25 December 2019

Two studies recently presented at the recent San Antonio Breast Cancer Symposium focused on a subtype of breast cancer known as Her2/neu over-expressed, which include up to 20% of breast cancers. In these tumors, the gene that codes for the Her2 protein receptor has more than the usual number of copies. These tumors tend to have more aggressive growth patterns and up until the development of targeted antibody therapy, prognosis was very poor. 

Targeted antibody therapy including trastuzumab (Herceptin) and pertuzumab (Perjeta) is now standard of care for Her2 breast cancers, even in the setting of early-stage disease. Trastuzumab emtansine (Kadcyla, T-DM1) is an antibody-drug conjugate (ADC, a combination of the antibody and a chemotherapy agent) and is most commonly used in patients with metastatic disease. Unfortunately, not all Her2 tumors respond to therapy, and some tumors that initially respond can mutate and become resistant to therapy. Brain metastases can occur in up to 50% of patients with metastatic Her2 breast cancer, and can be challenging to treat as medications may not be able to pass through the blood-brain barrier to get to the cancer cells. 

Trastuzumab deruxtecan (DS-8201, Enhertu) is an ADC and results of a phase 2 study (DESTINY-Breast01*) were presented. This study included 184 patients with metastatic Her2 breast cancer, who were experiencing disease progression after receiving 2 or more different anti-Her2 treatment protocols (including trastuzumab emtansine, median 6 prior therapies, range 2-27). This was an “open label” study and patients were not randomized. Median follow up was 11 months and findings included:

  • Median treatment duration was 10 months
  • Overall response rate was 60.3% (at least 2 follow up scans, 6 weeks apart)
  • 11 patients (6%) experienced a complete response (apparent resolution of disease)
  • 101 patients (55%) experienced a partial response
  • Median duration of response to treatment was 14.8 months
  • In patients with brain metastases (24 patients), median progression-free survival (PFS, time to disease advancement) was 18 months
  • Adverse events (AE) occurred in all but one patient. The most common AE were nausea, hair loss, vomiting, constipation and neutropenia (low white blood cell count) 
  • 57% of patients experienced more serious (≥ grade 3) AE
  • 28.8% of patients stopped treatment due to disease progression
  • 15.2% of patients stopped treatment due to AE
  • One of the more serious complications, interstitial lung disease (ILD), was reported in 25 patients and 4 patients died due to ILD-related causes

Shortly after the study was presented, the drug received accelerated FDA approval for patients with unresectable (not able to be removed with surgery) or metastatic Her2 breast cancer who have experienced disease progression after treatment with 2 or more targeted agents. The approval is accompanied by a warning due to risks of ILD as well as embryo-fetal toxicity. 

ASCO Post coverage of trastuzumab deruxtecan

The other study involved Tucatinib, which is a tyrosine kinase inhibitor, administered in pill form. The Her2CLIMB trial* was a Phase 3 study that included patients with Her2 metastatic breast cancer who previously received treatment with trastuzumab, pertuzumab, and trastuzumab emtansine. Patients with and without brain metastases, including untreated brain metastases, were included. Patients in this trial received either tucatinib or placebo, in combination with trastuzumab and capecitabine (Xeloda – an oral form of chemotherapy).

The study included 612 patients. 410 received tucatinib-trastuzumab-capecitabine (T-C) and 202 received placebo-trastuzumab-capecitabine (P-C). 48% of patients in the T-C group and 46% of patients in the P-C group had brain metastases at enrollment. Median follow up was 14 months and findings included:

  • At one year, PFS was 33% in the T-C group and 12% in the P-C group
  • At one year, median duration of PFS was 7.8 months in the patients who received T-C and 5.6 months in the patients who received P-C
  • Overall survival (OS) at 2 years was 45% in the patients receiving T-C and 27% in those who received P-C
  • Median OS was 21.9 months in the patients receiving T-C and 17.4 moths in the patients who received P-C
  • Among patients with brain metastases, estimated PFS at one year was 24.9% in the T-C group and 0% in the P-C group
  • Among patients with brain metastases, median duration of PFS was 7.6 months in the T-C group and 5.4 months in the P-C group
  • The most common adverse effects in the patients in the T-C group were diarrhea, hand-foot syndrome, nausea, fatigue, and vomiting
  • 23 (5.7%) patients in the T-C arm and 6 (3.0%) patients in the P-C arm discontinued therapy due to side effects
  • Of the 215 deaths that occurred during the study, the most common reason was disease progression. Adverse events were the cause of death in 6 (1.5%) of patients in the T-C group and 5 (2.5%) in the P-C group

ASCO Post coverage of tucatinib

While these 2 studies demonstrate the progress that has been made in treating an aggressive form of breast cancer, they also serve as a sobering reminder of the work that remains. The hope with targeted therapy is that cancer cells will be killed with minimal toxicity to other cells or the person – we are not quite there yet. In addition, while the improvements in progression free and overall survival is encouraging, we are not yet able to ensure long-term survival for patients with metastatic Her2 breast cancer. If you donate to breast cancer research organizations, please consider this when deciding which groups to support.

*If you are not able to access the full studies and would like a copy, please email me: contact at drattai dot com

19 December 2019

study recently published in the Journal of Clinical Oncology* found that the use of some vitamins and supplements before or during chemotherapy treatment for breast cancer was associated with increased recurrence and mortality rates.

Vitamins and supplements may interfere with or prevent the desired chemotherapy or radiation therapy effect of cell death, so it is common practice to advise patients to stop (or not to start) taking vitamins and supplements while undergoing treatment. The patients in this study were all undergoing chemotherapy for breast cancer, using the same medications, but with different dosing schedules. The treatment regimen was doxorubicin (also known as Adriamycin), cyclophosphamide and paclitaxel, commonly referred to as AC-T. Patients were surveyed on vitamin and supplement use prior to starting chemotherapy and after treatment. Median follow up was 8.1 years.

There were 1134 patients included in this study. 251 experienced a recurrence and 181 died – these patients were more likely to be older, Black, post-menopausal, have a higher body mass index, and have poorer tumor prognostic factors including 4 or more positive lymph nodes, and estrogen / progesterone receptor or Her2/neu negative tumors. 17.5% reported use of any antioxidant (vitamin A, vitamin C, Vitamin E, carotenoids, and co-enzyme Q12) during chemotherapy treatment and 44% used multivitamins.

The findings included:

  • Use of antioxidant supplements both before and during chemotherapy was associated with an increased risk of cancer recurrence and death, but the numbers were not statistically significant
  • The researchers were not able to determine if there was any specific relationship between the use of individual antioxidant supplements and risks of recurrence or death. There was a relationship with vitamin A but analysis for this supplement only included 5 patients
  • There were no relationships between use of antioxidants only before or only during treatment and outcomes
  • Vitamin B12 use both before and during chemotherapy was associated with increased risk of recurrence and death 
  • Iron use during chemotherapy was associated with higher recurrence risks as was use both before and during treatment 
  • Omega 3 use both before and during treatment was associated with increased recurrence risk but not death
  • There did not appear to be any association between recurrence or survival and the use of multivitamins, vitamin D, glucosamine, melatonin, acidophilus, folic acid, or vitamin B6

One of the authors’ conclusions was that “we found some support for the notion that use of dietary supplements during chemotherapy could have a negative impact on recurrence and overall survival.” It is important to stress that this was an observational study, which means direct cause and effect cannot be determined. Relative, not absolute risks, were reported. In addition, the number or women who reported taking non-multivitamin supplements was just under 200. While news reports noted that supplements were associated with a 40% increased risk of recurrence a weaker association with death, these numbers did not meet statistical significance. The authors noted that “a review… in 2010 concluded that insufficient evidence existed with regard to safety of dietary supplements to make recommendations, and that may still be the case.”

Despite the limitations of this study and the inability to draw firm conclusions, it is still recommended that patients who receive a recommendation for chemotherapy or radiation therapy inform their medical team of all vitamins and supplements that they are taking, and it still is considered best practice to avoid antioxidant supplements while undergoing treatment.

*If you are not able to access the full study and would like a copy, please email me: contact at drattai dot com

12 December 2019

A study presented at the San Antonio Breast Cancer Symposium last week provides more evidence to support the use of accelerated partial breast irradiation (APBI) after lumpectomy in selected patients with breast cancer.

Radiation after lumpectomy typically treats the entire breast (whole breast irradiation, WBI) and is usually administered daily for 3-6 weeks, depending on the protocol that is used. There are several techniques that treat only the lumpectomy site, which is where most recurrences occur. The techniques include the use of a single or multiple catheters, or an external beam approach. Most commonly, partial breast treatment is administered twice a day for 5 days. Of course, one of the concerns in using a partial breast technique is recurrence rates compared to the more standard WBI approach.

A large US-based study on partial breast irradiation was presented in 2018 and was recently published. The NSABP B-39 trial* included 4200 patients, randomized to WBI or APBI techniques. This study showed that APBI was “not equivalent” to whole breast irradiation but absolute differences in local recurrence rates were small (90 / 4% in the APBI group versus 71 / 3% in the WBI group). 

The current study (APBI IMRT Florence) was performed in Italy and included 540 patients. All were over age 40, had tumors ≤ 25mm in size, and surgical margins ≥5mm [note – current US national guidelines support “no ink on tumor” for a margin]. The findings included:

  • Local (in-breast) recurrence rates were 3.9% (9 patients) with APBI and 2.6% (6 patients) with whole breast irradiation and that difference was not statistically significant
  • Overall survival was 92.7% in the APBI group and 93.3% in the WBI group
  • Breast cancer-specific survival was 97.6% in the APBI group and 95.7% in the WBI group 
  • There were 7 patients in each group who developed metastatic breast cancer
  • There were fewer adverse events and better cosmetic results reported in the APBI group compared to the WBI group

The authors concluded that APBI is appropriate to consider in selected patients with “low risk” cancers. While the Italian study has only been presented in abstract form (we do not have the full dataset or manuscript yet), it adds to what we already know about this accelerated technique, which does seem to be a reasonable option in selected patients.

*If you are not able to access the full study and would like a copy, please email me: contact at drattai dot com

21 November 2019

Following lumpectomy, radiation therapy to the whole breast is a standard part of breast conserving therapy (BCT). The use of radiation therapy after lumpectomy has been shown to reduce local (in the breast) recurrence rates. Radiation therapy can be administered in several ways, but most commonly, the whole breast is treated (whole breast irradiation, WBI). Treatments are usually administered 5 days per week, over the course of 3-6 weeks, depending on the specific protocol that is followed.

One of the disadvantages to this approach is that if there is a recurrence of cancer in the breast after treatment, mastectomy is usually recommended due to concerns about wound healing problems as well as toxicity from administering radiation a second time. However, newer techniques and the ability to target the lumpectomy site more precisely may give some women who develop a recurrence after initial BCT another option.

The results of the NRG Oncology / RTOG 1014 study were recently published in JAMA Oncology*. Patients who initially underwent BCT and developed a recurrence greater than one year from initial treatment that was ≤3cm and was unifocal (one area of disease) were eligible to participate. All patients underwent surgical removal of the recurrence with clear margins. Following surgery, external beam radiation, focused to the lumpectomy site, was administered. The study enrolled patients from 2010 – 2013 and follow up through 2018 was included in this publication. Median follow up was 5.5 years.

65 patients were enrolled, and 58 were evaluable. Of those, 91% had tumors ≤2cm (median tumor size 1.0cm) and none had suspicious lymph nodes. 23 (40%) had DCIS and 35 (60%) had invasive cancer. 44 (76%) had ER+ tumors. Of these 58 patients, 4 developed yet another recurrence, all non-invasive, for a 5-year local recurrence rate of 5%. A total of 7 patients underwent mastectomy – 4 with recurrent disease, 2 due to wound healing complications, and one in a patient who developed cancer in the other breast and subsequently underwent a bilateral mastectomy. Both metastasis-free survival and overall survival was 95%. Toxicities were mostly graded as minor.

The conclusion of the authors was that external beam partial breast re-irradiation is “an effective alternative to mastectomy” in select patients who develop a local recurrence after BCT. Drs. Cook and DiNome, in an accompanying editorial*, note some of the limitations of the study: patients were older, mostly white, with relatively small low-grade tumors. Therefore, the results may not be applied to all patients. However, they agree that for selected patients who are motivated to avoid mastectomy in the setting of recurrence after BCT, partial breast re-irradiation is a reasonable option to consider.

*If you are not able to access the full study and would like a copy, please email me: contact at drattai dot com

20 November 2019

One of the challenges in treating male breast cancer is that there are few studies specifically focusing on men. Breast cancer is much less common in men than in women (approximately 2600 versus 260,000 cases per year in the US). However, men tend to be treated using the same protocols that are used for women – even though we don’t know if that is the most effective approach.

For women with stage 1-2 breast cancers that are estrogen receptor positive (ER+) and Her2/neu not over-expressed (Her2-), additional tumor testing is commonly performed to determine whether or not chemotherapy would be of benefit. The Oncotype Dx test, one of several commercially available genomic tests, has only been validated in women. Researchers recently evaluated whether the Oncotype Dx test has the same prognostic ability in men as it does in women. 

The researchers used the National Cancer Database to identify women and men diagnosed with stage 1 and 2, ER+ and Her2- breast cancer between 2010-2014, for whom Oncotype Dx recurrence scores (RS) were available. 848 men and 110,898 women were identified. Associations between mortality and RS were determined. Overall mortality was 41 for men and 2527 for women. 

Findings included*:

  • Men had a higher proportion of RS ≤10 or ≥31 versus women
  • Use of chemotherapy increased with higher RS for both men and women
  • Among patients with RS ≥26, 70.9% of men and 74.8% of women received chemotherapy
  • In men, increasing RS were associated with increased likelihood of death up to a RS of 21, after which the risk plateaued
  • In women, RS was only associated with an increased likelihood of death above a RS of 23 
  • A concluding statement: “…RS is prognostic for total mortality in both male and female patients, but with distinct association patterns. Mortality increased in much lower ranges of RS for male than female patients with breast cancer.”

Some limitations of the database review were that only overall, not breast cancer-specific mortality could be assessed (so we do not know why the patients died), and there was no information on specific details of treatment or adherence to treatment. However, this study does provide some insights into the biological differences between breast cancer in men and women, and the researchers called for more study evaluating whether the RS is predictive of chemotherapy benefit in men with breast cancer.

*If you are not able to access the full study and would like a copy, please email me: contact at drattai dot com

AACR Press Release

13 November 2019

The UCLA Center for Health Policy Research (UCLA CHPR) is developing a report on metastatic breast cancer, with the goal to drive actionable change in policy and practice. On Monday November 18th, the community will be asked to provide their thoughts for the UCLA CHPR team as part of their research study. The goal is to hear from patients, healthcare providers, researchers, caregivers, and advocates about the different types of barriers and challenges that patients with metastatic breast cancer may encounter when seeking and undergoing treatment. 

No idea too small or idealistic – we want creative, actionable solutions! The information gathered in this research study will be shared more broadly with other stakeholders, advocates, and policy makers. Please add your voice to this important conversation! This study has been funded by the California Breast Cancer Research Program

The study team may be contacted by sending an email to: ajscheitler@ucla.edu

If you’ve never joined a tweet chat, click here for information on how to participate in the conversation.

Discussion topics will include: 

  1. What are the most significant healthcare communication barriers faced by patients with metastatic breast cancer? 
  2. What are the most significant barriers to obtaining appropriate palliative care faced by patients with metastatic breast cancer?
  3. What are the most significant financial barriers faced by patients with metastatic breast cancer?
  4. What are the most significant barriers to obtaining disability faced by patients with metastatic breast cancer? 
  5. What health system or policy actions do you recommend to address barriers these barriers to care?
  6. Any other comments or suggestions! 

21 October 2019

Especially during October, when everything seems to be painted pink, it’s easy to overlook the fact that breast cancer is a disease of women and men. Male breast cancer accounts for 0.6 – 1.0% of all breast cancer cases. In the US, approximately 2600 men will be diagnosed with breast cancer each year. The lifetime risk is about 1 in 1000, versus 1 in 8 for women. Male breast cancer accounts for approximately 500 deaths in the US per year. Risk factors include increasing age, family history including BRCA gene mutations, obesity, alcohol intake, prior chest wall radiation, and low androgen hormone levels.

Male breast cancer tends to be diagnosed in later stages compared with breast cancer in women, and previous studies have come to conflicting conclusions about whether the poorer outcomes are due to higher stage at diagnosis or other factors. A study recently published in JAMA Oncology* looked at mortality rates among men and women diagnosed with breast cancer. The researchers used the National Cancer Database (NCDB) and compared men and women who were diagnosed with breast cancer between January 2004 – December 2014. Their data analysis included approximately 16,000 men and 1.8 million women. Some of the key findings:

  • Mean age at diagnosis was 63.3 for men and 59.9 for women
  • 3-year survival was 86.4% for men and 91.7% for women
  • 5-year survival was 77.6% for men and 86.4% for women
  • Overall survival was 45.8% for men and 60.4% for women

Men diagnosed with breast cancer were older, were more likely to be diagnosed at advanced stages, and were less likely to receive conventional therapy. However, differences in survival persisted even after controlling for clinical characteristics of the disease, age, race and ethnicity, and access to care. Limitations of this study are that cause of death could not be determined (so it is not clear if all of the deaths are related to breast cancer) and the NCDB does not contain information on recurrence, BRCA gene status, adherence to treatment recommendations, and other medical conditions. However, the researchers concluded that male sex remained a significant risk factor for poorer outcomes, which suggests that there are biological differences in male versus female breast cancer. 

Another study recently published in the journal Cancer* also used NCDB information to look at treatment trends for men treated for breast cancer from a similar time period. The authors evaluated approximately 10,000 cases and noted that:

  • 24% underwent breast conserving surgery (lumpectomy)
  • 70% of those undergoing lumpectomy received radiation
  • 44% of patients received chemotherapy
  • 62% of those with estrogen receptor positive (ER+) breast cancer received endocrine therapy
  • 35% of those with ER+ / lymph node negative breast cancer had Oncotype Dx testing on their tumor to help determine need for chemotherapy

These findings are consistent with a point made in the JAMA Oncology study noting that men were less likely to receive conventional therapy – for example only 62% with ER+ breast cancer received endocrine therapy and only 70% of those undergoing breast conserving surgery were treated with postoperative radiation therapy. Some of the same limitations apply to this study, in that reasons for differences in therapy could not be determined, and there was no information on disease recurrence.

A few other important points to make about male breast cancer:

  • Most male breast cancer presents as a lump, but as in women, most lumps are not cancerous. It is important that a proper evaluation (usually including a mammogram and ultrasound, and possibly biopsy) be performed for any change
  • As in women, male breast cancer may present with nipple discharge (especially blood), “puckering” or “pulling in” of the skin, or severe redness of the skin which can be mistaken for infection – the latter may indicate a more aggressive type of breast cancer known as inflammatory breast cancer
  • ALL men with breast cancer, and anyone with a family history of male breast cancer, should undergo genetic counseling and testing. As in women, most cases of male breast cancer are “sporadic” (not related to an inherited mutation), but men with breast cancer are more likely to carry deleterious BRCA (especially BRCA 2) mutations
  • Men who carry a deleterious BRCA mutation have an approximately 8% lifetime risk (to age 80) of developing breast cancer. So while that is considered “high risk” for men, they are still more likely to NOT develop breast cancer. We do not currently recommend prophylactic mastectomy in men who carry a deleterious BRCA mutation but who have not been diagnosed with breast cancer
  • Men who carry a deleterious BRCA mutation are also at higher risk for prostate cancer, melanoma, and pancreatic cancer

Men with breast cancer are usually treated using the same protocols that are used for women. Unfortunately there is limited data to support this. Male breast cancer is not common, so it is challenging to enroll large numbers of patients in clinical trials. However, men have historically been excluded from many breast cancer clinical trials, so how can we even make progress? The US FDA has recently issued draft guidelines encouraging the inclusion of male breast cancer patients in clinical trials – this is certainly a step in the right direction.

*If you are not able to access the full study and would like a copy, please email me: contact at drattai dot com

Additional Information:

15 October 2019

Mastectomy (breast removal) rates continue to increase in the US. While reconstructive surgery is commonly performed after mastectomy, some patients opt to “go flat” or have no reconstruction. Some patients who have had reconstruction need to or choose to have the reconstruction reversed.

The aim of this study is to survey the “Going Flat” patient communities to assess patient satisfaction with their decision and results. 

This survey is being conducted for research purposes. It is a UCLA research survey. 

Patients should meet one of the following criteria to participate:

  • Single or double mastectomy for any reason (including if lumpectomy was performed first) and decided not to have reconstruction (decided to “go flat”)
  • Single or double mastectomy for any reason (including if lumpectomy was performed first), initially had reconstruction but then had reconstruction reversed or removed for any reason

This survey is voluntary and is completely anonymous.  No identifying information, including internet protocol (IP) addresses, will be collected. There is no industry funding or sponsor for this survey. The survey should take approximately 15 minutes to complete. We value your time and your opinions. The anonymous data will be securely stored by the principal investigator and may be used for future research studies.

To participate in the survey, please click this link or cut and paste it into your web browser: https://uclahs.az1.qualtrics.com/jfe/form/SV_7UPj6wVtZev9UGx

For questions regarding this study, you may contact principal investigator Dr. Deanna Attai

UCLA Office of the Human Research Protection Program (OHRPP):
If you have questions about your rights as a research subject, or if you have concerns or suggestions and you want to talk to someone other than the researchers, you may contact the UCLA OHRPP 

16 September 2019

The US Food and Drug Administration (FDA) has issued a safety announcement about a “rare but severe” lung inflammation that can result from the use of any of 3 breast cancer medications – palbocilcilb (Ibrance), ribociclib (Kisqali), and abemaciclib (Verzenio). These 3 medications are in a class of drugs called cyclin-dependent kinase (CDK) 4/6 inhibitors. They are used in estrogen receptor positive (ER+), Her2/neu negative metastatic (Stage 4) breast cancer, and work by interfering with cell division

The FDA announcement states that “the overall benefit of CDK 4/6 inhibitors is still greater than the risks when used as prescribed.” Palbociclib has been FDA-approved since 2015, and ribociclib and abemaciclib hae been approved since 2017. In evaluating studies of all 3 of the CDK 4/6 inhibitors, the FDA alert noted that 1-3% of patients taking these medications developed severe lung inflammation, and less than 1% died due to the condition.

The FDA recommended that patients notify their physicians immediately if they develop difficulty or discomfort with breathing or shortness of breath while at rest or at low activity when taking any of these medications. The FDA alert notes that there no specific risk factors that have been identified to determine how likely an individual patient is to develop severe lung inflammation while taking one of the CDK 4/6 inhibitors. They recommended that physicians routinely monitor their patients for lung symptoms that could indicate the development of severe inflammation. They also recommended that any side effects be reported to the FDA MedWatch Program. The alert noted that common side effects include “nausea, vomiting, diarrhea, constipation, decreased appetite, abdominal pain, infections, low red blood cell counts, low white blood cell counts, low platelet count, headache, dizziness, hair thinning or loss, rash, tiredness, and weakness”. I will post an update as more information becomes available.

Additional Information: