, exposed medical care providers were housed in special dormitories and hospitals to prevent potentially spreading the infection outside, yet this has not been discussed in the United States.

4.     Cancelling all nonessential patient interactions and scheduling telemedicine or phone encounters.

5.     Rotating our research staff, with half on site and half working at home on alternate days. This buddy system has worked well and now extends to our clinical nursing staff.

6.     Continuing routine cancer care and treatment as an “essential service.” We will continue to do this as long as we have the necessary personnel and resources and as long as it is deemed safe to bring in these vulnerable patients.

 clinical trials also as “essential research.” Accrual to nontherapeutic trials has been suspended. The FDA and National Cancer Institute have issued guidelines on clinical trial patient care at local offices and laboratories with remote interactions. Oral investigational agents can be shipped to patients. We will continue this approach as long as we have the personnel and resources necessary.

8.     Beginning to triage. Colleagues in Washington State are already making contingency plans to cease treating patients with cancer. We are not thinking in that direction yet but are certain to consider prioritizing potentially curative treatments over “palliative” treatments. Difficult choices are ahead.

The next few weeks will be replete with daily challenges and crises. I encourage you to read the 

Handbook of COVID-19 Prevention and Treatment

 which details management policies developed through difficult experience by our Chinese colleagues. The Jack Ma Foundation and Alibaba Foundation have enabled us to download it at: https://covid-19.alibabacloud.com.

We will continue, as always, to do our duty to render the absolute best care to our patients and remain healthy ourselves. I extend my heartfelt prayers for your health and safety in the coming days.

Oncology in the Time of COVID-19

Immunotherapy applications for head and neck squamous cell carcinoma (HNSCC) are rapidly evolving. The progress towards immunotherapy has demonstrated improved outcomes for patients with HNSCC. Human papillomavirus (HPV)-associated HNSCC has a much better prognosis and differs from HPV-negative HNSCC in its genomic and immunologic profile, with strikingly higher immune cell activation and infiltration. Despite an increased incidence of HPV-associated HNSCC, and differences in immune signature based on HPV status, the management does not differ from non-HPV tumors. Clinical trials are ongoing to integrate immunotherapy in the management of early- and late-stage HNSCC, and its current use is limited to the metastatic setting. This article describes the role of immune therapy in HPV-associated HNSCC along with the evidence and perspective behind differing therapeutic considerations.

In the United States, head and neck squamous cell carcinoma (HNSCC) accounts for 4% of all malignancies; its estimated annual incidence is 53,260, and HNSCC was responsible for 10,750 deaths in 2020. 

 In addition to the traditional risk factors of alcohol and tobacco use, human papillomavirus (HPV) has been implicated in the pathogenesis of HNSCC. The incidence of HPV-positive oropharyngeal cancer has been increasing in the United States and worldwide. Although HPV positivity is seen in all areas of the head and neck, the majority of evidence on the effect of HPV in cancer biology and prognosis is in the oropharyngeal cancers; estimates from the American Cancer Society suggest that pharyngeal cancers make up about 17,950 new cases and were attributed to 3640 deaths in 2020.

 The treatment implications of HPV-associated HNSCC are important, as the risk of death has been shown to be 60% to 80% lower with conventional therapy as compared with HPV-negative oropharyngeal cancers.

A study published in 2006 by Weinberger et al found that molecular classification suggested a favorable prognosis in a subset of patients with HPV-associated oropharyngeal cancers that overexpressed p16 with lower levels of p53 and Rb expression.

 The DAHANCA 5 (Danish Head and Neck Cancer Group 5) trial demonstrated that p16 positivity was associated with a 5-year locoregional control rate of 58% and an overall survival (OS) of 62%.

 Although conventional treatments including surgery, radiation, and conventional chemotherapy have good efficacy, patients who relapse with distant metastasis often have dismal outcomes.

 These poor outcomes following relapse after conventional treatment have led to a call for more research into tumor-specific targeted therapy. Immunotherapies offer promising treatment potential as tumors in the head and neck generally infiltrate important structures and complete surgical resection may be difficult, leading to a poor overall prognosis.

HPV is a virus that can infect the skin and mucosal surface of the oral pharynx, throat, and anogenital region.

HPV infection is common, and it is thought to occur through mucosal contact with an infected sexual partner. Patients with HPV-associated HNSCC are usually younger and healthier, with less lifestyle risk factors than patients who do not have HPV-driven tumors.

 A key aspect of HPV infection and the development of HPV-positive HNSCC is that it occurs in the setting of a persistent HPV infection.

Evolution of cancer is a multistep process whereby cells acquire a number of traits that enables transition from normal to neoplastic behavior. Ineffective immune response results in what may be a protracted state of inflammation. While the heightened immune response should be associated with  robust antitumoral activity, the inflammatory response has the paradoxical effect of promoting tumorigenesis. Further intriguing is that the tumor-enhancing effect is disproportionately mediated by cells of the innate immune system.

A recent study conducted by Sonawane et al found that 1 in 9 men between the ages of 18 to 69 was infected with oral HPV.

 Several strains of HPV cause infection, some benign and some with high-risk potential. DNA from high-risk HPV strains may be integrated into the genome of the human cell, which can lead to an overexpression of viral oncogenes 

 is thought to bind cycle cell–regulatory protein p53, leading to its degradation and subsequent uncontrolled tumor cell growth. 

 has an additive oncogenic function whereby it binds to and degrades Rb, a tumor suppressor that blocks exit from the G1 phase of the cell cycle, thus regulating 

HPV infection is now responsible for the largest number of oropharyngeal tumors in the United States, accounting for 45% to 90% of cases.

 HPV positivity is detected in 25% of all HNSCCs.

 Notably, survival is markedly higher in patients with HPV-associated HNSCC compared with those with HPV-negative HNSCC (3-year survival rate of 84% compared with 57%, respectively).

Research has identified that HPV-positive head and neck cancers are a distinct subset, genetically and molecularly.

 There are several mechanisms by which immune evasion in these tumors may be explained. Some of these include interference with antigen presentation, modulation of transcriptional activity of genes, upregulation of cytokines, and interaction of immune checkpoint receptor signaling. HPV-positive HNSCCs have more markers of immune infiltration and CD8+ T-cell activation than HPV-negative HNSCCs, a potential target for harnessing adaptive antitumor immune response systems.

 Infection with high-risk HPV types (HPV 16, 18, 31, and 33) plays a causal role in the pathogenesis of oropharynx squamous cell carcinoma (OPSCC), and has distinct clinical and molecular features. More than 90% of HPV-associated OPSCC in the United States is attributed to HPV high-risk type 16, with rare accounts of HPV type 18, 33, and others reported as responsible in the literature.

In addition to higher levels of CD8+ T-cell activation, HPV-positive tumors also have higher expression of perforin and granzyme A and B, indicating immune activity.

 Many mechanisms of cell cycle regulation escape have been described in HPV-positive HNSCC, including the development of T-cell tolerance to HPV infection, reduced regulation by interferon gamma, unbalanced signal transducer and activator of transcription (STAT) 1 and 3 signaling, secretion of immunosuppressive cytokines, expression of programmed cell death-ligand 1 (PD-L1), and downregulation of human leukocyte antigen expression and processing which allows the immune system to recognize and tag tumors before destruction.

 Higher expression of the immunoinhibitory receptor cytotoxic T lymphocyte-associated antigen-4 (CTLA-4) has been found in HPV-positive HNSCC (

 = .003) and appears to have a correlation with higher regulatory T cells (Tregs) expression (r = 0.866, 

CTLA-4 is a protein receptor that like PD-L1, works to downregulate the immune system’s natural response to attack tumor cells and is generally expressed on Tregs. Interferon gamma (IFN-É£) has also shown to play a role in HPV-positive HNSCC pathogenesis. Escape from detection by cytotoxic T cells is thought to be related to IFN-É£ deficiency, which activates STAT1 transcription to prevent tumor escape from regulation.

Current research surrounds treatment that may alter the tumor’s inflammatory and pro-growth environment, including toll-like receptor stimulation, inhibition of interleukin-6 (IL-6) pathways, immune checkpoint inhibition, and modulation of Tregs and macrophages.

 are potential targets for immune intervention, as are T cells that express programmed cell death protein 1 (PD-1), a marker that has a self-tolerance-promoting and negative regulatory role on T cells, which typically attenuates infective processes and tumor proliferation.

Existing Literature on the Role of Immunotherapy in HPV-Associated HNSCC 

Currently, treatment of HPV-associated oropharyngeal carcinoma resembles non-HPV oral cancers. Although clinical trials evaluating de-escalation of therapy are underway, HPV status does not yet alter the standard treatment course. The current management of oropharyngeal carcinoma utilizes a combination of chemotherapy, radiation, and possibly surgery. However, if patients develop metastatic disease, options are mainly systemic treatments with a palliative intent. There is increasing consensus that HPV-associated HNSCC may benefit from less intensive management regimens; however, presently only retrospective data support this. There are several ongoing clinical trials analyzing de-intensified regimens for HPV-positive oropharyngeal cancer. Overall, the strategies include modification of systemic therapies, surgical procedures, radiation dosing and techniques, and use of immunotherapy or targeted therapies. 

Significant improvements in survival have been observed with PD-1 inhibitors in melanoma, non–small cell lung cancer, and renal cell carcinoma.

 PD-1 and PD-L1 are proteins present on the surface of cells that function to distract the immune system from attacking tumor cells.

 HPV-positive tumors have increased expression of PD-L1, making PD-1 inhibitors a promising therapeutic option.

 Promising clinical trial results led the FDA approval of pembrolizumab for treating refractory or metastatic HNSCC in 2016.

 Patients enrolled in the nonrandomized KEYNOTE-012 trial had metastatic HNSCC, which had progressed despite treatment with standard therapies. A total of 16% of patients experienced a response to pembrolizumab. In 82% of these patients, the response lasted for more than 6 months and for several, the response lasted for more than 2 years.

 In the phase III CheckMate 141 study, nivolumab treatment resulted in longer overall survival (OS) as a single therapy agent compared with a standard treatment (median OS of 7.5 months compared with 5.1 months, respectively), with estimates of 1-year survival 19% higher with nivolumab.

 For patients with p16-positive status, the median survival in Checkmate 141 was 9.1 months with nivolumab compared with 4.4 months with standard treatment (HR, 0.56; 95% CI: 0.32, 0.99).

 The KEYNOTE-040 trial randomized patients to pembrolizumab or standard of care chemotherapy for metastatic HNSCC. The median OS in the pembrolizumab group was 8.4 months compared with 6.9 months in the standard treatment group.

 However, in contrast to the results of the CheckMate 141 study, pembrolizumab was not superior to chemotherapy in patients with p16-positive disease (HR, 0.97; 95% CI: 0.63, 1.49).

The KEYNOTE-048 trial compared survival and disease progression in previously untreated patients with recurrent or metastatic HNSCC given pembrolizumab monotherapy or pembrolizumab with chemotherapy (EXTREME regimen: platinum, 5-fluorouracil and cetuximab).

 Data presented recently showed that pembrolizumab monotherapy improved OS by 39% (

 = .0007) in patients whose tumors expressed PD-L1 (combined positive score ≥20) compared with chemotherapy. The median OS was 12.3 months versus 10.3 months, respectively. The benefit was higher in patients with a CPS of at least 20, where the median OS was 14.9 compared with 10.7 months (HR, 0.78; 95% CI: 0.64, 0.96; 

 = .008). When pembrolizumab alone was compared with chemotherapy plus cetuximab, the median OS in the total population favored the combination (13 vs 10.7 months; HR, 0.77; 95% CI: 0.63, 0.93; 

 While approximately 20% of patients in this study were p16-positive, they were not analyzed separately. These studies have been summarized in 

. Many trials assessing combination regimens with PD-1 inhibitors and HPV vaccine studies are currently recruiting patients. These studies are outlined in 

Prediction of Response to Immune Checkpoint Inhibitors

While tumor mutational burden (TMB) has been investigated as a biomarker to study sensitivity to checkpoint inhibition in different malignancies, PD-L1 expression does not always predict who will have an increased response. More studies are needed, potentially utilizing both TMB and PD-L1 assays, to predict response.

 Some of the results assessing biomarkers to predict response to checkpoint inhibitors are shown in 

Currently, several other markers in addition to PD-L1 expression have been identified and are being evaluated. These include HPV expression, IFN-É£ signature score, microsatellite instability, and neoantigen production.

 IFN-É£ related mRNA gene expression signatures have predicted clinical response to pembrolizumab in melanoma with some indication that IFN-É£ and T cell-associated inflammatory genes may predict PD-1 blockade response.

 However, none of these biomarkers have consistently shown to be predictive for response to immune checkpoint inhibitors and further studies are needed.

In addition to PD-L1 and CTLA-4 inhibitors, other monoclonal antibodies are being investigated in HPV-positive HNSCC treatment including monalizumab, a monoclonal antibody targeting natural killer group 2 member A (NKG2A). The NKG2A heterodimeric receptor is one of the most prominent NK inhibitory receptors. Monalizumab blocks cancer cells from evading immune system detection by facilitating activation of natural killer and cytotoxic T cells. 43 IL-6 is another target being investigated for use in immunotherapy, as it is thought to play a role in monocyte differentiation to PD-L1+ macrophages which may lower interleukin-12, increase interleukin-10, and have a consequent suppressive influence on T-cell activation. 

 Current trials evaluating novel immunotherapies are described in 

Immunological features of HPV-positive HNSCC suggest that this tumor type has a high potential for responding to immunotherapy, especially with immune checkpoint inhibitors. Given data showing T-cell infiltration in HPV-positive HNSCC, a different approach-one that focuses on checkpoint inhibition-may be beneficial for these patients. 

The results of clinical trials demonstrating response to checkpoint inhibitors in HPV-positive head and neck tumors are promising. Late phase clinical trials are exploring whether the use of immunotherapy in HPV-associated tumors will allow de-intensification cytotoxic therapies. Despite encouraging responses and improved cancer survival rates with checkpoint inhibitors, a significant proportion of patients are still being treated with them and will not respond. Hence, additional predictive biomarkers are needed to differentiate the patients who will respond to immunotherapy. In addition, there is a need for newer immunotherapeutic agents that will improve responses in this difficult-to-treat patient population.

Financial Disclosure: The authors have no significant financial interest in or other relationship with the manufacturer of any product or provider of any service mentioned in this article.

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A review of the role of immune therapy in HPV-associated head and neck squamous cell carcinoma, along with the evidence and perspective behind differing therapeutic considerations.

HPV and the Immune System in Head and Neck Cancers: Therapeutic Considerations

With the development of immunotherapy and targeted agents, the treatment landscape for patients with breast cancer has evolved immensely, progressing from one-size-fits-all surgeries to the current state of individualized precision medicine. 

 recently sat down with Joyce A. O’Shaughnessy, MD, to discuss the recent trends in breast cancer treatment and the avalanche of agents moving through the development pipeline that have the potential to redefine the accepted standards of care.

What are the major trends in breast cancer today? Do you think there is an overarching theme that is going to be reflected at the breast cancer conferences this year? 

Yes. At all the breast cancer conferences, the novel therapeutics are basically all focused on the molecular drivers of the cancer. For every subtype of breast cancer, there are multiple agents being developed that [target that. So, those are always highlighted because they go hand in hand with…any data on the new agents. Besides that, other things highlighted at the congresses will be advances in immunotherapy for breast cancer. We are kind of new in breast cancer in the immunotherapy space, but we do have exciting data emerging, particularly in the curative setting with triple-negative breast cancer. We also have a new approval in the metastatic setting for triple-negative breast cancer that is programmed cell death protein-ligand 1-positive with atezolizumab (Tecentriq). Everybody is keenly interested in checkpoint inhibitor therapy in the breast cancer space. At all of our congresses, we also highlight locoregional control. There is a trend towards doing less surgery over time, and probably radiation therapy has become a bit more comprehensive for the high-risk patients, but [it is a] shorter course. And even more limited is partial breast irradiation, not whole breast irradiation for lower risk patients. Radiation therapy is becoming personalized. The surgery is becoming personalized. So, we spend a lot of time, because those are very rapidly evolving areas, in locoregional control.

When you talk about “less breast cancer surgery,” are you referring to the trend toward neoadjuvant therapy to see if tumors can be shrunk instead of surgically removed?

 Yes, and so [we are] able to do a lumpectomy instead of a mastectomy because [we] shrunk [the tumor] down, but also less axillary surgery which is very important. [We are] taking out fewer axillary lymph nodes and decreasing the risk of lymphedema.

What are some of the more important recent treatment breakthroughs, and which studies in particular are you looking forward to learning about or hearing about this year? 

 We just recently had the FDA approval [of trastuzumab deruxtecan (Enhertu)], and a lot of these data came out at [the] San Antonio [Breast Cancer Symposium]. All these [results] are so new that it is very important to have our congresses to help bring clinicians up to speed on the data. 

We [can also] expect FDA approval very soon of the oral HER2 tyrosine kinase inhibitor, tucatinib, and for metastatic breast cancer, oral neratinib (Nerlynx). We already have neratinib approved in the extended adjuvant setting for patients with HER2-positive breast cancer. Now we are waiting for neratinib to be approved in the metastatic setting. Hope[fully] later this year we will see approval by the FDA [for margetuximab], another agent for HER2-positive breast cancer, a molecularly enhanced form of trastuzumab.

With regard to triple-negative breast cancer, we are looking forward, we hope, to the FDA approval of the antibody-drug conjugate, sacituzumab. We are waiting for that. Then we are really keeping our fingers crossed, crossed, crossed. We will have to see what additional data show, but we are keeping our fingers crossed for the preoperative pembrolizumab (Keytruda) trial [KEYNOTE-522] in triple-negative breast cancer to continue with further follow-up [and demonstrate] improvement in event-free survival. [If so, it] should lead to FDA approval. 

The other thing [that] we are waiting for [are data from] some of the adjuvant cyclin-dependent kinase (CDK) 4/6 inhibitor trials…in [patients with] high-risk, estrogen receptor (ER)-positive breast cancer, such as the PENELOPE-B trial which…should [have results] later this year. [In that trial,] patients with ER-positive breast cancer received preoperative [chemotherapy], they still have residual disease at surgery, then they [were given] endocrine therapy, and [finally,] they were randomized to receive 1 year of palbociclib or placebo. [Data] should be [available] soon. [Data are expected from] a couple of other adjuvant CDK4/6 inhibitor trials…within the next year, we hope. That could lead to FDA approvals of CDK4/6 inhibitors in the curative setting, which will be very exciting.

Do you believe that a lot of the recent progress has to do with gaining a better understanding of the molecular mechanisms behind breast cancer?

 Yes, and being able to choose the right patient populations. You could have a great agent, but if you do not choose the right patient population, it [will not] have the level of effectiveness it needs [to be granted] FDA approval.

On the community level, is matching treatments and sequencing tumors widespread or is it an area that still requires more education?

 We have had a sea change in breast cancer just within the last 6 months with the FDA approval of alpelisib (Piqray). It is the first PI3K alpha-specific inhibitor. [However,] it is for ER-positive breast cancers that have the 

 mutation, and that is about 40% of ER-positive breast cancers. And it is for [patients with] metastatic [disease]. So, you have…to now go looking [for the mutations]. You have…to sequence the breast cancer. You can also get circulating tumor DNA [through] a blood test, because many times you will find the 

 mutation in the blood or in the tumor. For the first time, we have a definite reason for [patients with] ER-positive metastatic [breast cancer] to get next-generation sequencing (NGS). 

The FDA approved pembrolizumab for patients with mismatch repair deficient or microsatellite instability-high breast cancers. [That is] only about 2% of breast cancers, but nonetheless, they can do very, very well with this immune-based therapy. Then the FDA approved the neurotrophic tyrosine kinase (NTRK) inhibitors-[larotrectinib (Vitrakvi) and entrectinib (Rozlytrek)]. [They are] for any cancer. It’s a tumor agnostic approval that has an 

 fusion at the genomic level… a gene fusion. And, again, rare in breast cancer, [approximately] 1%, but if [a patient has] it, you can do NGS to find the 

 fusion, [the] microsatellite instability, and [the] 

In breast cancer,…we have had a reason to do germline testing, blood [tests] looking for 

, since the FDA approved the 2 poly (ADP-ribose) polymerase (PARP) inhibitors that we have for patients with germline 

. So, we have been doing germline genetic testing because in the metastatic setting, we have…2 PARP inhibitors. So, the whole [NGS] thing is really gaining traction in breast cancer.

How many agents do you anticipate being approved in the breast cancer space this year, and perhaps over the next year or 2 as well?

 [I]n the metastatic setting, we are expecting sacituzumab, tucatinib, neratinib, and margetuximab this year. And then hopefully preoperative pembrolizumab. That is a little bit aspirational, but the data [to facilitate approval] should be there. The data look good, they just have to hold up. So, I will say pembrolizumab this year. And then next year, I…hope we have another antibody-drug conjugate called SYD985, which is another anti-HER2-based therapy. I am hoping we are going to have adjuvant palbociclib (Ibrance) and adjuvant abemaciclib (Verzenio). Ribociclib (Kisqali) will take another year or 2 thereafter.

Within 2 years, we might have adjuvants. We hope capivasertib, [and the other] Akt inhibitors. [Although it may] be more like 2022…the Akt inhibitor capivasertib by AstraZeneca, and ipatasertib by Genentech Roche, [which] are in active development, [may be available for]…ER-positive breast cancer [and] triple-negative breast cancer. 

Hopefully [we will have] some of the oral selective ER degraders in ER-positive [breast cancer]. There is one called elacestrant that is in [a] phase III [trial] right now,…the EMERALD trial, and maybe by [the end of] 2020 we will have [data]. One I really do hope we have next year is the oral taxane, tesetaxel, by a company called Odonate. Now, there were data…at San Antonio [Breast Cancer Conference], and the study was not done in the United States, but it was a very positive trial. It is called OPE. It is oral paclitaxel with encequidar, which basically allows the [taxane] to be absorbed into the bloodstream from the gastrointestinal tract. It is an oral taxane by a company called Athenex. The data looked very good. I hope it will lead to [an] FDA approval. It may be later this year, [or] it could be next year.

An important new area…is with trastuzumab deruxtecan. It was just approved by the FDA for HER2-positive breast cancer. A very, very important…new strategy is [when the] antibody against HER2 [is] hooked up to this powerful chemotherapy drug, deruxtecan. It can bind to breast cancers, particularly ER-positive breast cancers that…have a low level of HER2. So, they are really not 

-positive, but they [have] some HER2 protein and [the drug is] looking really, really active. It is being compared in phase III trials with [physician’s choice of] chemotherapy and [results could] redefine the subtypes of breast cancer. [With] 

 amplification, lots of gene copies. But then [there is] this 

-low, low positive, and that is where…we do not have [agents] right now. So that would be very, very exciting. I suppose that [this strategy] could be with us in 2022. These are my sort of broad estimates based on how quickly I think the studies will accrue [data] and the ones I think are going to be positive.

The other is the atezolizumab, the competitor basically to pembrolizumab. Atezolizumab is already approved for triple-negative [breast cancer] in the metastatic setting. It too is in preoperative studies in triple-negative breast cancer. I hope [it will] be approved [by the FDA for this indication]. We are waiting on the data to be released, but hopefully [it] will be approved in 2021. We also hope that pembrolizumab, will be approved in 2021 for patients with metastatic breast cancer. So, we are waiting for pembrolizumab for both metastatic triple-negative and then most importantly, in the curative setting preoperatively.

I know that patients, obviously, are a big part of what continues to drive your interest in research. But putting it into practice, are there any patient cases that particularly jump out at you or any particular experience that you had with a patient that was really rewarding?

 Thankfully a lot of them, because I actually have a strong interest in the area of exceptional responders. These are [patients with] metastatic breast cancer that basically go on to… get cured or they just do well for 5 or more years. Those [patients] are extremely gratifying because they are not expected. [W]hen somebody develops metastatic triple-negative breast cancer, the median lifespan is about 16 months. So, when somebody gets cured, you are standing up, you are doing cartwheels, big-time cartwheels. [Therefore], I have a strong interest in trying to understand the molecular basis for why a particular breast cancer would [be] so responsive, so unexpectedly responsive to…treatment. I have a number of those exceptional responders that are just absolutely fascinating to me, [and it is] extremely gratifying to take care of…patients. I have…a number of stories in that regard.

Is there any one story that you could share?

 Because this woman basically has directed a lot of my subsequent research, and she does not mind me using her name. Her first name is Donna. She does not mind because she has…done videos for our fundraising activities around clinical trials to follow up on her success, etcetera. She was diagnosed in 2006 I think, [she] was in her mid-50s, with triple-negative breast cancer, and [she] had [a] lumpectomy,…chemotherapy, and radiation therapy. Her breast cancer recurred in 2008 in her breast. It was node-positive. She had a mastectomy. She had axillary dissection. She had more chemotherapy. She had more radiation therapy. 

Between 2008 and 2011 (when I first met her), she had multiple recurrences, locoregionally on the chest wall, in the supraclavicular, infraclavicular lymph node beds, [and in the] subpectoral [lymph node beds]. But it was only [in the] lymph node[s], nowhere else. She kept having multiple surgeries, targeted radiation therapy, and more and more chemotherapy. So, she had had all our major chemotherapy agents for triple-negative breast cancer, including taxanes and carboplatin, etcetera. But the disease just kept recurring. It was not very fast, but it kept recurring. 

I met her in 2011 when she came over from UT Southwestern for a clinical trial that we had, and she had [the disease in] a left supraclavicular lymph node. It was about 3 cm in size and that was the only disease she had. So, we biopsied it. We did next-gen[eration] sequencing, and we did not find any particular mutation to go after except that she [had] a FOXM1 amplicon, and…somatic loss of function mutations in 

 (which among other things…is part of the SWI/SNF family of proteins that are very involved in DNA repair, double-strand DNA repair). 

ONCOLOGY® recently sat down with Joyce A. O’Shaughnessy, MD, to discuss the recent trends in breast cancer treatment and the avalanche of agents moving through the development pipeline that have the potential to redefine the accepted standards of care.

ONCOLOGY Vol 34 Issue 4